- .

.-
d --.i

- 5

WBneortasm requires that the pH of biologic flutd be riiaimalned

at-8 comtaot and charactwtst~cvalve rn? conirpl of pH ~nbody
W d s and s u ~ l l u l a carnpwvmnts
r ts ach~evedby a number of
bialogic buffers The most ~rnponantbuffers in phyrioiosr ryrtemr
bicarbonate. phosphate, and prote~m.-corwn of a weak
@.and - c
its that are in eqvlHbrium and a r e a
dnatpand from the rurroundtng medam. The
tdatlomhrp between pH, &, and the concentration of ths c ~ j l r
gaU acid and base qf u bufferrng system Is descrlbed by the
. Disturbances Iq the acid-hasm

m n m underbins add-basa equillbnum, the pH of varlous body

the rsopemes of the buffer systems that rerust fluctua

and am IS that&&
Many Imponant com-
Eacuc acuJ, and ace-

he proton is kmown as
~ ~ ( n 3
-
dCl n H2S04 are rmt mmpODteIy dlraiahad under the condftlom tha
ol(d w i W b#ol4)%sytem The undnwxiated f m (na) that realm
t h e m the correlpondiog
5 hat
a can accept
~ a proton to
terBm the add The reaction,.t ,
,
add k rhown b Hgure 1-t

KAPLM MEDICAL
@$TlSQWlDNAND ~IJFERIUOPROPeffMS OF WEAKAQDS
w a n be defined a s h ~ d d i t ~ oofna strong bare to a weak @ {W
aPbDnp acid to a -k befa) fpy the purpose of buffering the rolutlort LC.
m n l h g s tonstant pH. '

A Tttntion-. The dditlon of a strong base such as d l u m hyddde

to a waak acid m a y b Wfinan as.
HA + ~ a 0 d -MA +
~u~a~~~radd.QthspromnrrslasvdbYm~vraa*ndcwnM~*
hydroxlda to fam waqt. The wntlnwd addkknW d h W m l d e
,,w* the t u * ] ~ d me PH.. A prrph of the
tmmofs~ksdd*ntha~baaIr~I~~1-3.

~t th.midpoint In thetlV*tBn,WH of the add he btM M d k d

a n d ~ L t l * l - t A - J . . ' ~ h s ~ o m k ~ ~ r p u ~ l o n *
wrstvvhen~w~.ms~nbft(*~b~qll.ltoftUpKsof*
weak add.

unit above +pk&* pl;. tbe uMition pf Mw wid a

,
- "
 PHYStOL06KA.UYMWiWAMF ~
The three mort V
L&&p. and&hateGnlw
u
~
-
t war sm-a
G
,.- - - ---
ed6681e p a t r s a z a
S

.-
~ M

valua for t h e buffeh are summanmd in TaMe 1-2 The

plasma and intentitkt fluid is m t e , whereas
flh!26abw e q n n the ma@, buffen of intracellular fluid.

a Prot.ln b d h l W sWUl36. The -conbhs high conmtra-

tlons of proteins with amrw acid side cham that ere weak acKh a d

the m I _ h

&riw can &oe oraq~&tars ,,,

the fcfmtkm andkakrngdbmd~+

mlcroaAdmmM nmhin me mf
n

BRIDGETO P H Y S h 0 1 0 6 ~

tlon is 6 1 The strength of thts buffer,% ryrtem lie in the &,iny of u.

bonk acld to be converted to carbon d~oxide

'H + HC'%-

&re
,
@ Ht + HCO3-

1-4
H2CO3 pd

meh&natem2i~~~pm
p& = 6.1
COz + Hz0

C W-ptUa MkrtapryrtUn. IntriKellUbr flukk mnmfnhw m m n ~

bans of inwpanic ph0)pRate and many orgmc pkcrphaa chn
C W n b ~ t e6enlfkaWmthaM n $ p o w e r of& anmot m
phac buffOfbE lytpm of nitla l n p n t s m in p l m and intem#&l

RAP

-%
-
AND
 +i 4

Pf~befns,Enzymes, and Coenzymes 2

3C

TMy am the
rhenrlcal and s m s w a l p m p ~ l n laraw claa of

m metaboltc p.dnMyk The fundon of many en2ynu requires a

cofartor-4 metal or a small organlc cenzyme dwMd from a vlta-
mln pncuMr Thls chapter will revlew m e structure and p r o m l a
of amlm acids that a n found in pmtalm, the ktnettc and ragulatc-
ry pmpertls of enzymes, and the reiattomhbp W e n coenzymes
and t k i r vitamin pmurrors

I
A Uno add Ourtun. The hclding bbc*r fw pwtelrn am the l corn
. monmino~thataremcodd~ntheDNAofthcell
 c. PhorphmyrwIw, phorphaninr. md phorphmhnOnku am
formed by wansfwrincr

fwnd in manyenLymerand mte~~I$, they racM as r4)ula-

-rv dwak,
RDpntlno f m i r a ddr The prwrtlarof proteins are Wuenuld by
I"partkuln, the-
have an impact on the

1., - 5 %o
-f all amlno 4 s - dvcine
is linked to tour different chem~nl$#Oups makim the a-carbon
atom an center Ar haunh Figure 2 - l an arymmetrlc
centw bar two rtereolromerr (enantlomMal%hataref-
and are der~gnatedas D an-4s. Cnly Lamlno
acfdsarerrwwrstedW~nr.

2. h k prop.n** &&&SI on the gH. an ammo acid

&@&ge, or it may have either a Da;ithaor a nwam cbrpe. The
ptl-mqlvkha molecule uelec~r~callyneutral 15 M n e d as t h e m
-(PI), The rqu~tibriumbetween the ronlc fmof an amlno
t The Id[a values for the a-carbowl and a-
pridehdxrn Iq F i g ~ 2-3.
amlmga~&~ snare ~ ( p r o u ' m l y2.1 and 9.8, respctrvdy. At a pH
fhe @f&t b p ~ o m m t e dwide5 Predominates, w k e m at a
wt a w e 1(8P)G. the d.pmmnated I(*clar predminaws The pH
fort~~aodrhowninFigwe23ktheamgeof~eIwap&
 ppp

I'stnicWr
.
Amino aca q u m 1 hfawyavDrr r(w-*aftlhh.-

.. - .\
2.rmrtun aMw ~ * 6 R & l ~ t h . p " y s W m U Mrrrguax.ir
a
p~eer * > d i t m h a f h . p o ~ . i n ( ~ ( d p i n
J g
rhKaEl. o - , ~ ~4 ~ ~.,<+; ' ~ L ~I Y n e - w M W o n e l w

.stixbxe
How a - M and
$-sheer fdd &
rerpeRmeachomw
4.-n: MuO&pkpolypqrtK(e
chams
ci. r owc chams 6M mth
 nonmalenr-
a -In pWein b olssnirrd aWnd the pOl'p3F
ed by large numbers of hydrogen
~dehydrogen atom of one pept~de
atom of another RDfsbgmPb
structure a heInca1 &iCh

b Tenlery and quaternary structure. Segments of secondary rtruc-

ture on globular protelnr asroclate wlth one another and fold
a<-
of
tenlary ~umn. k M. a p R of the poiypeptMe chain
that folds IntD a stable ternary structure Pmtelnr that are com-
pored o f 'ppre thann#- have quaternary
-re Both tertiary and quaternary structures a t e m e d
by tontc and hvdroohobe lnteractlonr and by h*",

3
between rtde chaps

on a -a*=,
-
Denauraion IS deflned as the 10sof netwe cr-"--
~fany, -o
natlve protein Denaturation may be caused h) ,
Orbydeteroearr
B Fvnntoh PrDtelnr perfoiin mort of the Important rurlcrtonr of the call
Many OF the p m t o l ~
In rkb, bone, muscle, and haw perform structural
r o b Other pmteins cany wi the dynsmoc funnip of the cell Many
plasma proteins tgnrport small moleculer such as won or oxygen,
Irnmv~gldWllIns and clott~ngfactors panfic~pateIn defense functions.
hamwna* harmreceptors and tranxrwton facton pal-
u n {n the dl,an4enqmes funa~onas b d o ~=r&cc

ENA'MN
c
*
='
;
%+
:
I B. IRlfRdt* The hlnhlCv(lmeeifmW&-& mmta
 reactson by dccreplngthe actlvatton energy bador They have no effect
on the equ~lrbrzum c m s u m for the reaction, whuh Is related to Aathe
energy difference between the pmduN and wbrtrater

:1. 1
'
Factors affea~ngthe rate of enzyme-catalyzed reanlonr include t a -

, .-+*apical rate rnponrer-

concentration, m a substrate omcentraton.

T r a m n . he rate of rnm reactions Increaser approxirnareb

"-3
1 ;$.y
51 .
I
;

urbatrate tund~ngw for catalynr

r
a ulbrtrs-. A t ~ i o w ~
ARWQ~uws.nobmd.wkhmaraabhp~~
poniaul to IS1 Mmen the concantrnim of snimma h wffl-

~nt~erprsrwn,vmandK,~~cOnRentrrhnerarhar~ct
hsenzyme They are dMmada(kllswr:
a. T h e l l l q , V - k t h e 5 t e ~ W f i ( n d e d t b e ;
0' obtained from this figure. However, valuer for both Vm, and K,
obtalned from this type of graph are inherently subject to large
errom due t o the r h a p of the curve; the value for Vmaxmust be
extrapolated from an infinitely large value for IS]. Much more
accurate values of there two kinetic parameterr can be obtained
from remndary plots as dexribed below. Km is independent of
the enzyme concentntion.

3 Unywraw~Buhplm A more useful graph for obtarnlng values of

,K end V,., can be obta~nedby t3klna thcreclororalofthe
Mkhaein-Menton equatlon and rearranqlnq k to awe the Ltneweaver-
Buckequatton
1 K m 1
---.-+- 1
V Vmax 5 V m u

Figure 2 4 this equation describer a straight line when

nn tfisl. The slope of the line is equal t o KdVma,
he lineon the y-axis is equal t o INmm and the
+-ax& is equal t o -l/K, . .
 PROTEINS,ENZYMES, AND COENZWE$~

IN 1 N U I S H ~ ~ L

[Sl
Agwe 2-9 L m w v e r Burkplot of competrrrverohrbroon

b MOfKOmptMVe InhlMtors
- b IN A NUTSHEL~

w e d The effeci of a noncompetnlve lnhtbltor .. 1"-

ov+rconm blr lncrearmg the substrate ronrentrat~on In a
LInewWerBurli plet (Figwe 2-10), the intempt m the 1N axis tr
i ~ n a r u(lmneswndrnw to a d- in v,&, and itte Inter-
..
s!bpnoaases
rln*ptshrfk upr~ard
"&nsw'
upt on he101axk Is unchanged
c. UnmmWthm khibftm
-ex.
ea
tr--
but n o t m e . This bind c a w s wnforma-
- K,, aod V-are Olanped
Sbpe m m the rvne
x4oferCeDt hh to dp ah
u&?hMW mann (K,N,,& bnwsmW&& plmr at various
B mmqntmtiacpofthe intubltorwin be a series of parallel lone
 a p?orpholylatlonldephorpho~Iat~ancycle In w h ~ h
a rpeclflc rerlne. -

gpertler
3 k n z y m r . lurenzymesare different orole~nr-e same ,-
r s o n , but have d~fferentcatal lc and re ul to ro rtler and q.'7:
o~a&f!aww;egpearance
~

frequently d~fferIn tlsue an&or A'

of tlrruelpeclflc aroenlymer I" plasma a of dlagnatbc value ~n !dent#- : @ -.
:$ *

fylng rites of tlnue damage

Pmteln

-;
Altered
@-fw
 4. SmWelllymeKlNlty
( m l ~ ~ N p S S b I 0 f n y R H ~ k
k dm
i+ pmmtbnaI t o tAe amount of en- p m e n t me way t o
reguk* Muyme-catalyzed react~wnis a
aiMr the r m at ~ h & h
e s m a lrcnpltha4Zd Tha t ~ m of regulation n frequ-8 wdk
ated by steroid o ~d h o r m r that act ~n the nucleus to
m a r e or d e c ~ ~ a oft e &on, and mndarlly, pc-
*

w
EOENPIMPSAND vrrwms
Most

spot be r~ntherlUd
-
grw -lyre (ran8lr roectionr or ov~dat~onlreduction
t i D n r r e g u i ~ s c e e m p wthat-asan
d& funa?analgrpup -are small organic mole-are
e stable than prDtejrn Coanrymnpre dertved from v~tamlnr - reac.
lntermedlate c a r r l e w ' p e

by h m w tlsruer and must thenfore besup-

piled by the diet In addnoon to daetary srwrcw. wne rlutnimam a l r o p -
t h e m e d b y a
normalb present In the lnb&nal flora. Vkamara may
be clarrlfied as e~therwater roluble or fat soluble All oftWw&acso(ubk
vltamnns and some of the fat-soluble vltamlnr serve as pmw+on*n coen-
zymes Other fatloluble vitambnr control the rate of transaiphon of ~ p e u f -
IC genes, thereby ~nfluenclngthe rate of enzyme-catalyzed reactjonr by

aherlng the amount enzyme p e n t In the cell

A wataw&&-m
CLINICAL C&RIEL*?~
1. WlrL4aim~aYPslPLP&w"d,rpnrent1nnhok
. Up m MK of the body's nmbn supply can bs
lno md Nlactn is converted to
*kuunmmuvl~na~maruy~ar.I
These coenzymes are ver)~lg&Wantln both lhp"Lrnd
W v d r a t e metabdrfm, where they act as r&r~ers of hydrlb km
(two elenronr and a p&n) ur audatran ~d reducWon reaceom
NAD+ s generally i d w d in o.(ga(ve, oUI&k pathway5 Md i s
more concentratedh then m W:NAOPH s wed m

Lbonavin, v2-,
dal

and r
1s present ~n or an mea
oduca The two coenzymesde:"ed fro: *I i
nductlvr,aMbolr pathways and k h u n d plmarlly In the cytosol
I and

of wh~chact as camerr of hvdmoen atarm +nuddatbn

n tthe m~db
smr These coenzymes are ~ m p ~ f t a ~n
- '
1
I
% $ % $ d I t llplds, and amino =cads and are fwdp~marh. ,
~nthe mitochondria Human r~bofiavmrcqulrelnerlrr lnrrelre vnth 1
mueared p m l n Irttt,ratlon durmp gmwth pnod* Prsgoncy. k u
tnon, and wodnd nealtng Pattents wlth a of rlbofllln 2

llbuhe, vltamm 51,IS prerent m

~ e m y m -efrom thurnrie ?
# -,and a m The
which
NBDE 1: BIOCHEMISTRY .~-
,

poline and lysin hyUro+tirm for (31a

. -r
t w a n d . d a p m l n e hydrorylation in
Wamin C b o m w an d o x ' w .
s, t;iri
o r ~ n excluihn~y
, by mttr-m
~ ~
I Nb q 1% Ned i n animal Qgtm%vdbe it Is bund i n h?gh mn-
centmm?%e ~ . , U i s n q u I r e BL d the w e n m fw
twonactlons m human b~ocherrdray:the rnethylat~onof horn*
ne, and the -of rnethylmalonyl Co$to
-

I 1. VlMlln A is rupplikd by -a1 ma.% inciddinp p l l o w and orange

vegetables Ilver, mYk, and q p c Vitamin A :-n
*!
dlui. d n o l , ano rrtinoi:dd. as a &&r*r the
proteiv -sin lo form a rhadomh wplax. w h l ~ a G t h . & @ t
r e c c n m e . r..a&&s. a n nqulmd
for wunn o tterenppypn, and maintenance of e d h e l i d p Hr:t h y
UO nuclear rec* and-er of ttranrntprlon of
s&fic genes Patients wlth fat malabsorptlo? w celiac (Iiseaae may
-*tarnin A defielsnt, producing night blindness and dtyners
6 therailunctiva. cornea, and skin (hyperkeratons). Excwrlve

long b o n e ~ ~ 1 n g

CllNlCAL CORRELATE

B(rHtinal rnu&i -11 kt eiro acts I n concert HMh pahyrotd ha

mone f o m&W? d d u m ftom 8anr

thrombm, a effcfency i n prot I", and an in ease m -3olUng

tL~Newbo~-%ent since h&
*trei h
 7-

b
PROTEIN~;€NZYMES, AND COENZYMES

# ntrl Nrlle. -lotic s e r f h i o n of tte gut or ma-won

can lead to d e h w and bleeding cbmplrotionr.
ofht

? v W I m r, aho known
s - found In Iedfy w t a b k
-oil~ns. the nufor fundion of vttwnn E !s as an
mt whew Its of
poWtunted mIIulu i n e m b r a Fat ma!&
rorptioo muy Load ta v&in E deikiency. In new'dwm, wmptm%s
iW hmlolytk anomie; in adufa ens^^^ ataxla due D e e -
y a m - - arur. h) h w l s l a n h E defkienq IS
rew fwqkmtly in premdure Infarmand malabrorption5ynUroiM
 q t u r e d in the high-energy phosphate bonds of ATP. in contra%
naboiic (synthetic) pathways involve reduction reactions that
require the input of energy, with the reducing power and energy
plied by NADPH and ATP, rerpecfively. The pathwayr for

in the formation of H20. The oxidation of NADH and

anrport chain, is a highly exergonic process. The energy released

ion. The regulation of oxidative phorphow-

the availability of molecular oxygen. This chapter

form the basis for energy metabolism.

METABOLIC SOURCES OF ENERGY

I
Energy 6 extracted horn f w d via oxidation, resuitbng~nthe end products of
~dwater Thu pmcm occurs I" f a r stager (Figure 3-1) In
fwb are hydrolyzed to a dryerre set of monomeric
as&&amu
 " /C

NBDE 1: BDQIEMLSTRY

bon and arbonhyllmgan be& are tramfared to the ektron car%

W H and FADH& t h e m t h Mdrannn
~ of energy from h o d k

and FABHl C vla the

W M r AT.

L
me prmcpfer undmrlyicg energy mnabalhrn are b e d on the thermody-
narnlo of chemical reacttons m e of the VarieMes lnvolved are
G = free energy (energy aw11IabIem do w&

--
H = enthalpy Oleat coment of a compound)
S entropy (randomness of a system)
T absolute temperature (measured ~nO K )
R = gas Constant (1 987 caVrnol.degreo)
F = Faradaylmmtant (23 kcaf/voh-mol)
l~&k-& *mljrr.mew
*.--(PBF~(:
' hbtke~Ofgu~enogymat%ardi(abkfrrrurrM~
Forgny&&4l%MUht,the AG 15 equal to the d~fference~n energy
Tne free energ, mange prc
d ~ U t h e ~ i n r v h l c h a ~ w l ) l ~ ( p o r r t n ~ .
I ,
S t %#&~otentlalfor an oxldatlon nduct(on I

r n n d a E o . - 3
AGO +FA@
Fmmttlk ntatlonshlp,
.
~ P~-*.

h *that for an oxidation-nductkn' mc-

'4
I tlOn to be uersonk and to p r o d rpontannourly. AE0 mr4k
-
a
c9kwk'=.
4 Usmp*.Thew thomdynamk prlnclpk can be-li byatnkbr-
ingthetranrferefelrmoMtromWHtomol&aryb.n bgUI
 '
Fwm 3-3 7 h redvcnwr af WDt m NAOn
2. PA0 ~s the electrm-01 In reacttons hwiv~ngthe -f
.
i adjacent carbw1(, resuffinm,rn thtr f01IMtIonof a orbwxarbon
w, b w r t l ~ &
3-41 A hymegm atom is 1 e d fmm each
raben am@ rsbentsfted m EAD m'torm rhby

Hgure3-4 lb reduma of H\D m FAOH2

 BFk'aTBRFSFi* a l L W & atu s e w % 3
w ~ ~ ~ ~ ~ J ~ u O J P W ~ ~ ) * H ( F ~ ~ W
woy r w q u l l e 4o l a p m a Las
ow rg) s a u h w q l te uatl &&
-saleml atu 'Wxlulau lvww5wu m,wa UI P P w w a s q*w
' s ~ u ~ ~ o ~ 92NIJml
v K W ID$ Id.3Ya XIJ)PLP pIIPUOq3DW aI(I Y
~ ~ ~ H S L ~ N V N -I a m ~ a s M a q l ) o r e w & w y a ) o ~ v ~ ~ ' ~
oa wlw 40 uotpqfmaqa pts ' 2 ~ Bupnpo~d ~ 3 'aw~uum#oa cwup
-3ns 40 u q w p aqa .ruotvea uolaeptxo m apnpuo hqi
6ulaeiau@@lXq eq: a~slduro>sualpeal 6uku1eluwa q ~ el*
*'?--,!?, -vanuouw~ur ale sqnwou onn)aqa PUP d1v 01 auale~~nbe KllmvS~aua
ice t ++ :r 9 d l 9 'd PuPdOD wol4 dm 40 SIULBUQaqa q a l paldnm
~ rl vo>lKu~mns
40 slsAlolpKq 'uolvsal axau eq: ul m q l puoq aaeqdroqd K6~aua-q61q
e 40 srraqauk aqa anlip 4 Kbeua auelv))nr seq aeqa a6quq lawaog:
a ru~eaumv03-16ulnns HOVN o: suoaxla u y e n pue Z m weal-
HQ4N
 " .,4
7

<C*
>
*
. .. % %

NBDE 7: El-RI
,A-b

A "
-.
r.

*
L
.
, .a
- *

~+Hoe&Q+ATP
I O;QlOautaQ+mP+P,

@h=a4

I m J - 7 T t I c m - m

n m o v s d f o r ~ p u p Q a , t l u y ~ b a t o
1 *sure tnat acety~.CoAcan Conrmde to be ox dlzea Th. mxi important
maalon for rcplenarh~ngthe cycle with ~nterrnedlateis th0-h
a ppyruvate t o oxaloacetate Thlr reactJon, catalyzed by wwae a r e
boxylare, requlrer blotln and btcarbonate as rubstrater, am ha$ an
obsollun requirement for acetyl-CaA as an allorterlc
7).RHprcumulat~onof acetyl C o 4 due t o ~ n r u f f ~ c ~ e
aUt..actwater the syntherts of thls ~ntermedtate
" ' T

I -nc and WK rrsuirui br electron t m n and d&th

pka~-

(Fin3-8).Tin amponents d tne mam a n bc separated into Eour

the and to a kexlent f m n p s c 4 1 c ox&
~a11dttuFADHaraahommltochonWal~

p i c " " &xq w dcMon tramport CMR E l C d m " 5 from hAD4

mtn I. -,e
d a h y d m ent.r et.k cvonr from w e r a
h
1t~
.~
m~ nrcd
I
d r i Althwgk
~ m%t oxlddtim acw In the rnRoChondna, there
a n s few omdatlve reachow m the Wml that pmduce W H .
I
Rr ~-,e. however, k imwnmaabls
the O m of tkdm fmm n/tomlc NADH tnto the m b
e

AGO. -n~& =- (2) (23 kcal/volt)(1 14 volt) = 4 3 kcal

IThe
- S m % in theour.,the oorldnton
of one male of NADH M u l d nl- rufflcfent energy to drtw the
ryntherlsof 7 mole of ATP However, slnce only three moles of ATQ
are rymhenred per mate of NAOH oxtdi2gd the eficlency of oxlda-
t~vephmphotylatlon s approxtrnately only 40% The rernalnder of
the energy Ir releasedas heat
3 Mednirm of energy usnsductnn. The
s mu-

when electr~nrare flowing through the ETC, wrnplb-* -.--..

and RI
are purnpmng pmtonr out of neattng a proton gralient
Complex II does not pumg
The derniolrnotlc hypoUIcwr a%emthat the protornotlve
EMe WWthe proton gradtent ewes ht-
The movement of protons down the gradbent as they re-enter the
m a w rekuer enerpy that Is avalablc for ATP synther~s w
-be k m -sa IS ~ t e withd the Inner mlto-
qhbndrlal msrnbrane>n core proimlty to the electron transport
&a4 [Figure 3-11).
NBDE lr BIOGHEMISTRY
!s

MsW; ATP + R ATP

L
X(smbram

I
 mrrh.ninnr for npuktmn P l u m u s dlntcal emmplor will be

. .
- ;ally be re&nted by the fonrmld I ,
where "n';r/
a mln+mumof three rarbonr Thlr formula emphartzer the tdea that th
h s of molecules are-.
than&, one of the hydroxyl gr
nf In some romepec~almedr n o n o d
my be replaced by another chemlcal~
gmup, swh ara- h atombere ~nDNA). anppllno oraqg(glu
k rmmina ~nprot late oroar (n

') *-ratem'
 charides always stam with ths carbon atan near& tlm u-yi

33' " c n n 4 r - % * p e ~ m d e w r ~ ~

h a ~ r , f l a ~ o n t h e ~ s a n ~ - a I t
lrnpwtant monosacchander m human btDchernlNy haw the D-
cmflguramn
d Ephmrs. l i v ~rnonota chandes are eplmen if t h y differ in the
--+nac d h n atom. Ea w+, gsbr
mrc is a 4 - q of~glucore Thus, knowing the strumre of gh-
rms dl- yw W automaUcaliy recognize the structure gf WE-
CLWCDSE - tms. Enrymcr that catalyze the interconverr~onrof t h e m-
gourukue qmerarer.
2. Akbmbhm Glwore, an a h , and f r m , a I;ptoos.
G t arb 5 p w t b n of the carbonyi group In glucw. the
prboyl@wpbatC-1.whereas #nfwaose It IS at C-2
; 2 Cydit-d The stra~ghtchain mwture of
-@XIS k ~ u wlmma nng structure, rosubw
~mthe~ofIh~ofthrpwwfunutFurbnrrrkhmS
 d-
frmn olurumnsc and The
&- w d m the
c o g f u m s ~ l l m tr formed by the

H-
I3i3-p-H HO-C-H
I I
H-C-OH H-G-OH
I
H-C-OH
I
CYc+r

B Dlylaharidn are formed when two monoracchartderare c a m *

gycosde Ilnk&$ The anomerlc carbn of one monoraccharcde IS udty
Ihked to a hydroayl group on the second m o n ~ ~ c c h r dThe
e glyrorld~c
bond is dayrnated as a or B, depending on the configuratton of the
anonrenc caMn in the linkage The two most Impattam dirscchhander tn

tose, also known a r p k ~ u o a rIra dlracchar~deof oalac- %P

:ed through tb ancme
 + 2 hcmse, or u r e & c ~ e and fructors
, is a d l ~ a r l d of
linked tDgethar through their anomerk carbon atoms In an
Ilnkags. Sucrose u hydrolyzed to glumse and fructose ~n the small
IMedhe by the enzyme-

C. OY)ouccharidaare arbitrarily dPf!yd asn- two and tan

-
m Ihnkedbyglycrn~&chcds. mey are fwnd lnmucopro-
q m end glYToltP!d3
D. *dm ~e a r b m l y defined &%- more then ten mono-
racchsrfdennlu. They serve as structural mmponem of cells and the
extracellular matrix, as storage fotml for monosaccharidPh and as
db
-er The most common polysw+rtdes are starch: glycogen, cel-
lulas, and progoglyuns
1 S t m h and gt&m era 4ath $?sf* farm for glwye. Starch, the
malor plant pa-*, r) ~omposedof

I . -llma I r x r p , u n b r m drsm ofglucore unm l~nked

b y - b o n h . o a u m ~ h r s M ; r d m butR.Imcon-
tans branches, where the monowcharida at the b r m h point is
l l n k e d ~ a n o l a c d r a r t d eIn the straigln rhiln L w a n l y C b
rtd~cbond. t h e malor animal , - Is mcturally
nmllarto mynwctln, excW II!a won hWWbraw7hrd
2 WlulouiraI~dlnfDBtVIBCCh.nd+COmpOMdof~unb
C Iycmdk bonds. Cellulose Is not d&sd by
no W ~ Iemwm or h F G Z F g l u -
&,fe&%tmaP rtrretore, ~elluloseace
a s a d ~ f l B M . a ~ W ' ~ h a s~n " dWt. b,dly w&d'I!
ethe
3. RaaOplyMbabo lman a s p c o p o l y r a r c h a ~are M o r rtruc- / L--

o
n
e
_
-- k ~ f ~ ? ~ & p dm
-
atMlruIfae There compoundsa n llmarcarbohydrate polymers w#h
l en* . covalently to=-
-ti

The carbohydrate portlorn of proteoglycanr are known ar

-
6ccne
~ o s a m t n o g l y c a GAGS
. contam r p a t l n a dsacchander.
uwally a hexorarntnc (plucosm!ne or galactoramlne) and a w o n l c
~ l c ~ a racid~or lduron!~ l c aad) The polymers are usually
&>- &Sed and the hexoram~nerare acylated The i s m NOTE

--. pmteogtpns are hbhlv1-1 and haw a huh d

m of
&
-$8!E%
! EMLM* !n

the d l rurfdce of s h and flLr&Ws

a w , allnmrg them to alwori~l i ~ g u a n t l t l d
a waW and
f m VM~UI 101ut10rn These phy~tcalpropert& L.)TCOYDt forW d l l F
tyto sew as excellent skak absorben and IubrbQlUr
4. -ins and mucopmrnrnalro contam c&hdraecmknlly
l~nkedto mein, but there are no'repeatlng d~racchanderand the
P

K-wMDLCAL
MBDE 1 :B!oc~fMISTRY

carbohydrate porthM wualiy n 20 nmmsxsha-

r W 6 GIycopKRpIM a(cfoun$
n l k @ h a pmtains .f!d anru, on4.llrWtm.r
~(%hb)Md~),a~wq&pnW%dmucur,Thpare
three w e f l m k a l e r be(vreenpmtea,and -hydrate The ammo
d d side&an i m i v e d In th.WnCarbDhydraOUnkage an:
a. Asfmr.ghr ( N - l i n k ) is fovnd In p l m and ell urrfacc pm-
. - T
teinc
A'b
A,.- >
b. Uln Wlnbge) rs found br mucous and w n m u h H)wa p
*Ins
-a< r Enydroxyfyrhre (0-linkage3 b W n d in mHagen
. I
m w h e l stam h-eht micuhn, Is com-
picled In the Gob1 Mle d the lest stew in g l ~ e h Is r ~
-;."a
putUng ?S~l(pc&eL'on pmtelm that are tsrgPtedta8 paltkulsr &
tirpth. for sample, dgloprotelnr that a n targeted f* lylorol~ler
have ri~~~~~*d-phosphate In thew carbohydrata (hams.RsceptDrs
ar lylawatdlrrmgnlzethirsgndand take* thae pmtah.

~ L U C C & ~ A N D ~ R E H L S
Orcuketag glrrose w
ghcminto nib P
m all cells wim a sourns oT araqy,lim eneney of
p
k ! J
4
nuwad by mupling glucose transport pharphorylat~ona procen (hiR
~ r a c e l l u l a glucose
r concentration low and continuer to rhlftthe
e@kJw&toward hh v-# (Flqure 4 6) The membrane k d
~mpermeabletO ttte phap ed mmpounds. Thecefom. p h o ~
mlat~on renderr glum$etr~s(r b
-
3

1 W r k r pmtein
(tiwe specific)
II
 GLYCOLYSlS 6hmkmss a a @ m fwghcare,
wth TK, and SV- * d m notseem
tlycolyrlr, also known r h
yt-,e/ a the $#&&&I m"am"u"tof~-

rmat~onof lamte provider a m h a -

H. a condlt+onessential for glycolpr
an important role ~nATP productlo"
g , m exerclrlng skeletal muscle or In

r ex&@, both glucore 6-phosphate and

to -1,w through

I phste groups to both ends of the rnonoraccharlde The two key

eluymr on stage 1 ore h b n a u and ~ o f r u c l o k h a c(PFLI)
l

K m u M m 369
 wi&sbofmulaWcn in aIvc+ts.
C -Uhcf end phosphofrucmW~ss-2both use fmc-
a
-s rubRIake.Howe\M,the two d~fferentenzyme
ham d M f n d l y d f k w t WrUw The product of the PFK-1 m.
fion ba-n I

m%km p a m d is to act as v r n ~ t k a t plycoly

a
*and fnhobtClthcoppaingpthway of gluco-nas
2. 5- 1 ot gb;;olyrk. The function of the second stage ts toa
e.
It begms with the c p e by
~&dw into - w t (d~hydmxyacetone phor-
phate and gl~eraldehyde+phmphate) There two mmdwni* are
lnterconvertlble through the anlon of trlorephorpbatc b a r a r e .
Thlr reaction allow both trmw to proceed by a commw pathway
Thur. beglnnlng from this step In glycolyrir, v n
bg&nr~deredto produce two rno~lyceraldehyde-3p h o r w
-11 subsequent ~nterrnedbaterThe nma~n~ng steps ~nthe path-
&y areconcerned ~ 0 t h ~ a r a u n ~ haw9 ~ shs-. d ~
sy phosphategmwthm a n be trmfmed to ADP with the tamra-
tion of AW NM ~(nmediata,t . ~ o e l V c e m t eand pkn-
PhmoIwnnmm, haw droueh energy to drm th
There are three Important e n v a th m e 2 of
aldehydc.3-phosphate dehydmgenae (G.3-? DHL Zpharphoglyw-
ate kikinare, and Wruvate klnase Under anaerobic conditions lactate
dohydrogenires an alro ~ m r o ~ ~ i n g l y c o b s .
a 6lyceraMehyBe-3.phorphrt. dehydmpemse catalyzes a
n that occon m two st.@ Hrff the aldehyde
&ulth NWbelng r&ud to
w&tkQ re.ctlan m glymlyrlr)
inorginic phosphate k covalently l~nkedto the carlbxyi
group, -yfcerw The phosphate M a e -
I ated tn f M s reactton a, s- h wnh a
-qkrynrPmlucf kCaVm0l (only7 3 kwhml are M.dadto mnvcrt ADP to Am.
- 7 fiV4fG- AlP b. 3 . P b p h c q ~L w
l transfen the hlgh-energy phosphate
% A*
g r w fmm , - producing ATP and
Tkw. 3.pharphoglycerate k ~ n m w one of
@ggg+ Bmea) ATPpmdUcha%- A t th6 po~ntthe ener-
OY mnuMgf in rtage lhas been replaced In the n e a rwo rcac-
60n,(he Ph6sphate gmw of 3-phmphogharatais morr*m)ed
t o form another high-energy bond ;-I

A ,<A
 to form ,
-
A@ of -14 8 lroUmo(
c. W a t e bcatalyzes the
e high-energy compound wtth a

phate group irm phorphoa~lpyruvste4

W p
In glycolys~s
st r m D P

result5 an a net of tvm m l l l ~ a ATP

f
phot
2' formmw

me
e Thus. the pathway
oer mole of ore Thlr
-
-,sguredby:

W m

b(oodce(lhs-andrr
h

$ ~ f l ~ d ~ & ~ m m
8

reaction u w, and pyuv- bnare 15 a w o nde wfor A* n ~ l n p ~ ~

regulationof gtycDPFls.
d LHW d.hybog*rae pamclpaar ~n yt- under -
w dehydrogenara -dn
In a reaction that um NADH and ng.n@zatsr NAD*. In cetlr wkth

amouna Howaver, when oxygenefim Ir pwr, as in hoavlly axerds W,ng

anceandcausermohcfrag~I~
lng m v v k r h a k or canliopulmaaty ~ a rbath f the u t r r add mNvel'~andbu
cycle and oxfdnhn, phorphorylat~on become pletiwlv mactly.
and rnort ofthecsllufw AW u grmmt&kyg!ycolyrk Since -1-
Y? -r 6tep *a" above), the fornutianof lactatea m
as a mechinIan for regeneratmg MAD+ to that -Ips can con-

'
tlnue In sta- of prolonged a lame ameunhof!xUe accu-
mAate The c.&m s transportedto tho Ilw wk.nIt (an be used
to w t h e s k e glwase

C ResuManofgtycdwkThere are three aws in g@!ysi$ that .we r e g ~

lated the of regulationmml, the e q m e that catalyze,
Um - in the pathway
klnwlslumkiMsa and pyruvate kin-
- fS
The r yOfl uwishon anbO-a
l m t y propenles of*
these e w m m are summarized In Tab!+ 4-2 PFIL-1 b inkblted by A A T P - ~ '
a&#, molecule6 thnt IndlCate a hogh-energy status When AMP
m m t t l R u , rlgnallng the n n d for ATP. W - 1 1s amated. Pyruvate
,- k i w b k dro inhibited by m&uk that h d k s t e ~ h mar e
can md MWOA) when fru-i,6-blrph2a(CmU~ate~~t
fa6detem.W and 8ctmatos pyruvate lama8 In lk,
the most impme.nt
* ndllCtw of glycolym k fructv43.CMyJwsphete, a compound whose
 imemdlnaer brtaedfor gkmemeq~~i+
Fyiuvm can ako be car-
ycrtedb-wMch~nbruMdgabuildingbldfor* /

m.te+ COA + NAD+ - r ~ c c ~ +i co2 w + NADH

lhe enryms complex 1s taoted In the mltDchcndr~aand wnriltr of
three distinct . n ~ m activni.~ L m s e . dibvdrol~~ovl
s
-te Md ' e). Five m n r y t n c s
% - -
are requ~red ( Coenzvm A. m,
and lYBp7. The TeemMl wmlr in W r . 1 stnyuar shown In F~gure
4.8 In the first rtqp,th. &arWxylwe el)
aRd itr wfador, thiamrne
pyrophorphm mP) r d s a w CQ2. The q frapmem that remalm s
oxidized by Itpo~cadd. tmmferted to @A, and finally releassd as
acetyl-Co/\ There reactions are catalyzsd by dlhydrolbpoyl
tramacetyb Ez) * k t *P. otalyt*d I8dlythoDoylWroge
wa (Ed and i t r c o f FAD ~ and WAD*, resmwratesthe lnitlrt 0x1-
dtzedformof I l p d c ~ l dThe&WWsTPP, llipo~cas~d, and FAD never
*aM*tlremynrrmx.

KPgtAN MEDICAL

1 ORELATE
qyruvate dehydmgenase
dn acqurredoran m h e r g E z b e
The Mmgi form hequmityprwmtr in
the neonatal perrod mth
toma neurobgicdeficltr, emipsstmi
aodorts The accumulat!onof p w t e
behmd the metabolgc blockpu5h~1the
equ~lrbnumof the r e w n b ~ elactah &
3. Uanwlogy or pytuvaia dahydwgmase with other snz#mm. 2'm
othn-e romplexesin human m e t a ~ h w d m i l a r d O u c -
tunsto dhydmpware. Therp are &&oglutarate d e w
U n l h a T C A ~ a n dbranchtd-cham hacid d e h y d r a e
Bn a ~ n sdd
o otsboliwn). AIIthree of then muitlsmymc * ,
c c d s l y r a t h e ~ i a e ~ ~ ~ o f o k ~ ~ a l l h w e
&*hdqnyalaad~t&tmqttrethesameRvecoenryna
hype
E
1 w g m . WhDR w n s Ihmlted. giyzolyrls can be wm-
miad by thr equaUmgiusn below For e a h mole d glucae mn-
&cQ two m o k af -1 and tuo moles of ATe are pmduced
T h e i r Wnet a&J#mlPhrm of NAOk
Glum~1+2ADP+ZP,+2lacfate+2ATP
manrednfalbm
C * ~ ~ M ~ + ~ W * + ~ A D P + ~ P , + ~ P ~ ~ W ~ ~ ~ + ~ A T
 and W H afa p-
. The NADH can undsrga o x i d a ' i phaDpha
rvlatlon ~roduclneeither 2 or 3 mobs M Am. dumdlml On h W

whHe ux of t n r n w l a !n 2 mdn of
ATP per NUXI. MbiioM111, each mok of w n ~ m can be hanpwt-
ed into ths mndwhdfia and oxdhcd to CCQ and Hz0 by the TW
y e a d s x ~ d m u sp h m a t i o n . raulUng in 15 moles of hgh-
-e phgehac (ATP or GTP) p r mola of p y ~ v a t eThe enzymes
involved in p m m t i n g ATQ (or GSP) from glucose are summarized m
Table 4 3

twmsoll
GLYCOlYSLS
- 1. Glycemldehyde-3-P
+d?hydrcgenase
2 NADH Wdatiwphwhorylat~on 4.6.

r PhDapha~lyauk ' 2m WatdsMtphwhoryt.tlon 2

kin-

3.pyWrteluture 2 AlP Subrtrate-lwelphosphorylation 2

1 Net ATP kw&cd&lumre as' I

~MITOCHONDRW
PDH & M CYCU
1 Fyrwate .1WltB( OMet-Imt~on .6
.dehydmsenasr

6 M a t e dshydmgenare 2 NADH O x i i ~ l d m n
-
6

Net ATQproducedpgliKae 30

Total AW per glumre (aotOLliE widation) = 36-38'

TM~IATPW glumre (anaemb~c oxidat~on)a 2 ( r e a d 3d9WYsk)
I __.I
'wander d clMrons In qstol~rNADH ria m h l h M u pma- mlmhondrial Wlat nd 3 ATP.
C )
W t m e s u m l f a v ~ a a g ~ P ( h u n * ~ F ~ n d 2 ,A T P
. B* MP-eFsp F4.e-3
am- m
. % ?sL. 53P-SWcc
\*
mm

@.d-rQ C
 E& OF the four en- unique to g(ummognair cat- a
i d
k y o n , bbuf in tb -ill dimtion fmm the comrpond-
ing mrym m g(ycoW.In mda , - tot

2.

%
r,
?%%
-
I
I
PbmphoenalpyruvateCarkuyk~~ase

?
GMH
GTP GDP

K
AWMEDICAL
NBDE 1 : BIWI~E~~JSTRY

3 - t ~ M p - t ) ~ t h e h y d r o l v r k o f h u c -
-7 64is ha to -how snd Wrgank pha-
/I) ;
P h e ! thr imwni%step in g w ~ cat-
s
alyzedby WK-I.

FBPast.1
Fructrar-1.6-bi#h@ate + H2D ----.--, fruct-hwe + pi
-1 k a o l m W l r ( e acthted by ATP and &ate and lnhlb-

--
nad by rudP end fructose-26hh ate These same compoundr
alrath. ern of the w n g en%, PFK-1, but in the opposl(.
dlnnion (see Table 4-21, Wa ghimlysis k ~rhbltedwhcn ~IUCMI~G
paair lrowmlm&and vkc w n a
4 t66P.y) cstmlyzei t h e In gluconar
warh by and

GWase
Glumre6phorphate+ Hz0 glwse + PI

mb wctm bypassespthe- i in
G6PMe n Beoclatedwkh the endoolamr retWgm and tfwndonly
-ni TheaTheabrdofa$em
*Met& m a l e accoums for the fact that m u ~ alnqgan
h cannot
v.
C Orrm I..oton of glumneqlenais.The convenion of p y w m to glu- 9
a
rore g l u c n n e c a m w hown bc,& For every mole of glmDIs sp.
WY4d six ATP ~~~~~~ps an required A T equhlems .re
%iwr$to convert, - a d m n
hSdlhdtonra~the rtepin#w&%mr
rUron k usd to nrww the st*) catalyzed by gly(rpld&y&hWo~
~ ~ r o p m s l p

a o d s . l t h o u l d b s W m a t t h e ~
than wru* s r i w the Isctsa-dchydmpwe ma& k m.

cl~nolactate formed p and

-e
I. LacMe Ir releanod from these tlrruss Into the blood
and n taken up by the Ihw ff a then reconvenedto glucose via glu-
coneogenesls t o provtde more glucose for e n e y The recycling
pmceu 15lllunrated In Figure 4-13.
 Lactate d
I

-
hgwe4-13 me Con v i e

2. M.nhu. S k e w murdc nbarea large amountsof alantne formed by

thm .
The alanlne a taken up by the l h r
and which 8s used fw glwsre t y n t h d s .
. -
lhb crrrclhlg & .r the alanlne cycle The p n ~
v l h a me& of conrwving orbohvdrate. Note t h n neither th .la-
nine+ mth.W cy& m u k in r k net ryrnherlsof glucose.
3 -k amino adds. All of the commm amnw M M s ~ l v r m
@' w e are gl-ns 1.e. they can be w eded to KUMIIWIB-
ate5 m enher glycdyris or the TCA d e , and tkui U n w as p m -
ron for glucose syntham The nitrogen ame fmq thnc amlno
aads h d d l w of as urea Lyslne and k w n e am
and cannot be convsmd to alumr~
4. G.-
-
The h lyre of trracylglycer916b &w+ tbue pmdum
glycerol that a s s i n t o e. blood. Ihar Wn Up plyremi
and converts it to #ceral 3 phorphate. whkh can be midrzed to
diivdmx~acetonephosphate, a glue- imtrta
~
5. Odd-numbered fatW adds. iha ddatlrm of * r e d fatly
acids prgducn one nm*arlc 04 uraplonrt-Co* from the-
Pmpmyl-CoA can be mm*odto I(xTI~~.W an i m t o In
t4e~n~anda*ntopltrrac.~ronaart,degr~6
'~~~~fstty.eidr@yLoIrmhr~~whkhknataprecur-
g+ lor O t s l u C m .
& & ?waamhuncee (from dHtY swtw1 can b e p h o w h o ~ t o
~ r " d d D M d t o & c m t & h y d e a n d d t h y d ~
!(ta-- (MA* b -i *-rn ~htar~lhhydc
mlCrorivertedta~---C~
$l&mlwmYP
7 mi-. GalpnqCm be ~~by the livw to 1
 Gkogn h a hgblyoranrneo p e mnainmg gluma mohcuks Hnkd
b-bonds w ms - 7 s between tb h.QI*

,
, .
"
? e-
i-&-

%$q
occurs at the ends of the brahrs@nt%
Ir the r : : m f a m k - e 5 T h e
of glycogen an rkelet#wugle d~fferrfrom that 10tklliwr,

2 Urn usn glyc~gcnmpinly to rflgkte ?load slutore levdr. In

to !&$,@lyccgen s degraded, and
e d into t h e m m # w r p l y p p m atorea become
'
depleted after apparm)CUbl. 12 hp4n pf m. In nrpense to
 -i

NBDE 1: BIOCXEM~S~RY

B Key mryna in p)y-olysk

of the branchr, where duc-1-P
Glycogen degradation occurs a t t h mifs
unta are lequent~albdessrd bv
#
s f y e q l ~pbesphorylsb, the m a t Impomnt enzyme In glycogenow.
Totnl degradation requiresan additional 'debranch~ng"enzyme ryrtem.

ed both allarterlcally and hormonally The giycagen phwphorylase

rOidlon k rhown below, where n is the number of g l u m unlk I"
Blyc09en.
glycogen phosphorylase
(GI-), -------, ( G k & n - l + Giucole-1-P
f

wlth~n4-5 a r a branch polnt when !t no longer b~ndr

y ~ l t of
sfAclently to the pamally dcgradsdglycogen
2 D a b r a m e m s . The complete wadation of glycogen r e q ~ ~ r e r
twa addmonal anzymr that make up the "dabrahlng qatem "
a a-11,4l+ e I l A 1 g l u m tranrfcrae remover three or four glumre
ulia from a branch mint and transfers them to the end of anoth-
er chain In thls reactton, one a-1.4band e

ME

EL.
 ~bmat%fQr9$-%n 1-
b. al,6 -remover thr- unit remsming at

--
the bradl pdim and releases ~tas free alumra
c K q ~ h s f V l r p r n W m M r & ~ i n F ~ 4 - 1 4 , t h e ~ ~
ot e&asm Wnr wlOrsluc~sephasphwylatlmto &- I N A h'UlSMEL1
T W I f E . u u a n k u t a h a a d b y ~ a n d r m d ~
?&#&& ~ ~ r a p l d k ~ l d r a v - w t o uuva*
g h a m u - l - p t m p W by -e. kfore glucose can be Murde AMP m
a#dd to N.m n pdymec H must be " " ar enerpued This
Is &mad by the (onnrUon do
-no
-rof of
s a
g l u ~ o to vnrrmar Most are act~vatedby
ra - er
1 Formstlon of UW-glumae. The phosphate group of glucose-1-phor

the hydrolysis of pyrophorphateto("organic phosphate

me Ilncag. h e n glucose and UDP s bond making

i t a subbb donor In maw bksmthetk &bmm
2 E l m of glycogen chairn. To be active, g t y q m rynthale
ngulrC nn existing gtpsgen chain rsrving as a g p r If tha main
habamt&liydegred&thrn h
-et
aervesarapr~merforqbmpnlymb

u c r a ~unm have been

,61 glucan wanderere
-1,b l~nkageand cnat-
produced can now be
 T
NBDE 1 : BIOCHEMISTRY
4 I
3
alowaid by giym$m rynhere.There are d w v at l a M fow glu-
'I
1
aaemo$cu*r~kmrt,porn~.
D. Coadlnate nguhtion of glymOcnsri5 and gfycogen&pa. Glycogen
-and g b m m 9n%m are regulated In a redprml maw
n e r M ~ c w h a n e d m e g ~ ~ s ~ t h a & n ~ n a n i w
llx Wmary Wde of regutatton for both enzymes b-aI and s
mediated& ~rphorylat~on~dephorphorylatIpn In sdmtlon, both glyco
gmMnharesndphorphorylareactlvltler can be affeaed dlomrkal!y
2
8

1 6lymgm -p Phorphorylatton of a spectflc rertn-ididr

chain activates the enyme, rerultmg In p l m e n degradatlo~The
actlvatlonof a pharphorylare Ir ln~toatedby the blnd~ngof g l u m
to ltver cell receptors or by the -phnne to muscle
receptorr. Both of there hwmwres nurease the ~ntracellular+whes~s
of CAMP, resulting In the actlvatlon of r CAMP dependant w t e t n
lunae (woteln ktnase A). A rlnglemolewle o f h o m e mgcnwate
many moleculesof W P , each moleculeof cPJUPdqtsndeMpmtetn
I N A NUTSHELL
klnase can phospblate (and acttuate) mmy nwkarles of m-
rylare klnare, e& m o h k of phaphayleMkhse on phasphory-
late (and ectlvate) many molecules of g- phvqhtylase, and,
flnally each molecule of glycogen phosphwyiere can r e h s many
molecules of glucose-1-phorphate from gl- This %am&" sp.
tem ampllfler the response ln~tlatedby the binding of a taw hor- @
mone molecules by generating mllltons of mokwks of@g(worcl-
phosphate. It E noteworthy that phorphwylne k i m ran aho be
activated directly (without phosphorylatlon) by bhulhrgcalom. Thb
IS particularly important In skeletal muscle. whae the cmpltng of

excitation with wntractmn 1s medlate calclum. Thus, the unu,

dbv
regulatory molecule that actwater contractton also aalvates
glycogenolystr. which provtdes the energy for contraction The actae
r
--.
*,, form of glycogen phosphorylare can be allmterlcally~nhab

- lted by glucose and ATP, h e m a s the -0) farm ran

be activated allorterlcallyby AMP Thus, although covalent mod~f~ca-
tlon of these en- a the primary mode of regua
l-ty
of the phwpho- and dephorpho- forms can be f~ne-tunedby the
accumulation of lntraceliular metabolites that act as alloster~ceffec-

6lyagen ms
e The rame rlgnals that actlvate glycogen phospho-
ryhre Inactlvate glycogen synthase Glucagon and epanephrlne ("la
WPdependent prmeln klmre) rhmulate the phorpharylataonand
inanivatronof glymgen m a r e The coordinate regulat~onof there
~uymcr prevents M i l e cycling of substrate that would e*n ~fboth
enzymes were mlw at the r a m tlme The lnectrve (phosphorylated)
fwm of &cogen wnthase m muffle can be altorterwlly adivafed by
glucooe6phmphne Many textr refer to glycogen rynthare-l and

KARAN

- *
 -
CAf

C H N I C A CORRELATE
~

-
1. HIDm. A l m a S of the NADPH req K

p m audrdl*qE+htherkr of cholesterol, fatty a c 1 4 Ml(l SteIakl

m b n w . comzphwii the hexare monophorphate rhun %uer
hm lyrnkswaage a F u n t r of there compounds hdYI L Ig
ih e
lM b
~ ~ P @ P t t + d u c t n g enzymes ~nthe pathway R e d bkOd cdls
;t &t- mf
t h L % d ~ ~ d
'"--ware-
helps prevent hemolysir
ong -age:$-such
z u p e r o x l d e and Sdrogen peroxrde Ueutr@~k, macrophase%
t&ocvter, and other p h m ceUr WUIMlhnp quantltlsof

*@ $g" p e b m a The% &Ik u s r , m @ a s a put

fork~fllngbarter~-If.-
~ermolecular_axygen to ruperox~dem fh.ltt4kAdLRdaxyln
& i k m ~ s w oudare H can r w k t n &rank Infection,
2.'Ra(Pner. tk.Iynthesm of nucleotiderand wxne Eoentymer WAD+.
r
'
NADP, FAD, CON require nb5-phorph*, whwhlch h w i l e d by'
6 me HMP shunt
 ue phase. Gpho~phogfu-
, wRh tha fotmatlon of
4 +

2. The nonoxldatlve phase Atl of these reacttar are &@gplle

Ribulos-3.@!m$@irte K to ribs--, the p e ~
tW r&Jw&fQI nk1wthi-s * t h i s . The remaintng readiMlr
Invohe,tkr w a n h of Cr and <W fmm one to enothwrw
Imnedlatrhaving 3.4. 5.6. end Lcarbons are lnvdnd The key

.
snayms in

phhte as a M
transfer m o n r a
Tramketot~setrar\* w it
s
r
,using t
e and-
m '
r btMaah donor and m p t o r Tranmldd.re

tores The recydlns k a c h W by ttw formatton of frucfme6-ph-

phate. a common intermdiac m the HMP shunt and glycoWu.
I ~ ~
end-d.
h o b p h s t e
Faevery 6 m O k C l o f g l ~ wed
c a ~
~ ein me
~ ~ r i n d ~ I t

HMP hum 6 m k s of *are pmduced and 5 moles of frucme6.

6wpgate can be rsrurcwdto W ~ I S .
C. R q l u l M k n o t h t , ~ r h u n r m s r d V n M n g I f e p k t h e p W n l h e
Initial reaabn Eitalurecl by sJuUD1&-pha$phate dehydr-. The
a m o w of this ewxnc present in fwer btid Mpm
%t Contalnr l a r
-ttw
m carbohydrate, a condltii that to
@*
acid ryntheds md an m a s e d requ~re-RL
phwhate- Is anOlQRDIIYaFLRlDtedbyW a W m ~ ~ f b i t -
ed by WDPH snd palmWCoA

FRUCTOSE METABOUSM
-%6
fmUOSe Mad 50UTCaOf carbohydratqsffkmm-
ly derived from the *brush border I
w.me pr~maw=-~*e~ I !@
!%
$
blcwd mtm the Ihnr, fnxtore k my natraad rml metabolized
by tha Iluer. The liver has threa Huymer l f r u c t o ~ k aldolua
, 8, and

1
1 - 1 Mc W c 1 0 1 e "to trro* ImWnudIatn in glyo4.
ysis. eKlruset M reanions bypur the racwlmnhg rtrp an glycolpis hlK-
'

-
~(1v
Is marbolind ur wrwfie

allow d&m
~uymn
.hof g
hUttm to be p
yc
io
y!l
-ateca
gg.~cneogem~s, and m.. n.n k a12

very d d ~h&xohorvlfilonof frucmra bv h h k i n a r e maw rcwn In a t m .

s

The .
-
1
&urt hrnvqin lntnc~llularphosphate mncentratmns and a d m

- ilaEwp
 I

-
W s e e,ntoleran&
from a d&eng( gf aid&&
Mirawme t h a t & w frqcme-1-php
&& 'o &eraldehyde and dhydroxy
g&p phasphare Ths resols ,n an
srmaulatioo of fmdme-l-phasphateh

qteiin &wW. lkey an k funher KWW*giw@bqr,thr/ts

ronaard r n ~ l . 6 b l r p h o s l h a t eand vscd tor glwamug- or
tpyrolcnsnr
0 ~LAurmanntabdia~fm(r,dr:RElen~infnnWd
and dddmm I a y m a unique to hurt- catabolh. A dafkta-
Z-* in CII.nti.1- ixnign corvii* in I
- -

Dihydrwacetone-P

Ft?Mo=

4
7
Glycerol
\tosekinase,,/

Glyceraldehyde-3-P
f
,

Fqure.4-1s &mss m e t a h by the lrw

1 rn the ne-
~ n d k m o f t h e e p e
m t k a -
..-....
sphare arcornu
 and functionally dtverse They can be clarclf~edInto su malor
ketone MdleS, Choksterolphor-
groups fatty acids, ti~acylglpre!~,
Eash Eh dlW pfwarpRmc role
pholipds and sphingollpidr
on &her egggy produelon, W@ggtand-e, or as a struchlr-
al co of cell m
- NWWWS dlsearer lncludlng obe-
~
m-
, ~
* ~ C i n
abwmatii
e mandlsph~ngol~ptdmer
a % are char-
m lrptd transport andlor metabolism
othw minor daeasof llpids,'lncludmg bile acrds, fat-soluble v R b
mim, an$ e m $lay ImpMtMt role5 tn normal body fundon
as +I a ln&dridlreare stater This chapter describes the major
cl- d l@ I&
meir cellular funct~om,and the metabolic pathways
tMmhnMtkm
-
CLASSIFICATIONOF UPIDS
Ths mqor d a m of lhpfdr and then, funct~onsare l~rtedin Table k l A brlef
deariwon of the major structural features of each rlas followr the table

W e $1 M a p clarrer of lrprds and thwmotaabrr fund

nsport form for fatty act&

Ketone bodin Solubk metabol~cfuel for skeletal murcle, cardlac mu*
de, kidney, and brain
Cholm~ SVwwral componentof plasma membrane, precursor of
Mle nods, vitamin D, and steroidharmones
Phorphollp~ds Major bulldmg block of membranes, norage rite for
polyunsaturatedfqtty adds, slsnal tranrdunlon path-

KAPLAN MEDICAL
 A Faty.cLkarsc~npmedofaIeuy)hy~h~nHmh(~~arboxyI
group a one end. They are amph~~mhir
-1% contain~ngboth
dr. Fatty acidr can be W b e d using BNO differ-

a d and the-rrng at t h e w . The @-&an

a adlacent to the carboxyl group. Fatty adds ace frequently ldenufied as
erther "saturated" or "unsaturated,' depending upm the abrsnce or
presenceof double bonds, rwpedvely.
1 Seturetd fatly acids contarn no double bondr The most mnmon

,
wturst8dtattyPdQimpalmltlc and rtearlc acid Their fMmuI.~~and
Man o f ~ f 8 S -m&%und
j m human tlwer are lidTabk 5-2

W61 L e n g m a n d ~ o f c o m m a t m f U M f a n y a a d r

Fatty acld bm Sbuchln

Ic c, CH,.COOH
lOniC c3 CH,.CH-COOH
2 CH,-(CH J,-COOH
Lsuiic % CH, (CH,),&OOh'
MWK % CH.-lCHJ,, COOH
Paimrt~ c,, 1 CHJ,-COOH
Stean~ cm I CH),.-COOH

-
Arachldic ca I CHJ,, C o o n
Llgnocer~ C, 1 CH,),,COOH

CLINICALCORRELATE 2 UnMunmd fatly .ddr m i n 3 or ma* double bonds m the ck-

conftgvraion
- A
Oinole!candl,nolenrcmds)15 seen ~n a M~rmumrmnOdfatty& CO d. me mmt
common monounrnucated fatty scld is the
whlch has one double bond between
&&p
CHj4H2h<H=CH-(CH~flMm
b Polyunsaturatedfnty a d s contam t w w n d s
(1) Unolelc aud IS qn p- wlth N o b l e
fatty acid because it must be obtalned
bondr It IS an esrent~al
from d~etary sources

CHdCH2)4-CH=CH-CHflH=CWCn2)fio0H
h m a n physrology The brolog~acnwrof
h s e compoundss different f o r d (2) Llnolan~cacid a an l
cfgan Mlm UateIet-n s
w e bonds
mntd~edby t ~ h t a g o m m ceffecbof
CH#flkCH-CHfiH=CH-CHflH=CWCH2)7<OOH
f
(3) hachidona P ~ Ms * ' I whth m b l e
wmdmbon of emsnotds from bDnh ttm be s p t h w e d by humanrfmm Ihnol~aad
v~a
ara&&ir a d bathrerun fn a dw
-e
 0. M.cylglywds (TAG) -bin s g p r o l bacXbona IMlh thn.fotN .ddr
linkad as nmThk h the mort c m o n stwage form for f* adds.

t&m~&F@ one fatty attd generatesa d~acyhJly~I, whlkh xb a a&-

I r+gnal MnsdWtiM pbthww.
f the trlacylglyceml m h l e
the end pmduct of TAG digestlm in thermCfI

a C h.ve either a &to or a hvdmxvl gmUp

.ddFnJvns5.2 and 5-3)

o. AI;ndm~dahntlv.r mnmm a mwm rtomd n v

fwd faffmmber nng W e m that contains f@*rrbn,
lmmr (ClgM
 The metabol~smof lip& frequently requires that a parttcuhr lhpid be t r a m
ported m the b l w d betvveen d~fferemq n s The maln v e h l c l ~for trn-
pMting neuwal llpl& m the b l w d are the l i p o p r o t e l ~

A Sbunun and cmposMn All lipoprotetnr consut of a

ll-
and
- a The I- mntalnr mas
pholl ~ds,and 01-amphkpathlc molecules that
~nn
-vco
rnment m-e k i
contains the neutral I@@, triacylglycerds, and chhecte-h~rh
a n h i i i y 1n10Tuble
in water
B O.sses. The four major classes of Ilpaprotelnr In human serum can be
separated by alecbophorms on the bars of thew s~zeand c h a p or by
yw
n
te
drie
ht-c
1 Chylomlcmns are thee-I o f the l~popratelnsand d u t
I mgrate in an clectriif&kl. They are h e d in Intestinalmuted

dl
or d!as m&, sketetei m d and achpose tusue Chylomwons mmaln

/
rpwral a - cndnliw Is.--
m
is u ~ t -tcmn+o
, till
=-.aase,
- - -
a p , C-I
and -I
result.
i)
lnp?n fatty acid r&ase t o heart skeletal muscle. and mammary

--
g N n L The -P
kmmnk by the liver
of aim E f ~ d p a : : n ~ o f ~ m i u m

2. Vly b w d m l t y Ilpo@td(~ (YIOL)a n@ -I In t&,gliver and

transpon TAG and CE MDLr a n compared malnly of TAG, yet are
mZEin71ched an 2~
tham c h y t m r . VU)B mntatn ~JIIII
m. and 1
-. Uke chylormcmns. VLDIs are metabolized by
lipoprotein to p r o d u u ~ m n s n bntermedlatedenslty
a llpopro
telns. I Thew ranmaws tan be further metabolizedt o partdw
of st111Cower dendty. or they c ~ be
n lntwnaltzed by the lwer

-
bwdensiiy l i ~ i n ILW) s are ge-fmm VLDp-&ID-Lr
by the action of ltpoproteln h, thus ~nvear~ng the relattve pm-
portlon of cholecterol NOe6 I" the neutral core The major function
of LDL 1s to t r ~ s b a l w t o r otaemahepaic
l w r , where ~t Ir
taken up by recoptor-medlated endocytonr The WL panode wains
only and the uptake of LDL by cells IS Inrtlated by the ~&r-
a c t l w o f g p p e , w ( LDLjecegtgyon
& the plasma membranes
4 Hlghdensity lipoprotelm (HDL.1 are @%!zed byJheJaer and are
approximately E p r o t e l n When the particle a secreted by the laver,
Y
 the core reglar k relatively emF+4R?b pstfom two major ~'J?P

a Circuktlnp f b v d fw apop
and @RaR'twilN
. batwaRlo$hrh~rotern
%DL p a r t ~ cobtain
l~ m a
rarrvonfdkwiingmettrm
b. llmrvhDtbbmltrnnrp~rtHDCIn.iRlpxtaMInmwinJdlw
lemrolfmh Sruahepatu twuer to+& re' E h f w i b-

HSL m, and u t t h x m t o
me II
transter of clrolartemt esterr to VLDL and
followedby runcant uptake. T)uo pfotek\l
revem c h o l ~ r atRNPort
l
(1) ~ l n c h & R U d ~ t m ~ & C U ) k a
t h s ~ e r ~ I . R M f s t ( y . c i d 4 f a ~
m
e,efflon comes from (Phoy,hatldylW) UU b
vatad by- whkh IS w d w i t h HOL
QI OlolaurdSR transfer p&n DD)s sugctaud vmth

mere are mi rn* -of fattyafd and l~pidmetabolism Fatly acids

*- -.
*--
4 %
.
"
'- @WE 1 : BIOCHEMIS~Y
'C '< " ' '

. - 3
,, *
#

,
>
,,
A
MWdtbar-w-bvw @-
A@' : - .
a*; ' -
a imd i l w t i n n ~ i
r a M P and fnrultn d
*
r - here excerr~vefatty acid oxldatlon IS occu
curs ar a means of convert#"-
an be readily transported ~n the plasma. llwllp'

M Wdnarrra3-r.Wz

* ' .
J

:
Oxidam for fuel- - - --

1-1 " .
. r-I.
L I I
A +.rid lynh.l(r In humans. fatty a c q ere ryntherlled fromaCetyC
&A ~ n a t eand
maryt of Bo.tdation. wrth two dntlnctionr the two ~ I Y 14s
f6rWltuWWm and occur ~ndlfferurt cellular c o r n p a m e m
.1- w h e r e D oxidation
&@ WIMW can WhSh a1 of th requ~ndfavy aohsrapr-
In-
, NADPH The Wlm that occur ere e n t m l l p 1

sdd and linden4 .rid, whch/ are tAeretML &rzential dfeta(y&e.

B.fors f a w r i d Nmherls can b g m
I dif-

!
-4
r a W h t h e m t o t h o n d r i a where ~t8s pro
Inner rn~to<hondr#al rn

-.-
N-
$.
.r
.. . -
h u t a n u d f n a f i -
and then t r a m Into the
by
I Onu m the Mytad, rlwate Is
lyma to f o r m z I w dhdoWloaCeUte, h u h h
ronvwtcd through tm,wqeq~entlalreactlorn to pyruvate. PyWvaM Is
r e t u r d to the mkomondria, wnere t is <a*&
m m p b th. h i d e . %e- alw,
to o x a l w to
mother
-f required fw fatty acid rynthnh. Aboul half of the NADPH for

Frgure 5-9 The ouareshu~e

3
lnfaiwacd
I ~ey~uym n synthesn
a -A
&t
ulaoMasa catalyzes the
The enzyme requlrer the preren
for conveflsng acetyl-CoA to ma WI (Figure 5-la.
*

mlonyl-CoA is a threecarbon rompau&kd as thedDnar

0 Acetyl CoA
II
CI$C4--CoA + HCOi + ATP -----+HC
(Dm)
Malonyl CoA
NBDE 1: BiOCHLMlSTRY

Frgure 5-1 1 The enlymabc wtrons of FAi

Qr
At the end of the fim cycle. butyry-CoA Is transferred onto the
rynthae so thst the ecyl carrier protein can be recharged with
another molecule of mdonyl.coA and a new cycle ran begm
Each cycle ~ ~ ~ o f t k e f o i i reactwns
~ ~ ~ n g f ~
(1) ~ondenrat~on~d mlonyl-CoA with fatty aqKoA to produce
a p ketoatyl CoA ~mermed~ate
'
Q) Redualon of B-ketoacyl-CoA to @-hxdroxyacy-CoAtn an
NADPH dependent reactLon
(3) Dehydrat~onof Bhydroxyacyl-CoA to pmduce%n&I-CoA w ~ h
' adouble bond
(4-of the double bond by NADPH to produce s fatty
acyCEoA that has been lengthened by two carbons Th~scyclic

.. paitern ts repeated until palmitoyI-Cok the product of the

FAS complez lrformed

9 d fatty arldr that are requared for use by tk Lea

1
l mew
runion% whtch =cur prrmarlly 8" thee do In culum, rely
upon th urs of mafonyi-CoAfor slonaa* m a n ako
mur in the n r r t p r h e a : w b r e prrtyCCoA, i~ of mlonyi-
-A. i W'M OLQL~~in me ~dop101mk
7&& r u0 d x that contains
I 3.WdadondfaWkid.ynawlr
IVnd
IMthe activity of &-CEA&&E8+ ths eD2PW thpt
Btalvler the fin'step an the !nrtaai r e a m wnvwWg a c e t y l a M
denyKcrC Thh reactlon 15 the
*.
high-carbohydra
15
, f a t dlet. ~t Is -fatty
atrate, ~ & k &end r
acidr,

by aPdependult ph06phOryLalicn*XI extEWmd by insulin-dvn-

da d ~ The synthejr at ~
both ac-I-CoA csrbcxy-
.
Immd fmy addsjmW cwnplexY s- 1 lnsulln

B ktg rid aidmim. Moa fatty ac~doxtdahon occun ~nthe m e

&la, .Itha& j h ~ r a m e rare lmpartant I" the oxldatlon of very long-
&ah fatty r c i d r s n d a n c h e d cham fatty acldr A separate set of
~ y r m e r o x i d ~ fatty
r m acids ~npProxMme5
1. w.and oxIdation of f a y arldr. The uptake and oxidation of
f a w. widr bv
. cells can be divided into three major stager: activation.
the transfer of fatty acids into the mitochondria. and @oxidation of
fatty acidr.
a. Activation. Fatly acidr are convertedto fatty acyl-CoA immediate
y upon ents nnto tne cell. ~ h reaalon s yam ths fattv add l ~ t n e
cell ana nerater a hiah-enerw thioaster - H. The
r ~ m i o n ? ~ a m i p e dby f n t y .cyldbA syn=="d -- e
driven by the.-

b. nalahr of f a y r i d s Into mbch Fatty ~ I r enter

k the
mvtochondria vla the I, dhich conrinr of two
mzpes (1.c.. carniti-l transferarc( and c a r n i t l ~trans l
frrase-11) and o n e t r ~ a (ife , l c l l r n m transllorare)
(I) C & t b e y l t m e s b a d (UT-0 Is a m ~ t e wlth d t h e m
p a n t h e . It wansfexhe
fatty acid horn fatqr ~&CPA~P$amtineto form fatty acyl
urnlme.
(2) Olaign trdsxam t n m w r t r fpthr wyi carnittne mto the
rn-rla and trartrp~afree camttmne back out of the

wmsfwww(u.u~(t-bated w ~ t hthe
4 H u 3- nimhndrld-ambrane n ratal~zest h
xhchondnal matrlr
 -atad fatty actdr s also important. -9-f
hllm.hU a r . r a h 1.~~yaMIlnn8t-
ural fat contaw nr double bonds wly, bJt the enzyme enoyl-CoA
h
-- i c h catalyzes the second reaction I" the p oxldatlan
yde, a m onk on vans dcruble bo ds An auxiliary enzyme
,
i s ~ ~ - t r a ~ ' w e natural r t sor bonds t
the trans conftguration, allow~ngcont~nuedoxbdatfon o f the
unrauralad few sctd
g*icr of &=&&an. Oxidation of#
?cuIes Of amyl-Co& 7 mokules ol
$AM2. Further oxldatlon of acatyl-CoA by the TCA cycle n r u l k In the

-
follow~ngstoichlometry for the owdat~onof palmite ectd.

CwxpOZ+Z 16CO2+16H~O d-
ihe (dad w b l e el + fmm oxida-
tson I npfaCld. of i WU 1 Stme

' Ir amned as
7
.,,,mmmatelyair
the UQ for fatty aud omdat~onIS
In coneast, the RQ for the mmplete oxdatlon of
glucose vta glpoiynrand the TCA cyde ts approximatelyJ&
. of kny add oxIdation IS &#wed by e rate
at whkh faav enter the mttochondr~sC A T - l % $ k $ = % -
onyl-Co& the f ~ m compound commmed to fatty acd synthesis Thls
ensurer that a fade cycle 6 not generated by r~multanewsrymhes~
and oxldatlon of fatty artdr The rate of ondatlon Is also controlled NoTf
by the rate at which fatty acldr are released from trlacylglycerol
stores ~nadlpore tissue

ences between wntheslr and oxtdat~onof fa* acldr are rbrnmar~zed

etone bodes are

that d l r x ~ l a t et o acetoacetate
spontanedur decar6oxylatlon
 Utr& #iuate a n b Katyl gmup
trammito matrix 1nto-I l n t omtnx
f r r n - ~ ~ t ~ b ~ lmlto
WADPH' ' a r
Eftebdhigh Ihtsulllrl Pathw9 Wemd

IMbltel by maloycCaA
~ i *myme p ~
AWy!-CoAcarboxylers

1 - @nUmslroown In liver mltochondrla v ~ the

dl@ 5.1%.
a reacttomshown

of three hloleculer of acetyl-CoA In two sequential

I -.
redcbons generates phydro~pmethylglut8yI-IbA (HMG-coA)

-
* -15OA w formed I" the first reactton and actr as t h e

1 2.
cb - Q
farthesecond

~ ~bHf M
aGce
~O
,
t oA a c e t prcddcGacetoacetate
bte and
to 8-hydroxybutyrite a-oA
pmduc4 w
ucllhnlonby edrahepabc tkruer octun In the rnnoJIondria
1

' /
m n g the uptake of ketoier. p-hydroxybutyrami s Dirtdmed back
t o acetoatetate. The fate of acetoacetate m v a h tvm m h c n b a l

I k 4 b e d by an
a. ~onwrruonof acetoacetate to acetoacew~-COA
enzyme that transfers CoA-SH from rucc~nyl-CoA to w e t a t e .
The abrence of this trandnars n lher accouna fw the l ~ b t l t t y
of Ilver to use ketones ar tuel
-b , n l e w two molecules of
W l - C o A . This reactton tr cataiyzed by thtolase, an enzyme of
thr gmk*tion pathway.
D. tmw~cd- ~ a r n t h e f g & ~ ~ g e
NOTE

de novo rvnthar The rynthertr and degradl(0n o f tl ycerob

involver formaton and hvdrolvrir of the efieYbQndsbritm y rcidr
amdtheglycerol k k b m e The cond~t~onr that pror &Pa

9. aSlrylglyrwol symheris occurs prlmar~ly~n Inn &msa m e

Symhsu Rqulrer glycerol phosphate, which s formed by the reduc-

- bon afdltQdraxyacetonephosphate (DHAP), an Intermedrate ln g k

e

EdYJls Fatty act& are transferred from fatty t0 carbons 1

& 2 of the glycerol backbone by fatty a q l trmWaLb Hydmlyrls d

- the pkwphete bond at cmixm-3 m e t e r dfarylgtycerol, which b

then enerlfied with a th~rdfatty xtd, praduc~ngt r ~ a c y l g l y eA
wmmaryof trlaqlglyceml ryntherll ~r
shown tn Flgure 5 15
 '
Z M x y t p l y a m l hydmlyrls tnvofva a famtly of llpaxr that differ on
thew I d n a t i o n and rpec~fidty
a HOrltion~.nsitlve Upue Is found prlmar~lyrn -e
where k hpmlpa the flm fattv arid ham. Thn is
hc ratelimiting step in mobdiration of fatty acids trom adipore
*res The enzyme IS antvated by d M P d a p n d m t ph&mryla-
Con A n u m b of hormones, mndudlng a P l n e P h r l a p ~
m&ne, stimulate o4MP pmduchon an adtpae tlrwe and a
-s The fatty actdr released from adapse are carried m
the plawna bound to albumin -1s release4 and extracted
by the her, where n can be used far w rptypthe-
olr- The -onmi ~ l gtycyceml
e dl
the absence of ah-e
'
h ' h c r e a t ~ r lipam hvdrolyzer 'd~etaryt r ~ a c v l a l v c e ~
I J ~ QHydrofyrls
~ occurr at por~t~anr 1 and 3, rest
I releare of two moieculer of fatty acid and 2-mor ride.
There compoundr dlffuretthelntertlnal mucoral there
they are relsterrfied to triarvh vcero a n d
1-i Tne chylomicranr are released into the yn .. md
enter the bloodstream
. .. by-

c U p p m a l n iipue (LpU a produced bythe endothel~alcells of hc

vsculature tn ad~poseand muscle
?"I and VLDL tnacylglyrerol into
The fatty acldr are taken up by ad~poreand muxle ttsue In adC
core tlwe they are r d r i f l e d Into tr~acylglycerolrf o r m
In muscle, the free fatty acids are ondlzed for energy The glyc-
erol produced by the anion of ' *ein lhpare Ir taken up by
Hver The chylomlcmn remnants. ed on cholesterol, are taken
up by the llver where t h e m Ean be c o n ~ m d tobll.l,
acldrar r w lnto YY)Ls

Cholemml syntherls. The mdjar site of cholesterol synthesis is the

The adrenal conex, the ovaries, and the tester also produce rignii
amounts of cholesterol and re ~t for hormone w e r ~ rThe
to syntherlre c h o l m e % % ~ & , a l and
are W u e d n eltner p l u m me
required for cholesterol synthesis are ~tvl-CoA&yJgL

+9
 r S D p a of rholcrtsml s y n W . The rynthet~cpathway occurs in four
stager.
a. t&mlmic&l synth.M. The first rtsga of holeterol synthesis is
on of t h m molowler of awtyl-CcA to

+m
HMI r mevalonic acid

nt sets of enlymes, and the cytorollc HMG-CoA p w l

sir doer not mix with the mitochondrial p

w\C-C&~-O- TC=CH-Cy-u+@
Hb c d

we- 8.9 D~methylallyl

Pymphosphate

&5 trvatedm

KAPMN MEDICAL
 f e r n e r y ~ w + ~ ~ - f a r & + ~ + ~

d. Conversionof s u w h to Th.&mh a& RneI .(*lr

KO
of cholnterd synthestr, InwMIIbe
f m m l , wWdr b
form cholesterol (RpiikhW.

squalenw - - c",
- .,
HO

-
'33 CH,
Lanodteml Cholesterol

.6gure 5-18 Cwrwmon afsqualene m choieIem1

2. Ch6bsted .st.r hydrolysis and formation. Apgroxtmately 7 e -

m t of Iha cholerterol found ~nhumans w e r
The moat mmmonfatty acid found esterlftedto the 3-hydmxyl group
of tt* Aring of choleRcml tr
s Uydrdyriroflnlenedmmn
teml(na H D L A C A T S I M R ~ ~
(1) h a w t l c cho*nnol &rase
- h
.auRwggMddnkrtwolmcel&
.- Reuterfflcahon a- a f t d~ C
fMon into the lntartlnal murmal cell, but prlor to Inmrpora- .
tion inm drylankram
 a p ~ . r t ~ a ~ .int * rs s r m -re1 tranrpo~by HZ
mut ti an ilwolvn the t r r a f a ef a tmuy acid tmm d 2 -

o ~ w y l ~ t r ~ ~ ~ ~ n , ~ f o v n d i ~ i
is involved In .- E.1"riRCnlm 1nw)Y.I ttU
traMhr of a fmy Kid from fatly aqi.Co* m choWml.

regulated. D m high ~n fat and rMnULat. HMGca*

e-r thew llmltlng enzyme in* pathway. thr&vltyn
auweesdby~dk8neho~*dtWfaimHhidnlhnarth.

b r a m m d are mMrvllnd and hydroClrrd,ykldlng *-

-
l
W- I I" tn.cholateml In the cell h a two rmlw ~ h t q
a
- at N=.I th.IC
smthsk
I of w o n (-dovnnpula-
trim'), thareby &creasingaddmonal uptake of LDL&okrt.ml fmm
- ns
plasma and thc Nnthasofcuse, thus
decreasing the denow rynthewr of choleRemi by Me cells

R Choksteml derlvdnr Cholesterol n the precursor for bde &,d and

1. Mlc acids aren

d
s-2 dsrtved from cholesterol
Synthees occurs in the liver, and ~nvolves
four runionr, each of

wes a thrce-Ellrb0n frag-

\hh!& t e h a l carbon

intheriylswtn

and t I k 8 P l y n d by r n t u a o d
in~lonrthnrsnnreboth02md
sdd m a a d ltr mugptcd
 5-19 C h o l ~and and t ? w x b I ~ aad ,

11RactiOnlthat have tiwe and cell rper!ficiq

NBDE 1 : BIPCHEMIS~RY

ATP ADP Cytidine-P-P-P P-P

0
Ethanolamin &J'rth9nlsmmeS a COPemanolyninr

F@WEZl A ~ n o F ~ n o b m m e
'

B. Immwmemh of
$ i
h kMWW-
T Bw

conversion betweenthac three clasm of phosphotlpim.

I. Polar head plwp *xshange me Uhanolam~nemoarty of phol-
phatldylethwfamtne o n undergo an adrsnge with a
-
rovttingin &&&&&p,
2 ka- of i+ws&tidgwIne results- -
ciamrle.
3 M*hylatnn of p h o o p h a t i w In three eoma~tiue repc-
tions rerub m %&eMIylm&dw W)Is
IN A NUrSHEll
used as a methylatlng agent. l b m lntpmnwsiola dn i
iW In
F~gure5-23
 SPHlNGOUPlMAND GLYCD~flDS
This -p of lip& k &id into five m q M u t e g w b : . r p b ~
I
-hides. nlHa*la &bddss. and All fiw duvl am
catesorked a$ whin@&d% c o n t a r n m g r r ~ 1 4 , ( ~ w ~ h i ~ ~ ~ .
A&tBonally, all of the cldsn extept qhingomyelln a r e i d v r to
-sht

i s t h e .
Tha awnmon ~ ' r k
mre a rynthcw2cd fmnt Lree gmnwfs pkn'ioyIGz4 swim and a
bnpchan fatty .@&A @I &sm uf EpKmSdtplds and *lip&& are
formed by the t v frmiholr . r t l v a t d carrwr to
1'
hydmxyl ~ ( o u pon Ib..Ormlrvl whm of unnM..Actwaad carnus
used in o h l n a o W *Id W D ( d -IS Indude UDP-suw CDP- 1

W o u r rynem If b the only sphlngolipid that 7

T h e p f o m
Iphng~l~h.
2. Ccnbrolldl md sulfatlder. Cerebrorider rpptaln eltker gl-r
-The ' rebrortde gena-a
&&&, -MyS and m a r .active
sulfate.'
i r I

caf mambrana
t Gm@Wdss Glymliplh ramainlng
D. Iandlns, t h r a n h ~ ~ku
~-n*

os@dpr&, w r erter~f~ed
to c a r b o w ,
Thsreleast < rom the membrane I S &

BMeXa

- ~~~~inemrarordmhsm

mmphdip.u ill
MIMl
Rolcgm wh!doluc sdd from mawbranestores.
mhar#cd by glucomrticoMr (e.#., CoRhom)

1 Catalyzes hlftal step in the pnthway that

catwecis aachtdonk add to pmrraeiandlnr and
tkmmborarra. mhihhd bv nonsterolc4al anti-

1- Wrn the 1nltl.1

~ a ~ m ~
stap on the pathway that
~ t o l e u m II -
 Amino Acid Metabolism
b

9 .

-+'* .
e * I L l y o f ~ d ~ t i o m h . o c m a ~ ~ w t h a ~ ~ ~
b c l d desradaBbiMW59 WI$
stgeiuo aha-

, . - h * I V V U ~ ~
-&lwruC-C*
~~~wlndigntbnMd~p6mvvq.forsynth.m
 una inaa'i trypjnogen totrypln. trywin, In turn. scWwter the othar
pmm%atrp.- There Mqmes mntlnue the hydrolysis of dietary
m p a d M n p a mixtureof free m ~ , d-tdes.
acrds, and*

L of amino =id% S p e d c trampon rysfemr absorb amino a&

end small septtder lmo the ep~thel~al cells where the W d e r and
e w e r are hydrolyzedto free am > a<#& before they len* the cell
in the IntWnai cells a n rim~lar a
 rympavm are dan in W C a ,
rramlde defic- Up& W 4 of
hc metabdWaftyptophln
r cymwri. k e m ot f k mast common amino .riduriar R k n wno ;klnsuo#ic
od~~@ba-Inme'tf~a/phw
lyrins-e&amithl(r,minW-k

P m m A
- "warn ol mwhP@-rk

A Dl(poo* ef WW m p s .The dCgrsdatlon of amino ark& usually

bagk wifh renWIl of the a-anuno group. Appxlmatsty&&of the
@
c&orrm "3
nitmaen uLmateW gas
in the flow of
rea. The two moat l m p a
amino acids to ur&a ara
annmhtiem and the oxldaka hrlnlnmhn ot giwnute, All of the
~WlfcC
~rZnni.CA
c -
*)no wrh e threonmc have spedktransaminare~that
l ~ n and
'Whvmp
-A@P&
sretnvolved m the i-l
I m d -
of the a-amlnosmup
, '
are s family of enzymer that transfer the uilrn#no
F m m 4 rnsrwnz- of*-*+

the m m o n (Hgure 61)

pa, @mupIfmm MY

tl9 w m R o group of
aadffnerwof
MdiSMu
'rail-

&

417
 I . I--3 -
1n.tlon. Tkts martlon

a
Is catalyzed by\

-*
b TRn.rttlaWDD t o - m i a ~ t a t a%me ofthc =-ammo groupr
h B a e n @%tad 10glutamuter are - t
aftate, In turn, acts as s donor of
of una. Thk w t o n occurr maarly

GIuWT&*- t-
I\ISIBnne-&"?.-L
DehYdrOge~~
- -- ,
a~artStZTanramtn~
ate tranlamlnare
7 Ad-,

a-Kofoglutarate + &partate
--
3. UU 5ynUnsk Urea sqntheris occurr onfv ~nthe lrver Urea contaim
tm,em(m grarp that a n linked by a carbonyl group ne ammo
group comer fmm a@ammontum ,081 and the other a L b y
'
a=, The carbonyl group comer from bicarbonate The synthesis
of Om mole of web rwqdmfi* Huymer and three moles of ATP
MH.+ + %-*&&we + 3 ATV +urea + Fumarate+ 2 ADP + AMP + 2 P, + PP,

iwon of the enzymes

WLAN
7

NBDE 1 : BIOCHEMISTRY
3
c2,~ ~ y l . ~ ( - ) ~ ~ t
carbamoyl
,msuitmg in)
h
@ e j,
ttm mnar mito-
chO&l mlorhranl mto the cytml, where the remaming 3
1 reactinn~in the uraa c y c b ~ .
(3) Argh-nm .ynh.Pumode- -mthlpar-
tate to f m amlninosu@&e.The u-amino group of arpar-
Ute 15 linked dlnely to c h l l i m ~nthis remion. The anew
.
I for forming the boW Is provided by AlQ hydrofyrb to AMP
and PPi.
(4) ArglnInorurchIrte lpss deavBI arolnhlmcclnate to form
arg~nlneand fumar All of the w r t a t e moloolle e m p t
Non t M r e i a a m d as fumarate, the a m i n o gmup
bemmer a part of the argknlne rtde chain
(5) Arginan n A x s U ~ Mfrom the sde chain of &irm Th.
other produn I S orn~thmne,whtch IS transported W i m t h e
m~tod~axlria for part#c#patlon
q&m&%aPe-
~nanother
-
@. The urea IS excreted ~nthe urtne Note that urea contain9

b Abnormdith In the -
- O ammo groups, one from m t e and the other fmm
W

cyck. lnherlted def~aencleshave hen

reported for each of the an-r
dlsti-fmm
of the urea ~ l Teh e can be
one another on the barlr o f the prod"* a
'

Merend mble 6-2) Amonla accumulates ~nall of the defioen-

am but Ir mon pmnouncedtn defic~encterof CPS-I and OTCare.
TaHs ~ r 2Defem ~nurea gWe mynw

I-- CondmDn ~llu.APUmUla~ I

Carhmroyl.Ps,ntimt8se Type I hyperammommri hmonla. giufamine, alanlne
O r n n h l n e t t ~ m o y l ~ Type 11hypenmmonem~a Ammonia. glutam~ne.orotate
Arginbcawdnate$ynthF(He Citrulllnrmia Citrvll~ne
Arginlnoo-
Ar4inare
!yam Argi~mxwdnccincac~dura
~ramlninem!a
Arginlnauconate
Arehine .
4 A I n h r Skeletal m l e uses atanine ar a can@ fw tranwrting m

1 .
w m o group to the h w , when urea ryntheur accun Ar shown in
-63. the amlno gmupr that have bnnc01lect.d m glutamate
, an subwuequ.ntlyasmfened m p a t e VlthflC fqrmatmn of ala-
nine This r-lon a u t s l y n d by alanlne amlnotranrfsrare (also
k m u-am~nare) Skeletal muscle releases
large amoum of dan~neinm the circulation Atanlne Ir taken up by
the liwr, where the IWem re& ocmm Thm cycle allows amino
Vmup from rlnWz.1 mwle m be *an&& %othe hepatic pool of
glutamnte The aianine amlnotransfera~~ of both skeletal muscle
and Imr en L!ver rerycies pywate by mine it fa
g l l ~ ~ n e s ~
 1

1
NBDE 1: BIKHEMJ~TRY

I Of-k aMIWclne, Phenylalanine, twine, and ttyptophul). The

wWh?wmacicllarestrktly9hxwanit

-Jn_

meo*-*o&grWr

C. D.VadMm of branched-chain amino acids. Liver has little, if any,

b a w m i n a e a a i w for vailne, iroleucine, and leucine. Thawom, ~n
conhast to the othw amlno acnk. the degradation of the branchsd-
chain amino wdr starts In skeletal muscle, where transaminare &vny
khbh. The fiim two Raatons m the degradation of these three amino
ad& are c a t a m by common enzymes (Flgure 6 6 ) Bnnchd-rhain
am(asrcM hnaraitw4 (BCII uanrwnirule) transfen the rr-amlno
Bmup to olemglutOratet o form glutamate and a-keto a d s rorre-
Ipond(ng to tM carbon &ahtons valme, iroleucine, end lewine Thlr
*
*nym pmeM i n Ngh ConCemraNw In skeletal muccle and very low
~~ in tha IiW. In thl nnxl step. tne a-ketoaods are dnar.
bo-ted by a W l e b r a ~ ~ ( M & m kemacld dehydm- (BCU-
BlO. rrarRh?qin brandmd-zhsm wI-CoA a n a l The productr of the
W W W rrctfon mwed akxq &Wesent pathways. The end pmdum
fwlhc ofeach anrim .c?d are shown in Flgure 6 6 me end
poduEh d leudnr, and ~s~lcucmne are used by nerve tisue for thl lyn-
thabof llp(d.
KAWM

> - L
 &a-ln .wI-CoA analogs

I \

~IIamrlcon
i
FT€iwM-
JlcaPy(w
Aceto

F$u*&d &gradam ef*w~o a d

~ h BC~CA-DH
s 16 a mult rtructurany hornlosow to
-ate dehydM-ate dehydrogenwc All th-
ratalyrc the oxldattve decarboxylatron of a.ketoadds, a d and- corn
pored of three dlsttna enapes that requlre the actions of five CeW-
qma (NAD+, FAD, Eok th~amlne-PP,and llpolc a c d , They are all loat-
hd m the m e of most ceik

D IPITrniWn of pOplonyCCoA into the TCA W h . Proplonyl-CoA results

from the
.e
nin
oih
m
e
n
1te
-a
dra
e
q and fmm the W d
df odd-chainfatty acids The pathway for vlnvertlng proptonyKoA into
luchyUoA Is shown ~nFigure 6-7 A deflcltnq In enhn proplonyl CoA
a r t d m or rnnhylmalanyl-CoAmutare results in Qganlc actdurla.

-
Thad~tfoa n w l l y sen m c
h- with wan5 ofat&

d.velopIng a
d e f k ~ hading
q to There set-
orrqiaraMaa~m t ~ d b ~ w + - ~ l
-.-zyw&y

NBDE 1 : BIOCHEM!STRY -

P r o p i o n y lkngi~ con-Succinyl
~vitarmn
~ ~ CoA
t
Thrwni"s m
KMkyrWhyI con mutam

SYNTHESIS OF NONESSENTIALAMINO AC#l@

m i n o and., are synthsrmd fmm idermedlmes in glyc&& w We TC*

mle, from errontlal anino acids, or from Interorgan pathways Only the key
mncapaof these pathwayrwlll be reviewed
A ~ ~ ~ i n ~ h s Elghtofthe
~ T C
~ ~amno xi&aon beryntharlzed
l fmm Intermediatem glycol-
@ s- the TCA M e mntarmedlafn.Ths s Illustratedm Figure6.8
The mwwninatiqnbf Wruvate, c x a b a m e , and a-ketoglutarategrve
dntlrdrnh aspawand glutamate, mpebively. The addltlm of an
1 nnrde QIWto the Slde c h a m of aspartate and glutanate reruH in
*par&mgld glutamvn Phorphqberate w a p r e a u w ~of s e w and

pzG"l 1-
G k r c Q ~ ~ + P h ~ ~ Pyruvate-a-Ketoglutarateara-Oxaloacetlte
~ e -

*dine -Alattine
4
.Glutamate
1
./Upart&
'
.Ghne
J I
Cynelne
J\, 4
Prollne iilutamine 'Asparsg~ne

FI5ure M Aen,rsmfor fhe nonegeond ammo mds

 - -- - a

- "I
t
Acto METABOC
r
4 B.Syntha*horn~~ltOddr
tyronne, and w n e w l
k mt precunorfor

tytorinisnd ~ I also
mahlarvlJm
TMrsfwt, H either p k n y i ~ n l m d ~
M become e n t W mtm a<&. T l ~ ks&mkn
wmesyrt.mtforw-
m gestatnm
i T*o.lna.The w d o n of phenylatantneto W n e is c a w by CLINICAL CORRELATE
(Figure6-3) Thk mzyme r
w r
es02 end
g@) Durjng the hyd(o*ytationreaction, THB n
oxld~redto dlhyW0Ptwln (OHB) b r the pynthpnr of tyrmne to
Continue, DHB must ba rehnmd W b tHB. The regeneration of
THE r q u h n NADPH Wd@&d~%WpreflnIwludase

Pheny!aMm

reductase N

*t-
NADPH

6 9 hpowfaton ofpha,yiahine to m e

2. Cymnie-. are areired torthe

t&e. Key steps in the pathway are shown in Figure 6-10 The sulfur
atom In cyRPMcortginner In d~aarymethbnine.,andthe remainder
of the cyste~nemolecule 1% derived from urine Methlonlne Is first
convened to hommytelne through several step Wtathion~neryn-
t h w , an enzyme requiringpyrldoxal phosphate, cdndenm homo-
tclne with rerune to form an adduct of the two amcno ac~dr
CyrUthionase then cleaver the addua so that the sulfur atom 4s
m@& to senne, generattng cysterne Excess homocyste~necan be
mnwmd barL to mshlonbrnby the add!!ion of a methyl group from
mtrahydrofolate ISthe only enzyme m human
hzfwmtstry known to ure THF as a m y l a f i n g agent Thtr IS also
in humans that requrrer vbmtn By
oneofthe two RaR~ons
 &lit from N n g glurora m ketDRssduring stanution sparer protein.
Red b i d cells and rehal medullan, cells that have few, i am. mlto- I
chondnamntinuatobe deprnderrt on g k K w for their margy
I
F ' r b o h y p
Wuo
-s
int of fat results H(lkcailgram compared t o m
derived fmm carbohydnte, pmtain, and ketqner. Ihe storage capacity and
pathwayr for utibatbn of fuels varier Mth dtfferent o r g a ~
pnd wtth the
nunit~okaistatmofthewganim a,awhole.

- -
Muxle glycogen a m n o for appmximately hvathfrds of the carbhy. I
drate rmrago. A i m l t f r & i of the total cafbobydrata h found ar glu-
rorhW drtulatlon. Fats are stored h adlpors tlmn.Whish comprises
anywhere from one-fourth to one-third of the h m body weighi
Pmteinr are tbund m all body tissues whete, on the avhsge, they

- -
aaount for thnofourths of the tlrwe mass. ~ d a ' i of n more than
' _ 4
omthird of the protein in thc body k inmmpatlble wHh
life. ThndwZ mmdn marina by shiilng mtWm bt fud ut[lb.ation k
e%$mtialto s&l d"r"y p m l w tarNog
6. U t i W o n .
Rlgsrdes of
: which fusl Is u ~ they
d are all degraded to ecetyKoA, whW k oxidized
by wmmon pathww to COI and Hz0 The fact that all metabolic fuels
gtve nre to a common lntermed~ate(acetyi-CONpmv~des a mechanism
for mtabl~rh~ng prlwrtler on fuel util,rat~on
I . PrforlMs. The ,
R the fastingstate, gluconeogene-
14 proteolp~s.and I~polyrlsare ail activated The ammo acldr a n
supplying carbon sMotas for glumrt rynthss and the oxldatlon of
fany act& to -1-CoA pmvtder the enwgy for drtving glucose ryn-
t h u s The accurm&on of sKtyKoA i n h ~ M spyruvate dehydroge-

m. A
-
n m , the enzyme that mewrul,iy cower& pyrmte to acetyi-CoA
When"'
U n d e r t h e con-
digons wwne (derived from eather carbohydrate or mlno ac~d
Itracwsat) can be &lvwted away fmm oxMMion and toward glucc-
-mur-. ''W.tlrsrpu

t fwls. The organsp-

 A M I N O ACID METABlJpSM

SAM ar ylatlng agent. The nwthyi Vans* potentel of SAM k

much higher than that of mMhyi-THF SAM [Isyntheslzed bv tihe mndm-
(Fgure cll). A high- band attacher

CH~
d 2
+ ATP - Mg2
FH, S C H ,

C H ~ -4 Hlgh Energy
Bond
Methionine
methyl
vansferare

S-ade
hom$&ne

W r e 6 1 1 Synthem of4adenoNmethronrneWMI

B Hlrtamlr -~rboxylatlonof Mnidine rearltr m hlstamlne. an !mportant

medlato
b connectivet i w e near blood-1s ,
ammatory rerpoAs. Histamine Is rynthdred ~nman celk

Hutldlne
D-rboxyiaK
+ Hidtdlne t Hihamine+ CO,
Pyridoxal-P

Fgure b12 Synlhes ofbmmne

C .yMnabutyr(c acid (GABA). f glutamate results in

Wan-
*: :.
am*
--. _Am-& acid (GABA) + col
rvrldmcs1-Q

DSworm r dha rim attrvptaphsn folw-by

mtofdl tam-
p&. lmphn
 Wn%qIesa ryulrQi 0 2 acnl Mtahydrab-ID N B ) Dl-riq 6
I rrductarssndMAUPH arerequmdto w a t e T H B .

Ammatic anim add

decarboxylase
~rypmphan.+t 5-OH-TfyptPphm-tSemtonm
THB DHB Go2
CI,UPC C L A I-I
.-

,
wub fmm a

E are all derwed fmm

1. Orrchdilmine6 act as sr- when rynthes~zedby the
bram. and act as when p r o d u d by the adrenal N d u l l ~
The pathway far wnmedr b the same m both ttraues (Ftgure 6-15) n
~ I c h n f nhydmwlatlon, dwarboxylat~m,and methylation reanlow
Qm5Ine hydrqlase and dopamlne-ghydroxylase have dtffermt
cannot- the bk&ra,n bs&-- 1 ~ r ~ u ~ n 0

Cataholaminw are rapidly degradedby two wqms that a n w dely

1-1
dimibvtad In many tissues: (coMn
and -MAO).
2. Mdanlnr are he-t . ----
-The InMal remion Is catalyzedby-
The isozyme present ~nmelanocyter, also known r

two porltlons, creatlng a very reactlvc m o h i e t h a t pohmmlms and

glms rose to a ser n of mmpounds, collectmlyk n m x 'w
Some forms o f c r u l t from defichq In tyrmine hydroxy.
lase
3 Thyroxine rynther~raccurs in the f o l l k k cells of the thyroid.
Synthesis requ~resthe ryrdne-ndi pmtein, thymglobulm, and the
uptake of ~odlde.T h e m m u s t br d i d to It before It can be
tncorpnted into tymrtne side &in& The mtroduulonof one male
cule of If grver monotodmated tyroslne (MW,whereas ~nhodunton
of two moi~cules of I* produces dilodlnated tyrmtne (Dln Covalent
cma lhnklng of two LNT maleculer results In tnra~odothyron~ne (~4,
whereas crorrilnking of MIT and DIT p d u c e r tr11odothyron8ne
(Tg)

T* X a l - &~l?fT
 Figure 6-16 S ~ e s ~ o f n i m c ~
I
G ~ ~ . t l qmhssk
ns r a q u m ~arglnlne, giycine, and 5-arknorylmcmiontne
(Flgun 6-17). C e e t h phosph.te Is a s a e form for hioh-
phc&ate m murd.; It can be used to rapidly regenerate ATP fmm ADP
by the enzyme c m n c phmphokb~aw(CPK)

orn&inw w g~dsnosy~harntsrne ZTP A ~ P

Fq'ore 6.17 Synfhesrs of creafrne and creatinephasphate m

Beth -$pontamwly cllze to form ve-
at~ninc,which I I excreted on urlne Under normal ctrcumrtances t e
FM of watlnm excreted rs c c m t d and u d l n c t onal l pto
, funcUM
Blqd lNdr of cr4nine are ursd dlnlcaliy to @ireskidney :&-
horsurtne~pscImsn'canako be uad tovalidate thecoppletenwof a CL,N,Crl CORRELATe
fphour rpdmen.

& kt, .
-
*synth-
hslrd
.mtkeh
. .
yutres the -mbiy
-.
of a porphvrm nix, whkh k
,tmm okine and rvcunvlI~A(Fmure 6-18) The inttiai

~ r t r ( r b r h c m q ~ a n d b m n W b heme.thepmb
y
' act #the Nbq.Con&matkan of two rnoies of A-AM producer a

--I-% _%w---
 4
NBDE 1 : BIOCHEM~STRY

,
by uroWotphyrinogcnI mthp, bca forrrvtion of t

Mse The ~ ~ d l a erecunor

r~ltitr
itl %me
t e
&b&w the enprne heme svnth@<, abo k m ,
tm konra
$hatleads to heme requ~reranother p r m n umpwphynnog.. 111
to h e m ir- L Immm
--
t

WIdehwalsse
Um-Ill Wnhsse

1
PmtoparphyonIX

1 beainr in the miwloendott*l~.( wllr, where m e

w.

-
oxygmaso opens the flog vnem to give t k linear pyrmle,
and carbon monoxide (Figure 619). Thls Is the mly reaction in human

one or two molecules of

w.me major forms ow Is known-sa w
~::;:F%!%?olwm"#& knwfi as
or bc~~rubtn

Blllverdln UDP-glucwonyl
4snm
,
oxygenase

Og NADPH
reduetase
* Bilwrdin ~
transterase
B l l i m b l -*BillNbln
NADPH
n
UDP- UDP
dtglllcuronlde

gluwmnate
I
 Summary of MetaboJlsm 7
t -

W.k bUmtd by the body iwJde*r5 fsrty adds. waiq anb

amlnoacldr.E& W W r W ~ t O n n , ~ f o ~
and inhacellulsrmadpWs. T l w i M fDRm can be intercon-
wrWd via sopmas synfhetk qnd &e$rad~WLwthwayzthus
sflauli~Wt~bkstetedor~~iy.The~th-
*rap ?ofm.01md mkiU@tIon we rfzguhtud in a ncipmcal
fshioh ~ a i # i c qWlq cycles aeatcd by sirnubnnewsqmhsrn
nrd d.sraWon. ma dupter wlU rev& t b fwprm agm fcraa
of energy, Wm typarof fuelr used b y e M organ,the hormcmcsthrrt
+are M mnatrolnm, Md the tramltians +hato w h gdng
fmm a wetbfed state to an evemi* fast, and fmalfy. to a state d
!mb& f&ng

PATICWAYS OF FUEL METABOLISM

Euh metabolic fuel has t k e a pnmary forms. a storage form, a t r a w n
fmm and unlque intracelluiarmtermedlates.The relniinrhrpsamong t h s
dWeRmformraf each fuel are shown in Fegure7-1
 A. R*rdiomMpbawrrn $tOfwp.nd f m . F a W j PA&,glucWe,
and ammo adds sew wthe kmspmt form of Mglycerlde&alymgm,
and @dM iewxWb Tha
T+myL.LI-_*w r e w or taken by uU* 4
depandm on the nutritional status ofthe organism The

Whenf+mdqkkltcA kpmdrrcinga@yi.&~f&tlun ncanbe

d,the p .
Tha ketones can
then enter the b i d rnd be.1-
Thap~bywirk~~rmofh*Le~~oMHWimvanqlMt

-
fwmr and vke mrse we uo* MdWP...&smd In Qtsil m
o m u ~ ~ ~ . . t R * ~ ~ b t f a r m ~ m ~
s r i d t M d m o ~ o f ~ * ~ " ~ - b d i f k r s m
~ a ~ , r ~ U q m b y O r e r ~ ~ a c o n n n o n p a fh tehsaawy.
re-ip
teiin *w
wcrtr tar @ c a & d q b s kand * d o n and for pro-
S h e d l f f m sml oppwng patkrvyr
~ s m f & e ~ t n n r p a $ l f o n n r o f h f i l a ~ w u a lregulatedha
ly
~GfWxabmmW,aRhlr~ that* Me pathway s on owdUMI, the
olh%rkdwmsnt
6. n&&&dp bnyMnmMyrort Terms m d i n t n d l d a r nMabdiM.
WW the as,&#i&t&p&k (.mmmtd t o one or mo* charact&
t* hirw#dw hWaWtm. for ~i.mple,amino and5 are c@P.dod W
&yc01yWerTG4 m e d 1 C t a 5 giumxs i s degraded t o p y r w . and
fa acids ere Dddieedio acet&coA ff isun 7 4 . Oppos@but
1 ran !MtluWSos rho prnsnt in rellr, allmng there fual-~m~fic I*-
rn8ijiSw W & c~ursrtodto tkcdr cwre$@ondw@ t r m fwmr and
relaaed iMo the Mwd. Once again, the opposing wtkqs sra W y
(egUbfe(t~)tMmhdwdrenotbing-@
*. As rkom In Fisure 7-2 a11 of the nratsholic fUds are

-
a mmmn pathway The energy for s,ntheJdng Nat of the ctlhslm ATP
ConWs frcJn th TCA cycle, the e l U t m n 4 r s chain,
~ an0 oxMativc

c Ra&Was Wriu/ nr(aboik W.Ceftaln transhonr among the verl-

our fUCb u s pam?MIWe and 0th- are n o n w s b k
ydranwbe

-
u d edforthp ~ymhcrirof the nonesentla1anlino acids and proteln
m-
how eve^ cannot be converted t o pyrwate and, therefore.
cannot act .ra m sw for cartdydrate m proth wnhm ?he . I,

~)no
C
W€
-canr~' t
.--.--."-, and there a no oppmlng enryme in hunun W e s
that will get around thar irrwwbte step There- the
 ,.mi" D
c Cholea(erol-Swmd H0mm-s
---we ~dda

a Fsny W d s

KebgwdcAmino Aads

Fgwe 7-2 Relatm~hrpof carbohydrate, fat and ammo aod rnetabolrsm

D Re@etkin of fuel metabolirm. The pafhwsyr that are operational In

*el metabol~rmdepend on the nulrrt#onalIfatur of the organam Shim
between storage End moblzn!on of a partlcutar fuel, ar well as rhoits
betwen the type of fuel being wad, are very pranwnced In golng from
the &fed Nna to an wmnlght fe& and fn~allyto a prolonged state
of mwation The
. 7 n . ka
lb rUar k opfmed by a number of hormones. Including
&wpWnc, corttwl and gmvth bwm- The major fuw-
tien -15m %1-

I. WdCW state. Immediately after e meal, the blood glucose level rlrer
and stimulates the releare of lnsultn The three major target tlwes

KARAN MEWCAL

- - -- -A - --
 f % Y d Q f ~ s g n q a h

NOTE
-
of the lhar EWUmf by*
Fdlavlng a meal most of the energy needs
oxidatlenof excess ammo acldr
Ownnbht fast. Glucason and eplnephrlne levels rlre durlng an
overnbht fiat. T k hwmmesuwt thelr effects on skeletal muscle.
adipose tlssue, and liver In Ifver, v e

r s a also stimulated by pJutarpn, bul the response E slower than

._.
thwwntacbnry- that of glyc-olym The ~r

?'-'-
c*rab
- The ammo acldr and fatty adds aretaken
up by the liver, where the amno audr prwlde the carbon skeletons
and the oxldatlon of fatty aadr provider the ATP necerrary for gluco
neaseneslr

10 hn. 2Ohrr 2 day 24days 40 day

Time fasting

I m * ! Y n . Lipeiydr Is brisk, resulting ~n

excess acetyl-CoA that s used for ketone Iynthes~r-th
--L.-ll^ Muscle ures
f a w Kids a& the m a p fuel at$ the bran &ptr to w~ngketones
A - ,
for vlme of tts energy the-
d r - a
-se me rhlft from glucose to ketones as the maior fuel
d h n i n l h th.h u n t of protem that must be degraded to support
gluconeogencsir. There tr no .energy-storage form" for proteln
m us e sach protein has a wclflc function In the cell Therefore, the
 -Mh - f torsual ~roblamrdue to dmp@
mentot* I ns H~rno~yn~nuna wy,k etther aqulred or ~nhnrt-
ed A 6 & - 1 6 ~ h~. i o r ~ ~~t a r n i ~ ~ BIt or an r n m *
ad dekcf m elthrr ~ m n e s y & e b r eor M l o n i n e s p t h
all result m the accumulatin, of hornayMbq-wIdch k rePdtlyax&
dtzed to ~kdirulfide form, hornocytrne. Cysmthlonme s y n t m
requlres widoxal phosphate (the aRlvaed tnmT%f91brninE & S ,
a cofartor, and methlonine synthm q u i m c m e r d e w
hwn both folateand 612.
1 b w i a n l n u r l a n r v b from a defidencv n d d o x n c or Fmm a
nair defect in ryrtathiwure. L a 9 amounts of q%mthnin
?a found h the urhe and blood.
C Wnthal.ot xginlne. The rynthnh of arginin in hunum k
~m~roDnbetwaenthelntan~tmucosaardtheWd
~ l ~ 8 m ~ ~ d t h w e a c y & a f u f mol n~Mns Md& ,
adrYrtMnt~fairthmr(msoftheryckam~ndintheW~.r.
- I W r f n a rcelk rynttreri2e~ l l l n and
e
R*u It into the blpo C trL me r extracted by the tadmy and mn-
vwtd to arginin. The k one, oar ow knk of arginnr aOivlty, thus
argkrir rm&W hcwsm, it don not accumulate I" llwr due to

SCKUUZfD PRODUCTSMWMD FROM AMINO AQUS

Ths ho& d many of dw W a i W prod- especially the b w n k
I am&, I&S~thm tms of rea~ons.dwriwxyht~on,hydrwhtion. and

equi
 F* actdr carmot
re not wed at ell.
wppliecl by eimu
hepatic glycogenolyrir M g l u c o ~ e n e r k rOnly on prolonged
fans d m the brain galn the cspaclty to me ketom for energy,
and even then ketones supply only approx~rnatetytwothlnk of
the fuel wppb The rernalnlng one-thlrd of the fuel mmue5 to
be wppiled by glucose.
~(ldneyme kkldney h umque ~nthat ~t -J
fatty acids, giucore, lactate, amlno xldr, cotrate, glycwoi, and
ketones The -reller prtrnarily on fnty acids and m a
lesser extent on ketones, but will also use lactate, ammo .?ads,
and glycerol The preprefertally user glucose
 w P-
ma
d-
'
. " I A* a rneak.itip glucose . e o ~ ~ ~ n t Wmi vthe
n
portal b l d U ebv&W,~Ttfc l imtruim excess $ I- mnd
r r t ~ a t h e ~ ~ i n h W - W ~ * r x s w d
glumu,k&bIh.Dvarto-krglycsgennoreranf
any &wqiKa?bmains I. then converted to a c W and
~ r c l ~ h ~ U ~ ~ h e l n c n a f t i n i l \ p ~ i n f ~ s
heal n~rnulstprboth glymgnsynthsh and fatty srd w i n
Ayar Thc f ~ t t yactdr are converted to trigiyteridh a d i n
~~TheahodrMoLaIntb-the&z
&vm W of ig cmrw horn the oxidation of axcaa am%
&& thclivw mkag
rglucom Into th blood. The increase in glucagm during fanhg
promotn both glycogen degradation and glucon.opengsis.
la$@% Srycefal. aml amino aadr provide carbon skektons for
ghosn qntheds.
t I r H p o U t l l u e . A p
Insulin also stlrnulate fatty acid
nlezmfmm MDL and chyhicmn VbkcerMe Lipopmtem lim,
(It an -me found in the uinilaw bed of ad$- u ~ u s eactivated
by insdln The fatty act& t M are seiewcl fmm llpoprotum an
taken up by sdipwe tissue and rmterH~ed to tngkcerrdc for stOF
age Insulin IS also wry e f f n r ~ em wpprsvrnp the releaseoffmy
acids fmm sdtpme t~w. Duhrring f&tfng, the increase in gluqgan
and eplnephrlna act%@#eshmmoas4ensitive lipare m fat cells,
allowingfatiyx~dftobe nlnrsd into the (Ircu!ation
 2 tbmwm I h t M w tbe nudeus. The other major srte where hor-
mones emtt ttmu sffmcts ns I the nucku of C~IIS, V ~ W Cthe hor-
monrrsceptor mnplex bmdr to DNA and alters the rate of gene
expresson. Steroid h o m e s , thyold hormone and 1.25-dlhydroxy
utoferol lact~vatedvttamln D) all bKd to urecflc receDtorr and alter
the rate of mRNA synthesis. Binding of the hormone-receptorcom-
plex to- 1 " n
i&. results in increased mRNA wn-
P
#
S
I, whereas btndlng a , resultr
mRNA wntheris. The mechanism by which steroid hormones rtimu-
late the tranwrirnn of r.+mnialat gene is illusrated in Figure 7-5.
The enhoncw region i n i t b W A slone has no rtlmulatoiy effecton
wn -. Hannvw, when the h o m o n e - w 0 1 complex binds

D. U r h . n i a n r o f ~ ~ m o t ~ r v e l ~ T h e h o r .
rL>
maur primarily r e s p ~ l b l afor- are glucdgon. at.-
.S
.*
cho(mlns (epinphrin md nonp(nqhnne),and <Ofti+. T h p F -
p o m a c r fuel I~v-, is i ti . A brief description of the
, , mom that
nwh.nirm f o r 2 ~ l - & ~ h w m o ~ h w h y cthevrmrdinsrsme vari-
bf
carbohydrate, fat and pmtein -mtabolirm is dimmed

@#+# MEDKAL
 pinephrine,end norepinephrine) bind to
wata adenylate cyclare, reruking in the
bwquent effem previourly daribed in

protein kinare. The enzymes that are phaphorylated

to glucagon are listed in Table 7-3, together with the

and norepinephrine are released fmm the adrenal

=pons to hypoglycemia.These hamoner have two
of receptors, a and 8. When t h w are occu-
 rues Iwr,ad- firrue. and skeletal mwle The enzymes whose @
syntherls tr mdured by rwtlrol are rummar!red in Table 7-4
w..*nr " ",'. - *
a~-mvely The synthslr of glucore from amlno
acid precunors IS increased in I~ver,as are the glycogen stores
Glumre utlWretron s deceased in both muscle and ad#- t w .
b Thyroid hormna m
and TI) ako exertthelr actton in the oucle-
us by a ? n Some of the m b o l c
sffectr of thyroid hormones are tncrensed o m wnrumptlon.
lowering of M o d cholesterol ~ m i v c e m t aahd
, thermogenslr
Reccptwr for the thymld hormones are fwn4 invirtuany all d l 5

-
of the body, and the lnteractlond h w m m with receptor stlmw-
later numerous pathways of protein. Ilpid, and urbohydrate
metabollrm.
c. 6lucagm and lnrvlin can alro p .
The mKhantwnby which gluugon altenguwlaz&wskm inwlvs
GI- CAMf-kpendent p - afnu6h.r proasn gall--
act With th. DNA The m e W & m t a g k W K k r , *%ugh
i t w f f a m as de&y aSwoniSic t o +he effem of piwigon
-II fic
f v IPewc, BpPel and glucow-6-phosphatare)
. and . ' ' . -', '. ' . (glucokt-
raw,W-1,Md w a % ekinare) s
of and- r

Adipose (issue
Hormone-sensitive Lipolyrir increased relears of fatty acids
(+"el far gluwmogeneris)

Protean degradation Increasedamino acid releare

& M a t e for gl-ogenesis) 1
 The nublc addsDM and M h am the informailonal manomole-
c u l r of the roll. ms byilding blocks for nuciclc acids are
nwlumW whlcb unnged in a m d r l r n ~ sequence
r and
M IWed tqelber by phaphdlaner bonds between the 3'OH of
nu* mttbS' pharpham eder of the adjacent sugar All of
tl%e.MmnatimUutspee#ks the pmpertjer and fumiom of a crll
is pmgnnmalhlto the nucleotlde wqueme of DNA DNA nmmal-
@ uat(ar a double helix The hellx Is rtablllzed by noncovalent
Wractions between the purine and w~midlnebases m opporire
rtnndr of the DNA duplex This chapter wtll review the chemical
structure and the nomenclature of the DNA and RNA bulldpg
blocks, the W of lnteractlonrthat rtabilue the remndary rtruc-
Nn of nucleic sod* the confonatlonr of DNA. and the maabp
ilmn of the purine and WimMlne baws. Dl* s%atwasd@d
with purfne and pyrimidinemcrabolm will ah. &&wad

, ~ % % b r &men
n d nuckettdes daalentty IlnLed to opls amthpr
structure of nucteic actds M e n to th.sequsnce d the
DNA or RWA. H i r ordm ofr(rumnsm dabiilud by non-

-Tb 0fpucleOtld.r. The nuclcrrtider are the bulldnng

M d e i c wid%.Nurleotlder consln of three cornpmrcna s
k%apntorr.Mde#a%phatequp Tttelj&$ieofths
ISSB to tka PaIttow s%mrawa nlicIMs(deMs( lh8ad&- d
g r m $ t a m e ~ ~ s i n l d m ~ T h . ~ c
hc*M.dln~~ofil%enR~~sba~sl.anr)tM
 figure 1-1 #m&xiiess lmb@ in DNA and M A
C. Major d W n m in DNA and RNA. DNA and RNA drtkr In both struc-
ture a d fumion
1 hmol..DNAmnto~mzdeokyrbse, w h e w RNA contains ribose.
2 Nhmgmws hou..DNA mmalm A T. G, and C, whereas RNA mn-
tam A. U, G,and C
9 3, MlmbM of strands. DNA s doubleltranded, whereas RNA a nngle-
stranded
4 F d m . DNA Ithe repornory of genetkc ~nfonatmn,whereas RNA
reprerents -work~ngcopter" of the DNA that are wed In the tran5fer
of genetlc lnfonatlon from DNA requencer to protein sequences

D Convem#ons
Unkage b e e n natmganou.base and sugar. In purlno nucleor~der and
nucleot~der,the nltrogen 9 of the rlng system a ltnked to the 1'-carbon
Gtyms!d,r bond cmnectr p ~ r o r e1'<
of the sugar In pynmkd~nenuclemfder and nudeottdes, the nnrogen-1 m bare. phmphod,mer b n d m n m
of* rlng tr lhnked to the l'arbon of the rugar (ree Flgure 1-1) one pentore to arnlherpenrm

E %cadmy mucM* of &lc acids. TheYjcondarystructure of DNA

referr to tts dwblesfranded duplex structure. Although RNA Is almost
ahmy a rmgle-strandalmolecule. ~tcan bend back on m d f to form
r e g h of double-stranded~condalystructure
1. 8.u pairfng. The double-ruanded Nucture a stabillzed by bare par-
IMJ b e e n purine and pynmldlner. Complementary barer that I.sCnnium=nudeofKkw-
~w~aan+vnGmdC(lnnhbNAandWlLAndT ~s~nniuk=b~heC%wkhm
fin D W , and A ad U (in RNQ

& C&+manded DNA

hM*tarY- ,
. w m an Rh*\
RNA and DNA
 are alrrayr olknted m an ant$raallql fah'mKM QM %and ~ n r
mUnl'ta5'W-andbhe~mmthePioYadn. '

5' 5'

hgure 1-2 hJb&tmnded DNA

3 5abiUrlnstwre*Thetwostrandi~~hd~tegetherbytwotypaof
~hydPogenbond~ngsndhaP~.
C ~ b a u l l n s ~ b 8 u p r 4 d . A - f W l W b a e ~ w r,
PR &by two hydrogenbur& t & p i~r k rfobi-
l l e d b? three hydrogen W r B ecaw of 6 9 BaLR hYdK*FM
BMI(L .6C &?a Mpmvlde b e e ItPbWm fIfIWduaCea
@#Wntl~mdo A-T or A-U pain. I s * ,
b. slre rtaclrlng lnteractkm. The ring aruawerd.&-iM
Rynrntdtner are sacked owr ons anather ln the rnt&r c4 the
double hellwl strutme, Hydrophobic bteracuom beween adla-
e-
a n t purl* andp@midine rings add rtablllty to the double hell%
The b a r i n t e m t ~ o n rare ~nterruptedby a number of
\ntarilfd%q qMnts such as actlnomyckn D. which have been
l m to %IdenI" k w e e n ne~ghboringbare pars I" DNA
Tkas4 agenu prevent DNA from serving as an effectwe template.
Winhibit~ngreplication (DNA + DNA! and tranunptloqKINA + >.
mm).
TOPOLOGY OF NUCLEIC ACIDS
DoublestrandedDNA may be ebther Itnear or circular MoR DNA forms a
nght-handed, antsparallelhelix.

A C o ~ o n ofrlinear DNA. Lknear DNA 6 the form of double-stranded

DNA found m most eukaryouc chromoromer Three confwrmtlom have
been ldentlfiied
1 6 DNA IS the most common form of DNa It a the c h c Watron-
Crlclz nght-handed, antlparallel, helicsl structure of DNA tn whlch
the basesare stacked upon one another and are prpendcular to the
axls of mt helix. The hellxcontam two g r a o w a major wld a mnor
groom, t h e t 1 5 r e r e DNA-pmtelnlnteraNonraccur
 . <
!p : bz-x*I,
mb.wourQIncniBhqh(R-#4IhrwirNdrD.
sd la tkr (Nreetla @ the inWl& wind@# sf the
helix.
2. MpOhMm.Us ace enzynws that relieve the Wnrwn by
-As In rcplnating DNA These srvyms make w& break
In the DNA by d i n g and rriullng ph~lphcdaterlunuk In the
~rhakswu~o-rn p.MI*.bnh.pllmniMramm and arpa-
-rmhc*m
sc~W&WQq*(l*fo (m.80th UTP and CrP are dwkd from OMP. Thymidma
"b"P@QqP
 nd function of the cell nucleus,
and mitoris, and the reductive

nr required for DNA synthesis. Additionally, there are reverd.

made rphnfneourhr or by ennmnmntal in*

I
NBDE 1: BIOCHE)V~ISTRY

2 RtJA symh*. Tranrnptm of DNA lrno RNA accurs ln the nucleus

of eUkaWic relk by three dldnct RNA polymensM, each rynthesu.
e
mg a different class of R N h
3. RNA bwcesdw. In evliaryotk ce& R?4A $5 syntherlzedas a prec-r
tlwt is convMed to mature RNA in the nudew bv a number of stem
collectively k n a m as 'processing."

8. Stmmm. The nucleus 1% the most conrpicuour organelle m eukatyot~c

cells. It contains almost all of the Uliular DNA and micrompy reveals
the foilow'mgrtNrturalfeatures.
1. Nudeaf UIY.IDP.The nuclew 15 K p a r a t d from the cytoplasm by a
dowe membrane (inner a d W r ) The outer membrane ts cornmu-
w s with the rwah endoulasmr ra~culumand therefore s a nart of
the endomembnnwr rylhn The Inner and ouar membranes farm
two concemrlc ringsandare ~epsratedby a pennudearwmpament
2 Nudear hmm The irmer surfen of the nuclear envelope k Innedby an
electrondenrelw cndatnlng thnte m a p pmteins T h n network of
protelns plays an vmpwtant role m the muaural wganlzatlar ofthe
nucleus by providing w n w between the Inner nuclear mem-
Ndearlammpmtevawe # w m a n f m brane and the chromatm
nuckw&mWand mammW dur-
g mrmra and maws
m 3 Nuclear pons. The inner and outer nuclear membranes are fused
together at the pores, provldlngchannels of communlcatlonbetween
the nucleus and the cyt-l Waw, \on$amno a,*, and small p o -
teonr can freely pars through the pores The pores a n auoclatedwth
pmtclns that are requ~redfor tranrpon of large macromolecular
c o m k a s Into and out of the nucleus. Tke number of nudear pores
k usually f i in a part~culor dl type but may vary at Ulnes h rela-
tion ts the tramcriptional Wny !n the ell.
4 (hmmath The chmmaroms and chramstin are cornpored of DNA
tho%IS &Watd WHIhkione5, a family of pollrfw4. s h a d po-
terns
5 tducleolus. The nucleolus br a v w dense region contain~nglarge
amouna of RNA and !t fuMlom as the rite of n b m e assembly
The nucleolus a .pociitedrrith the n u c k organuer region (NOR)
on the chromosome The NOR of the DNA contams many copter of
the genes for rlbmomal RNA. Electron mrcrowopy reveals three da
tinct zones In the nucleolus The periphery of the nucleolur has a
granular mne that cmtalm rtboromal precursor psrtlcles an varlour
stages of assembly The central reglon has a flbrlllar zone conta~nlng
nbonuclear protekn flbr~lrThe DNA I" the NOR reglon of the chro-
-me Is a pale-nammg regton of the nuciwlur
b
THE NUCLEUS, THE CELL CYCLE, AND MEIOSIS

The cell cycle begins when a cell comes into existence and 4when the
dl dm- into t-WO daughter cells The cell nple canb b Pl into two
d
v
M
maw wmpmms lmarpha~and cell dtvluon WeUte 2-1)

FigureZ-1 The celicycie

1
a lmwphaw Is t h e perbod of the cell cycle that precedes mttoslr It can be
svbd!vlded into three parts (GI,5, and 62)on the basts of d~xnneevents
occurring dur~ngInterphase

1 G, phase (gap phase) 8s s penod of cellular growth that precedes

DNA ryntherlr In most cells, G I la* approximately 12 houn Durlng
IN A
.
NUTSnELL
thos tme, Ihpldr, carbohydrates. and pmtennr are rynther~zedIn rome
cells, GI may be very long For example, In musk and nerve cells GI ~ d s p e d c mtherdifferentbfedfunc-
Is so long that It seems the cells may have completelystopped cycling
Such restmngcsllrare mud to be on a specmi G I state called Go
.tim whik in G, fcf G.)
Mimchondria and centrioies. which
mnein DNA drwde during fhe S
2 S phP.(symhsn. w u l l y bB for 6-8 hours and &tIncludes P M
the emtre pertad ofDNA rynthera and chromosomal repllcatlon The s wring G, each chromame cons&
rate of RNA ryntherlr i n u e a s and the cell preparesfor mltws of trw rim chmmaMs, mnertedat

3 (ir phem IPb between 3 and 4 hours, and resgmblestheGI phase In

t a r m of cellular actlvlty, except that the cell IS now tetraplo~d
(diplod x2), whereas m the G I phase lt war drplotd.
B Mltds IS the nuclear d8vtsrc.n of the cell, rerulting In the reduamn of
the rhmmDxune complement from the tetraplord ta the dlplotd number
fwnd In each dsa&ter nucleus Qtok~nerir a the d~vlrlonof the c y t b
plrm, reavbng m the emlosure of each daughter nucleuswlthln a Spa-
r a e &I rll- hownn Figure2-2, mttws I$
dormled into six phases
I

9N MEDICAL. &i
 Fig&= etarerofmm

1. Pnpq*ahmcchmanr~canloMeimor~k~
l i 4 r m m f i t b F n u c k w ~ ~ o f ~ ~ I B e a m r c -
tuns) 9 e W I O m t+a-.
+ 3 r'
z ~ . D m i n @ ~ s l a s ~ c o a & r o f e ~ r h ~ m c m
upac8t.d l&-v&e Inm . M n ~ s h r m o r c m e wlied
r p
r~&. The mdn $tfuctUN1mmpo&i of the mitonc appar* k
the mitaticrptn4,ryMm begins tu form n w the end of pmphaa. @
When tb cmtr3der bsgh to separate~-8Cq)clr+r& rnwafubulea
~ n d ~ W I end
b s of prnphase,

rometjds bagin to rpllt long~tudinallyand Ran

trr A nvt9rrror pole of the cell Once the chromatldr sp(h
wriMpkaiqeichdmmmemn-
m m m m n g s t e at the poles, and a cieav-
- w v k to f w n markmg the beginning of W n e n r
tsbr-
ia ~&&uI fwms and nuckar envelow appear around
cadi gmupdtdaughter chromoxuna The ~onden5edchromatin
expsni¶s win *nd begins to reappear The wtaplarm dlvldes by
'
3 decpannngthe deavape funow untrl *form twodHlghtwcaUs,thus
mmpletlngcvMWmis
3
 ' .
8 @wnd moiota d i v M . Thcs 6 shown In Flgure 2 3, step G, and the step
1
.
DunwmnarllsMw~of~
*

*e slmllar to those ~n a mltotir dlvlnon, except that no DNA syntherlr

+urs Prim to thw dlvlsion The 23 chromoromer d ~ v ~ date the cen-
23d-mfe mefinal& ' Brnere..and Mch of the newly formed daughter germ cells receiver 23
~~~mfranwkw 'fkromPtldx Therefore, each germ cell now has a haploid number of
okmmowmerand half the amount of DNA of a daplotd somatic cell
 DNA Replication and Repair . fO
b

Genetic mfarmatlona trananmed fro? parentto pmgeny by repll-

canon of parental DNA Th0 procasafreplcation requires a num
k of pmemr, xlme parWfw& ar enzyme6 in the polymerizat>on
of nuclwhde, 0% are rerpensibdg for u ~ n & s the dwble-
strand& DNA hell%hbldingit apan at the W M o f repliratfon and
preventing ~t from tangltng Maintaining the stability of the
genome depends on a Mmber of repan ryr(cmthat cMnd aca-
rional rmstak~made' during npltcatlonor mat o a r after rdm-
tlon due to anvlrmmental rnrult Thtr chapter review the baac
@ concepts underiylng DNA repl~cstion,the prote~nrand enzymes
involved in repinetion and rome of the rnechansms that have
evolved for repalrlng DNA Inhibitors of DNA repllcat~onusad as
. chemotherapeutic agents are revbewed, and some cllnlcai abnor-
malltles asxlclated wlth DNA repalr are aim diwurred

DNA REPLICATION
Wzat ofthe detailed aformmml about DNA replwton hpr been obtatned
from m nttu d i a wlth E mli DNA Although DNA repliution in eukary-
. otc %ptem s more m p l e %the same barlc concepts and mechanisms are
invohrsd
;q - A Mnmal concept%.The purpose of DNA rspltcatlon IS to create two
&ughter DNkmlecuier that erc identicalto the parentdl DNA This Is
whlwdbyaemicwservatiw replidtion (Figure 3-1)
1 Smubmmwnive r e p l i d o n user each of the parental strands of
DNA m a template for direclrng the synthens of one new daughter
DNA nurkqb.

KAL
 mokulc tM ir required by DNA polymerase

a free 3'-OH group. The primare does not require a primer for
tlon of polynuclwtide rynthark.
5. Hell-r. Unwinding of the two swards in the DNA helix must

of DNAto sparate ate replicationf o h

6 Singlertrand DNA biding (SSB)'pmtdns. Thesingle strands

,.i_&plicatiar fork There enzymes cut and reseal the DNA.

Clan I topoisomeas%do not require ATTP.

. Clan 11topoiromaraser introduce negative wprcoilr in the DNA
molecule. Thb process requires ATP and involves transient break-
ing and resealingof both strands of PNA.

DNA unwind, a fork-ryp structure is formed that is referred to as the

kI fragment$, which are thenjoined t

 figure3-2 E w k at the WIrcabon fork

IN A NUTSHELL 1 Unwlndlnq of parental DNA. At the rlte of repljcatlon, the two

parental stramis do not completely reparate but am unwound In a
8dh pkarpw and eukaryotr mdP

.
locallred region k n m as the repllcatton fork The repljcatton fork
vheur a MI-d
can move In either d~recOonfrom the orlgfh of repllcatron (or,)
DNA replembegmatan .M"
sequence m DM Unwndlng ofthb hela n the IeplIMlon fok IS accwnpl~hed by heL-
Two rep,rcaton fwCs form at each on case, and the w r a t h of the single strands 1% maintamed by the
.wte and mwe rn o p p m h ' d t m n s
E colr DNA mnGHnr a snde 017sfe,
whweas euCarphc Jwncwvner
b d n g o f several m o l ~ u l eofsmghestrand
2 Sy*M
r bandtng protelnr
the leadlhg mnd.A t the rep4lMlw1hrk. OM strand IS
each mntam many M ster rymhenzedc o o r h u w s In
~ the 5'10 3' dlrectlon as the parents DNA
duplex molecuk unwinrh Thur. the W i n g srand l compkmmtary
t o the paremal strand mat runs ~ntho 3'to S'dvecwn
IN A NUTSHELL
3 5ynthsrir of the *gglng RIund. The laggng Ifrnd tr also rynthe-
in baih e r y o t e s and wkwtes slzed m the S M 3' dlredlon, but the ryntheslr occurs drrmntmuoudy,

.
DNA rephcauon a r e m & m n M
m~"gstrands"&emhm
Uour/Y
producmg small fragments (approximately l . ~ Z , M Obarer) known
as Okazakl fragments There fragmem are later jotned by DNA llgase
t o form a mnbnucur lagging wand
The laggngstrand a made m drscon-
f m m O C 4 f ~IG$WI~ and men 4 R N A pnmarr. There Is no knarn DNA polymerare that can ~nltlate
pried
the polymenzatton of a deoxynbonucleohdecham Thus, the synthe-
m of both the leadtng N a n d and each of the Ohzakt fragments In
the lagglng Nand rtam wlth a short RNA prlmer (approximately 10
baser) The prlmer a complementaryand antlparallel to the 5' to 3'
parental strand The RNA prnmers are rynthenzed by a prpotebn m m
plex c m n m g both rmgle strand blnd~ngprotelnr and pramare Thtr
complex btndr near the repltcatvon fork and mover along the lagglng
st<& ar &.a opened up by hellcase The 3' OH of the last nbonu-

edd
A
KAPLAN MEDICAL
 F
DNA REPLICATION AND REPAIR

ckotide In the p r i m rerver as the mrte at whKh the Rrrt dloxyri-

bonucleot~dns added by DNA pdmera% El-tam of tha DNA
fragment ormnuntd It appmadleranother RNA pnmr
5 C a w y s l o n d O k e z a k l f m g l n n m m 8 ~ ~T .h e w
momnts are evamualk b i n d to fonn a comlnuw strand
that corn-~nsno RNA Thlr Ir acmmplkhed by iwo muentml reac- /
tiom. When Dypolymerase IIi appmPmer anathot RNA primer, rt
dfrpoclater and DNA polymerase Ienten M A p a l y m m I remover
( e m ) the rlbonucleotider one at a time from the 5' and (5' to 3'
exonucieaw activtty), then addl complementary deoxyrtbnu-
clsoudas to fill In the gaps Finally, DNA lqarc farm a phmphodl-
ester bmd betweentwo a4Kent DNA frapm~ts.
D I n h l b b n of DNA ysllutlon. The synther~sof DNA Is lnhlbited by a
number of compwndr, most of whkh a n eNlcr analogs of purines,
pyxhidiner, or follc acld mess compounds am frequently used as
chemaherapubc agenu becam of t b ~ab8Irty r to d- the rate of
d ~ mof ~rapidly l smwlhg cancer celk
1 mrtm mwiogs. The most commonly used purtne analog lnhtb8tot-s
are 6-mercaptopurlna. gazaguanlne, and 6-thloguanine
2 PynmWne ado$% Analog such as 5 fluorodeoxyundmne and 5-bro-
modeoxyuridms lnhlbrt thym~dylatelynthase, an enzyme rr~ttcalfor
DNA ryntheslr Cytorlne arabincrbde s an malog of rytmane nucleo-
rtdes m whtch the sugar morety Ir altered insertion of thlr analcg
!moa DNA cha~nstop elongatlo" of the cham other .di+ud&era

3 F o i acid
~ analogs The synthesis of both purlner and pyrtmndlnes
requnrer follc acld as a carrler of C1 fragments The tramfer of a C1
fragment from tetrahydrofol~cacld to an acceptor reruitr ~nthe 0x1-
datlon of tetrahydrofol~caad to dihydrofollcac~dIn order to recycle
the coenzyme, the cell requires NADPH and d~hdymfollc ac~dreduc-
tam There are a number of f o i acld ~ analog, such as methotrexote
and ammopterln, that spec~flcallyact as powerful competltlve
mhibttorr of d~hydmfolcacbd reductase

DNA REPAIR
The structure of DNA can be a b e d I" a number of wayr incorrect bases
may be I- during repl!catton, or changer can result from exporun to
ultnvklst radiation or chem~ralrfound I" the envnmnment. Stveral repair
rymnx hwe that correct many of t h e changer
A. ~ ~ y s n d d e f i n ~

$ 1. MuP(ia,k s hwrtabie&an* on the nucleotlde sequence of DNA

2 M
- s a chcmiral that &err the structure of a base in DNA

MQkWMEDKAL
 3. Po(nt rmUtion is a change in a single nucleotide.There are tw
of point mutations: transitions and tranrwrrionr.
a. lb+bm is the change of one purine far anothr purine
one pyrimidine for another pyrimidine. Transitions owu
from mirpairlngof baras during DNA replicationor fiom
inruii For example, nitrous oxide converts cytosine to

1 clynmoval o f w r m r n o group onthe cytosine nng.

b ~ m m t h e m ~ ~ a ~ f o r a p y r i u n e o r v ~ 4
VCM.

B 3p0r d D N I mp& UlMy of WR mistakes mcurnng dur~ngrepllmkon

a n nnnctsd by the pmokesdlng(Y to 5'manudmm) a c t ~ Wof DNA
41
polymer- Mdttha1 m d np*ir d a n k ex& which mmct
akeratsw dw to Chenbcaiff envmmnentsl injuk
j
r ~ucireW cxririoa.~epslr merhanlsm of UV-damaged DNA.

I u b i a k t light tnd- the formation of dbnen between adjacent

n w ~ e insDNA bualb betwsan adwont thymnu) The forma-
tion of ~ h l d i n dimen
e prcwtr DNA tEf41catlonand normal gene
expnrrion. As- in Figure 3-3. fow atop5 are ~nvolvedin nplr-
ing this damage
a, hdrlon. A U V - l p ~ n f tendonuciaase recognlzer the damaged .
DNA end N k e s s nick in the phesphoderter backbone several
b.srrawayarieachsidsdthdimn
b. @wrvaI. A h e i i c b tn the same enzyme compiex removesthe
oligunudeottde.
c Wiymerketia. DNA polymerase fdlr in the sap by addong
nlxleotldcr. NWng whh t b ddMon ol the fim nudeotlde to
the free 3' OH cyow c r a w by the h ~ k l o nand moving I" a 5' to
3'rkremon
d Ug.tkm. DMA llgase f 6 r s a ph- band &tween the
hwv WYAsegmentand theoriginal DNAsfmd
2. Bas excislm w i r . The mast c o m m bare vanntfon k the deami-
nrtion of cyt~slneto uracil in the D M depiex The deamtnatton
Ie- an impwpr bare p i r &n the n*K, strands (U-G imtead
of Cd). The repair mechatl~nfor thb typp of damage lnvdrer the
faw
il ng *w
a R e d d th uracil b&. A uracd-DNA glyroridase recognlzer
the mismatch and hydrolyzes the N-glycor~dcbond beween
uracti and the deoxyribme mojeiy, leavmg an apwinidmk site W
rite) in the DNARnnd
b. c h v . 9 . d phosphodlmw. A r p e o f ~endmulewe mognim
I th damage and wcks the pho$bdioM bMoI to the

11 mlrstng bau, thui reiwss&gderoyrfbpse and creating a gap

Endo-kares thY rIeane at a~rimidinicsites (or wurinlc slterl
below to a family knwn as AP nurleess
r ~ ~ d - g l l . U d C I D N A p o l y r n w a s e
Rllsthe gap, and thenick a real& by DNA imart.
 h eelnrnwaikmk a change in a nngb nucleotlde.There are two- @
d point-uandt~om Mdungemm
a. R ~ I I ~ ~ o f o b ~ r i n e f o r a n a h e r p l ~ l e o r o f
one pyrimidine for M&er pyrlmidlne TransWom occur elther
from rdspnrlng Of Ww&ring DNA repl~cat~m or fiom chemical
mr& Fcf example, n l w axids m m q t ~ i n e to wadi by
tbr mmovsl Mths amino gmup a t h e NmriM ring.
b mUawmion is the exdlwgc de purtne for a &d?dlns or vnce
VeNa.

B. of DNI @, Many of the mrs&W ecannng during repl~cauon

~~reasdby(tr.pmofwdhg(3'toP~n-la-dDNA
polymW33%. Addit*Hul Nper of nglcr lw&niina exla, Wtch mrmd
a k e r a t f o n s h * t o ~ l f f ~ ~
1. Nuclmafld. excirbn-mp8lr rneduldni, UV4mnag.d DNA.
IN A N U r S H E L L llhiwhfn light htndw tbr formaticin & d m befimn&jam!
~ ~ n p a r ~ a *dinas
W In DNA (uwallf bswm @pmt?AmIwd.Ttie forma-
duaerurtl~errrwnh~~ rionMpyfimia~nedlmersi*a~D6a*W1cationand normalgene
rn~lmMer cxpreston. Pu rhourn in Rgun 3-3 are involvedmfepab
ing thb damage.
a. lod.Mn. A UV-@kk$mlonMw recogntzeathe damaged
DNA and &e# ilnick'ln the.phaphodleste? backbone ~ v c r a l
bosraWQ)mthddr*€beW(ner. '
C. 4iamod. A htkMin tM IMe enzwe complex removes the @
el~gdnwlsn~de. 1
c. PaIyrw1iamt~l01l.b~~ polynferaaa fills in the gap by addtng
nacketidaz ryrtlnp @&lk+Tmaddlrton of the first nutkohde to
the Wee l Oh gmup ctwted by the m I o n and mov4ng ma Sto
9 Wreaion.
d m. WA 11- e m r a phos&odlestef bond bdween the
WDNAsegment and the origtnal DNArtrmd
2. B.u 6rdWnn Ap.k The most common base transition is the d m %
nation d qtosine to vracli In the DNA duplex The deamfnation
laarrp an imprqm b . 3 ~p i r batwen the two s t 1 4 (UG instead
of C-G) The eepSr &lurm fmt h m d damage i dthe
foliowilq step%
a -1 of th uracil bdre A waol-DNA g l y c ~ k cecq)ninr
h
the mismatch end hydrolyzesthe N-glyc~rld~c h d between
uraol andthe daoxynbose mole? leavingan apyrunidlnicrote (AP
wt*lnthemstrand
b aCrvap8 d EWSIIIIWIWU. A sped!% &udease recognizes
G - I e & ~ e a n d n i r l D t h e ~ ~ a d ~ t o t h e
midng bare, t h i retwing dexq&?qand creating a gap
Endonuckaresthat'ck,?~ at ~~i sites (or apunnlc sncr)
~ n g t o a f a m i l y k k D w naAP-
c -daa*W-vrrlm DNApolymrw
filkthepp,adthenkkis~byDNAllgase.
 '2 -.
B
P
,:-,
.-*-a
DNA REPLICATION
AND REPAIR ,
I

m11711mrlTllnllllmll1TT
@e
r" 3-3 Nuclmtrde ems,on-repair medranrsm far Wdamgd D M

c Dh..rcr a d a t e d with DNA repair. Smce repalr mechanm play 4

an mponant role ~nmutation rurvelllance and prevention, bnher~tdd
dekca that alter the act~vitlerof the repaw enzymes can lead t o dram&
i-ws ~nfrequency of mutatlorn Seve-I autmmal recesswedlseams,
such as xemderma plgmentora, ataxla teleng~ectar+a,Blwm syndrom
and Fancon, anemia are asmated with enher documented or suspects4
defects ~nDNA repalr mechantrmr All of these dlreaw~occur wlth hlgh
frequency and are arklcmed wlth a predspmltlon to mallgnancy
1
1 Xamderma plgmentora 6 an autmmal recessive tratt characterized A
by enreme reosluvlty t o runlrght skin changer, and a predlrporlt~on
to malignancy The dlseare results from a defectwe exclrlon repair ~autosomalrecerwede~c/It
nudeotrde e~lronw a r whrm
rnechanlrmfor W-damaged DNA
2 Ataxla tdngiatwla s an autwmal receulve dlmrder charabenz~d
by hypenammvb t o fonrzfng radiation, degenerat~veataxla, dtlated
.m-jmapmtosa
A" ama, &ficw&
k w s i w repawmuikmatmd
blood verseis chromorome abenat,ons, and lymphomas The dlreare waW1eRaya
mvltr fmm a defect in AP endonucleare

KAPLAN MEDICAL
 Transcription 17
b-

% pmcerr of making an RNA copy of DNA ilcalled tranxrlptlon

end is catnlyzed by by RNA polymerase. In any part~cular
regmn ofthe DNA double hda, mly one offhe two DNA strands a
tramcrib4 lnto R W . The RNA strand k aiwayr synther~zedan a 5'
toB hrprtlon but from an entiparallel and ~omplementaryDNA
template strand The completed RNA w mndwe amparallel and
complementary to the template or 'mtlYnse" DNA strand The
RNA lr, however, parallel and tdenMl to the 'reme" drand of the
DNA duplex (except that lt um uracil instead of thymine) Cells
contain three types of RNA, each haulng a Urfferent functton
Messenger RNA (mRNA) carcler the rnfcrmation rpaclfylng the
ammo acld sequence of protens, Transfer RN4 WNA) and rlbao-
ma1 RNA (rRNA) play important roles in p m n synthesis Tha chap
ter wlll review the key structural featuw of the gems mdrng for
the three dbfferent types of RNA, the tramuimnal machmery, and
the step lnvolvad in the process of WehViptton

STRUCTURE AND TRANSCRtPTION OF PROKARYOTIC

GENES
In prokayses. both the gene Nvcture and the m ~ h m r for
y tranxrlptlon
are wnriderably rtmpiw than m wkaryotlcryrtpna.
A DNA 0hmenW. Sper~fic
sequencer in the DNA ad as stan-and stop sgnalr
R fa mnwriptlon
1 Bdni.l promoter meion. lhe reglon of DNA that binds RNA p l y -
merasa and allows tranxriptlon to be ~nlttateds known ar the pro
mom regton. As shown in Figure 4-1, the promoter regran cntalnr a
staning point at which trenscrlptmn rn mittatad and hvo consensus
 a
464 KAPLAN MEDICAL
 FJ
i C ,
Y 0
o-CI
2 GG
C-G -
I" w -
.*,$*, - A
wA -
a
IWA tfor&n&tt
\

art~trthrt~ R N A ~ W R

6, -&&q
awt i r g r s a ~ t l m5B
lo pro*sf@%kwWq d f o m o f R N A w
n &arw~.
~ ~
.WtheRM-aSe
~ & ;
*@ ayne~lenitgd~-r~hww~~ 1
I. MKR&&W uu; n u l ~ ~ m t ~ ; r y m c b xtwo
poithir ~rtr~ d
~ a u w e n z y m e a n d a h o l o e n w h ememraenEymeherfirur
3 t h n - a -1, k a i l k ti Dolyrnert2bq ~ ~ W It ~ e %
dpss rmt r e r ~ g nuromotsr
l~ regionr m the DPIk 'Re h p l w w v e i
has an additloml *ma (4submlf that all- enzyme is-
nirc pmnbtPrre(luences 1
- a
2 Ragyinolnlr fw BNPI rymhab. The synthssr of SNA CemIlrer all
rwr r~boiluc~wtth CATV, ~TP,,CTR and up), a tiluaJm'6wiian
IN " I
-a
kithw* or ma%and a ~ p t ~gubtes~iwdd
e DM is tha ~~llynthsrw
pdwmd -law, bur dngle-$trsnd.d DdlA can a h be w d .
af s'te J: W earh m a b
n ~egur,~~p~ldelwrmrnpk
mgllfWmM?E
'4
MWaacfnd.&-- . C'Wmsatedd@naolmpdmb
r
eqw

465
c 5- w In tunrufptiolr Trinscnwien m prokaryotar involves @
t h 9 nsps:idtWW elongation andterminntm.
1 InHWon&isma wbunit~fthe maholonrymerecegniresmmnuus
WwmWh tb Xpl- MI& to DNA. a d heipsunw~nd the DNA
~ h e T r ( ) o t h a t c m ~ o a n x ~ u e a s a t e m ~ Inl*sllm
.The
nbonucleQti& ft!@m@& k LnuaIiy a p u r h (ethsr A or G) ~ f t e r
the am fea phmphodfertu bondr am formed, the sgnrs rubunit
dtraoc~aterfmm the Woenzpm m d the core ws#me begins e l m
gatton
2. Ebnaatlon. The core enzyme m o m along the templW+rtenLng
the RNA cham, and the ngiw of Ewl unwmtltlq) m w Prlth k Ar
the enzyme leave8 e region. the DNA duplex +ud W k dis-
placvd as a gmwlng imlynWckat~de dvlin. Gravth of W mdtr k
alwayr In the 5' to 3' dmction. RNA p o l y l ~ ~ ~cno~~Ilm
are the
DNAtempiatestrand lnthe 3'm s'dlremon
3 Tmnlnatlon. The DNA template contains Rw n g ~ l for
s tranrcnp-
tion, ar dnnibed above in paragraphA 2

D Inhlbitws of pmluryotlc tranviption. Many antlbnotta exert then

acSbn by ~nterterlngwith barrenal RNA or praieu, syn* while hav-
h%g no effecton eukaryotr RNAand protein rynthair
1. Itifunpin inhlbRI miuation ofRNA synthesis
2. D b~ndrto DNA and inhlblts RNA rymheais by blocking
mwement of RNA polymeras8along the template
3 UnpOdydiglnbinds to the a rubuntt of RNA po+m and bl&
donsetion

STRUCTURE AND TRANSCRIPTION OF EUKARYOTIC

GENES
Both the rtrvcWm of eukawtlc genes and the mechanlwmfor tranraiptson
are more complex than in prokaryotlc system

A. wmdptlml rrmrhh.ry: three RNA polymeraws. Each type of RNA is

namdkd by a differem RNA polymerase.The requirementsof each of
thae e n w m are the same a for wokaryotc RNA polymerase. None of
the UNA pDIymerurJ have the proofreadlnq act#vlWesthat DNA oolv-
mmrw have
1. llru tmlymwass I IS localized en the nucleolus and tramnber the 4
g e m for three types of r l b m a i RNA 285, 185, and 5 8s mN&
*NA kthe rnmt abundant RNA ~nthe cell
2 M A palynrrrma It ts found I" the nucieoplarm, wtlere it tmnxulk I
g e m coding fw protelns The pnmary tramcriptf rynthesaed by
RHA polymerase I1 are known as haterogeneous nuclear RNA

KAPLAE(F4WAt '
 @ (hnRNU, whlch are p r e c m n fbr mRI(A and SnRNA ( m i l nuclear
R W ) . The snRNAs Wl-U5) am a part of the "rplloea$pms" a rom
pkx~~Evedkrnnwingntran~immpransorANAmd-,
RUM
3. IUU HI ir brated in ths nucleoplPsmand transcribes the
westor ttansfu l a A ItRWUId 5 S r r M
0' SIAllhUOaDd tlMOIPtlOflof rwsonwl ANA 9eMl. Tk pons COdlng
+or rRNA are tnWblbed by R W polyme&e t ~ n 4 i i c ~ u c l e dThe
~s
nuclwlus m M n s l a w loop of DNA fmm -1 chrom- ea4
contaming a cluster of genes tor rRNA Multrple mptm of the #ens for
RNA are tandemly anangad $0 thM each gene Ir~ppuatedfrom the
natbyaspaw.TkgilmmRNAtrm~pt~~~pwarba
~SANAtha~1verasa@~wfo~lS,5.285&SlfirftHbThrpi-
mary tranwript dm containsspacer regons &anhot Clrs rftN&.
The spacer regtw. are r e m o dby a rnkr o f w & n w k W ag%
Proc-ng ofthe precursor rRFlAmlbbrqu~molar amountsoftMchof
three typw of rRNA. Follow~ngthe pmsessing, the ~ R N &spocb are
medlfled by methytMion of speelfic 2'4% ~ U Q P Wj
. rC*dlen is
-beltad Po confer rtabllity on the r W molecubs end proYWQlwn
from andanucldykk cltavageafter mLoTporat+mWariQolonar-
C. Genes coding for protein. RNA polymeraw I1 is found ih the nucleo-

8 plasm, where ~ttmnrcrieerthe g m a % a e W w f H be transl%Winto

protemr. RNA plymeraw I1 carmot inltlate traWrptiMI laaf and Is
absolutely dependent on addmonal protern lIhown as trsn5Ylptbnal
factors, that anat pmmoter rrter
1. Start rite. The Initla1nucleotlde ~np t t i o n +Iof me RNA tramcrlpt Is
usually& flank4 by pyrlmrdmes
2 Pmmomm. Then are two common sequencer I" promoters that are
utilized by RNApolymeraw I1
a TATA box (Hognsrr box) Thlr sequence of base palo. whlch Ir
Important m the initiation of transcription, is found ~nall eukary-
0% It ir loratcd approximately 25 bare pain upstream (-25) fmm
thamnpormand IS aim- idMticel to the Pnbnow boxfound In
&I m m s . TFIID, the cntkal transcription factor for RNA
&yn%sa n. bindshwe.
b. ClUIT ba This sequence n usually found between porrtcon -75
and -80. but ~tran functkn at d l s t o m that vay mslderably RNA pornerase fl initiationq u M :
r r m the mn point. Smnding of tramtription facton at thtr site speofk uammptnn facmrr bound 1
may influ- thefcmmion of lnitmlon eomplexer 81 other sits enhancersequencer
General transmpm facton b o d to
., 3 Wlmtocy ngionr. Sequences W either Increase or dweaw the pmmDtOISequeMeS
r e at whlch transalpon ir hlt(s(sd by RNA plymerase It ex#* at A S C O of ~ pdympd~en wrn
~ RNA
uanscnplnvr fachM m fomr ,",tram
uarlous placer on the gene. Although they are usually located
mmpk
upmeam from the rtan r@they may aho be internal to the gene or
 - downstream from the gene, Enhanmr sequences bind tranvriptim

muenmi bind tactom that dmess tha rate oftr-iptlon.

4 Exon and inks. The sepnt(d of the gene that E maima~nectm
the mmrc mRNA andcoder tor prQtein is known as on exon.
lntrom are the port(ons of the pnmary RNA transcript that are
removed by @king together* han (Frgure 4-31. The spi~~ng wu-
......
ally aCIIm at a uonrwr. w m u e I U AG) found at me bound-

primary h n R tramcript
~ s 4 &on 1 Hexon 2 ~xo4
n k3'

Mature mRNA

Fgqm 4-3 hnRM andmaNmmRNA

D Ge
m -for WINA 4 5 5 rWI. These genes are tnnrcrtbed in the
nucleoplarm by KNA p4ymwae Ill.The pmmbten for both the 5s mNA -
and the tRNA gem, Brh internaland are f w d darmdream from the
stargomtof tr-wn
1. 55 -gar Ex gene for thn d l RNAarp tandamly repeated
In r ringlo c h a r bated far w a y from the gem for t R N k These e
2. tRNA g6nm. The gsna-fortRNA a n &Herd and are trpmcr~bed as
laqer P ~ P N M TRNA molecular,which arepm(e&$y mdonurkar-
er. Internal m m a n found in ma m i o m &mm&eamfrom
the start slte tRNA is subject to a number of poatranxripttonal
modlffit1on% Indudha mcdificatlon of Uleciflc hand the add,-
tion of the requenre -CCA to the 3' OH ofthe tRNk

PROCESSINGOF EUKARYOTK BNA

The m m s nudear RN& (hnRNAr), rynthaa~iradby RNA pdymsrare
11, I w e the nudeus as messenger RNAr (mRMAs). The procerung of the
MRNA stam whUe transalption s Rill ocEunlng and lnvolves wvaknt mad-
~fiution of bornthe 5' and 3' ends, foil& by W i n g and splidngto eUm
i m the interveningsequencesthat s e p a e t h e codtng reglom.

A 5' Upp(ng. The 5' end of the RNA Is "ce$qadmrhwnyeftertha initiation

of RNA synthesis Thlr process involver the a+~o
itn of an *&mried"
methylat& guanmne d e c u l e to the f l m nude&& n the RNA tnn-
wrtpt The 7-mmyl-guanorlne is linked through a 5'4' tnphorphate ,
'tmlrag The 5' o p playa an ~mpnfantmle In the InitgtrDn of prcwn
syn- and in pmtenmg the mRNA cham fran drprad*lnr

K A W M!X@@l
,+-
-~-*
&,#&#&& e *-... -
 8. Polyadenyiatlond t h 3' OH end. Mature mRhlA mokcules have a p l y -
A tall that Is between 20 and 250 nucleotldeslong The tail is added to
hnRNA by the enzyme poly-A polymerare. A wnsensur wqwnce near h u r e in eukatyotes transcripm and
the end of the gene prwlder a signal that lnlttates polyadenyletton frambhonare not mupled, the pnrnary
Polyadenylatlon s believed to inmass the rtabllky of hmRNA. Not all transcript(hnRW is exfellsiwlymodified
in the o u c h . v+dina mature mRNA.
mRNA molecules are polyadenylated hntane mRNA%,for example, have whch IS then t;ansp& m the tyro-
no ptydtallr plasm for translabonrnm p m m
C RNA rplidng hnRNA wntatnr codtng sequencer (exonr)that are reparat
ed from one another by lntervenlng sequencer (mtronr) In the conwr
rlon of hnRNA to mature mRNA, the lntmnr are remwd, and the eronr
are spliced together Dunng the exclrlon of Introns, the 5' cap and the
ply-A tall are not remmd The base sequence at the beglnn~ngof an
intron 8s GU and a t the end of an lntron IS AG This consensus
sequence defines the sltes at which Nnlng and rpllclng m r The lntmn
a exclred as a Imp (lariat) of RNA that IS degraded Followtng exc~wm,
ligation of the exonroc- These reactions occur tn the nucleus

1
KAPLAN MEDICAL
 Regulation o f Gene Expression 1i
t

Regulation of pna .rp.slion a an slaantlalfeatwe In madntamlng

thefunrtronalm t q t t 9 d a &I. Rewlatronof a gene may w u r ln a
varieiy of w w , of wlmch a n polltlw while other5 are nrg.-
riva ReguIOtb3n nf w e aWsrdcn in prakaryotsr almost always
kwdws eIUw Bdtiffion or t a f w w o n d M~cnptionI" .&my-
oter. tramriFtkvI Is more mmpltcated man tn pmkaryotes, there-
tma,m m m nmm posibtestes for reguiatlon hbothprokaryotes
and eukaryotes Vwacrllulonal regulat!en k mually achwed by the
Interaction of protetnr with specific rsquaxn m the DNA rowiimng
Ine ' w a n h a a or a k r - m the rate of tranrcrtpttoa

REGULATION OF TRANSCRLPTIONIN PROKARYOTES

The regulation of gene expression in prabryotr is usual& pchimd by r e p
uiating the rate at which transcriptionis initiated. The uamplesthat will be
mrldared are the poritive and negatlve c m l of the lacoperonin E. wli.

4 Opemn mnwpt. In bacter~a,a set of structural genes and a regulnory

region c o d t u t e an operon. The structural genes mde for a gmup of p
tebu requiredfor a part~cularmetabd~c funct~onThe regulatory regton k
-(to ths 5' wde) of the stwctcturalgenes. The mudural w e s I" an
0p.mamuW&mtdy regulated 1 e,. the uprerrton of all the SrlKtural
gamr LConDolkdbythe same ngulatory reglon ln the DNA
0. LMvWondthe k o w o n . The regulatorygene (3 wdes fw a reprer
l o r that can Interact with the operator sequence (0) The operator Norr
$ sequence m situated adjacent to the three structural genes R, Y. and A)
E u h r t n x h n a l ~ m m e ~ c
that mde for ~ r e e e n y n r r r c w ewith
r ~ lactore metaboltrm (Bgahr-
lac mRW has a %me-Ddgam
tosMate, permean, and trsnuurhliw>. The cmrenlm of these three sepumce t o & ~ e m ! M 4 a c g A f f i a
genes is regulatedby the operator raquence. IINA polymerare bonds at
tbe p m m rm (P)

K48LAN MEOKAL
MBDE 1 : BIOCHEMISTRY
1.

mmmiption. When -
N*lattve Psgulatonof the i.c v m n . In the absence of lactose, the
repressor potetn binds t o the operator sequence and blocks the
mmement af RNA polymerare atonq the temolate. thus inhibiting
k pr- * inducer tranxnpbon by ths
followitq rnechanlrm lactose Is m w r t e d to 1,64loiactose, a mole-
cuk that blndr to the n p m r o r and changer Itr conformabon so that
t t no longer binds to the operator repion Thus, the repressor s
a
-

rekawd. and the three muctwal gamer are tnnwrlbed as a rrngie

mRNA that mda for all three pmtem Mes~ngerRNA c d ~ n gfor
more thsn one p m e i n is known as a polyclstrontc mRNA and tr
found m l y In pmkarydc system In this model of negative regula-
Won d an owml~, a pmteln aclr as the reprwor, and ianore (or I&
alldmk6e) Was the induatof tranwrlptlon
2 Paaim*nguMlon of th. lax opmn The fundlon of &galactos~daY
m IxUw mRabolrrm rr t o cleave lactose to glucore and galactore
lh3 g a b e ubmately converted to glucose by other e-r
Therefore, if the bacterta has both glucose and l k o s e In the growth
mdwm. there Is no rearon t o acttvate the lac operon When g l u m
Is low, the lac operon s actwated, and the bacter~abegins to u s tsc-
tore t o generate glucose The effects of glucose are mediated by
CAMP When glucose s low, CAMP concentration a high and ace
vema When CAMP Increases. zt btndr t o a protetn known as CAP
(catabollte actlvata pmtetn) The C4PicAMP complex klva ter tran-
xnptoon of the lac operon by blndlng t o the promoter region and
allowlng RNA polymerase t o lnltlate tranrcri~tlon.Thus. the