19.

Fneno Span of the Respirantory Chain ' l

alys
1 a d Phonpt.ates transiet t l nutchonarna espiraton chun
i y ATE
tt on
Ly be
n
njnsetd by the tret teactio equation chanter-
NADH H }0, H,O NAD
15
te sae (a) lerate the value ol A* lor the net reati
cy 'la
o mutohondana electron transíer
b) alrulate 40 for this reaction
Glycolysis and the
6traaxr
iamiis m
f AP to AP and PP, during
Arus od the a:tnated forn1 ef

(c) ilon many ATP molecules can theonetrall

e geeratel ty this raction if the Iree energ of ATI
52 kJ/niol
Catabolism of.Hexoses
t. 1
ATT epen:dentSTithesis unier ce lular conditons is
20. Dependence of Electroniotive Force nn Cou-
tate (oi -acCaA AMP PP, centrations Calulate the clectt omotive force (
wrs) registered ly an electrode inunersed un a sulu
tron contunug the follomng misturcs uf NAD anl D-Glucose is the major fuel of inost orgunisms and occupics a central posi-
Glycogen.
ald 2ialand that tur ivdroly NADH at pH 70and 25'C, with reference to a half rell ion in metabolisn. It is relatívely rich in potential eneny, Uhe complete sturch, sLCTOSe
oxidation of glucose to carbon dicxide and water procecds with a standard
(a) 10 mu NAD and 10 mut NADH free-energs change of -2,849 kJhuol. By storing gucose as a high molecu
e dan 1he erTe Uotganit lar weight polymer such as starch or glycogen, a cell ean stackpile large torage
)10 mau NAD" and 1.0 mu NADII
; thal at, atarth atalizes thehvdrr lysis of quantities of hexose units while maintaining a relatively low cytosolic os-
it ret tiret e the preset e ofthus ezjTe (c) 10 m NAD" and 1.0 u NADH miolaity. When energy demands suddenly increase, glucose can be released
n1 7 s s of acety! taA' Ea)lain quickly fron these iuntrarellular storage polymers anvl used to produre ATP
|Glucoie
oridation via
21. Electron Ainity of Compounds List die foil
17 u e Y for ' Pumping The panelal cels of the lowng sutbstances in order of increc.sing tendenc; either aerobically or anaerobically pentoe posphat»
i t T u d . i menbrane "punn that traIS
pathway glyroly
accepa eiectrons (t) a-ketoglutarnte +CO, (viel Glucose is not only an excellent fuel, it is also a remarkably versatile
r trsh the cytna01
*
O test Ceus 1socitrate). tb) ovaloacetate, (c) O, (d) NADP precursor, capable of supplying a huge array of metatolir ntermediates for
) ( r t i tantnbutng to the acidity
biosynthetic reactions. A bacterium such as Escherchu coli can obtain Ribose 6-phos phate Pyru
P i t aklate thelreeen"Tg' e 22. Direction of 0zidation-Reduction Reactions
from glucose the carbon skeletorns for every unuino acid, nurleotide, co-
ifu j1 ad of hydrogetn ons ihuough Which of the following reactions would you expeci t figure 15-1
t pceed n the direction sliown under standard cotus enuyine, fntty ocid, or other metabolic internmediate neoded for growth. A
irg Yapter 13) As5uTe a tem comprehensive study of tdhe metabolic fates of gluruse wold enconmpass
Major pathways of elucose utilizalion in colls (
tions, assuming that the approprinte enzynes are pr hundreds or tliousands of Lransformations. Iu higlr plants ad animals,
planls and animals. A"nougr n:t the oniy pos
N.Ainndard Hedartion Potentials The standard
sent to catalyze the:n? for glucose, these three pettway: üre the tnost
glucose has three major fates it ay be stored (a a pilysarcharide or as in termis of the amournt of glcose that flows th
tp fetrtisl. t." of ary redox pair is defined (a) Malate +NAD»
sucrose), oxidized to a three-carbon compound (pynivatr) Via glycolysis, or thern in rnost cells
Oxnloacetute + NADH + I1
'anb (b) Acetoacotate + NADH + H ° -
oxidiuedto pentoses via the pentose phosphale (plsphoyghuconate) path-
way (Fig. l5-1).
g bgti n
cdertrons reducing agent
B-hydroxybutyrate + NAD This chapter deseribes the individual reactions of glycolysis and the en-
if the NAIDNADI and pyruvate/ zymes that catalyze then1, fermentation, the operatio of sly colysis under
al ii 4'alr t o Jurs aue - 032 and - (0.19 V, (c) l'yTuvate + NADH +H'
anaerobie conditions: anul the pathways that produe the starung material
lactute NAD for glycolysis from nongucose hexOses, disacchasidos, and polysaccharides.
W h e vayupate r lasthe grealerte dency
(d) Pyruvate +
-hydroxybutyrate Using glycolysis as an exanple of a metabolic patlway udor tight regula-
lactato + acetoacet i tion, iwe discuss the general principles of metatwlher conrol e conclude
tWu h th tonget osiduzugagent? Explain wilh a brief description of the calabolic pathwny thut leauls torentoses
(e) Malate + pyruvaleOxaloacetale + lactit
egiuty wih i Moncentrations of eiclh re-
At anl jwiy'1 at jiH 7, in w hucdh direction will the () Acetaldehyde +5uccinate
ethanol + fumur.a Glycolysis
v t e NADI+ I ' l a c t a t e + NAD' In glycolysis (fhonu the Greck glkys, meauing "sweet," and lysus, neaing
"'spliting") a molecue of glucose is degracded in a ses of euyne
W i a l 1 t i t ali dard free-energy :hange calalyzed reactions to vield two molecules of the thwce carbon conipound
t ,1 t t rveraorn of pyruvateto lictate?
pyTuvate. During the sequential reactions of glycolysis, some of ie free cn-
tWhu h t ilibriumconstant (K.,)for thus ergy released from glycose is conserved in the form of ATP ani NADIH.Gly Fritz Lipm.ann
189-1986
colysis the firhetabolic pathwayto be
was elucidated and is probably the
best
understoodMrom the discovery by Eduard Buchner (in 1307) of
mentation in broken extracts of yeast cells until the clear recognition
fer
Fritz Lipnmain and Heman Kalckar (in 1941) of the metabolic role of li
by
 19. Fneng Span of the Respiratory Chain l.le
tron transfer in the mitochondna respiratory clai
4 t o 9 d a l ivtth n. 1y AT, nay be repnsented by the uet reaction equation
chanker
, wdt h a attales, fhil the e entr.a NADH H 20, H,O +NAD
15
17 -tie) y t)lain 1 the same (a) Caleulate the value of AE° for the net reaction
w
tt t
vTTIrdw th "Pn of mutochondnal electrontransfer
(b) Calrulate AG° for this reaction
Glycolysis and the
I leavagr
1rtabolism
af AIP to AIP nnd PP, during
.dhr as of the activaled form of
(c) ilowr many ATP molecules can theoretrally
be generated by this reaction if the Iree energ of AT
suthesis under ce lular conditions is 52 kJ/mol
Catabolism of .Hexoses
4, T l an ATP-dependent
20. Dependence of Electroniotive Force on
Con
centrations Calculate the electromotive force (
Atale(aiA7P-- acetylCoA AMP PP,
volts) registered by an clectrode irnmersed in a soh
e d n s i s of acety|CoA to tion comnng the followng inistures of NAD anl D-Glucose is the major fuel of nost organisms and ccupics a central posi1 Glycogen,
n) kmol and that for hydroly- NADH at pH 7.0 anud 25 C, with reference to a half coll tion in metabolism. Il is relatívely rich in potential energy; lhe complete sturch, sucrose
fATit ° n1i, is -305 /mol. Calculate ofE 00u Oxidation of glucose to carbon dicxide and water procecds wilh a standard
1h 79-ndent synithesis of are1yl-CoA (a) 10m NAD" and 10 mu NADH free-anergy change of -2,840 kJhrol. By storing gucose as a high molecu-
i- in a l r.s cotlain the enzyTe organic lar weight polymer such as starch or glycogen, a cell can strkpile large torage
o2.a1 t uturh atalizes the hydrcly'sis of ()10 m NAD" and 1.0 mw NADII
quantities of hexose units while maintaining a relatively low cytosolie os-
does (c) 10 m N.AD and 1.0 mu NADH molarity. When energy demands suddenly increase, glucose can be released
I fhat rifec1
thepresence of thusenzyTne Gluco:e
r th 53 21ltrs of acety! CoA" Explain 21. Electron Ainity of Compounds List tde quickly fron these intrarellular storage polymers and used to produce ATP 07idation via
17 nery for 11' Pumping The parietalcels of the fo
lowing substances in order of increr.sing tendetucy t either aerobically or anacrobically 0sph at lyrol
pataway
teid h itaty onl.u mernbrane "pumps" thottrans accept electrons: (a) a-ketoglutarate + CO; (yielc'n1y Glucose is not ondy an excellent fuel, it is also a remarkably versatile
1ft 111r from lhe cy1osol of these cells isocitrate). (b) oxaloacetate, (c) O; (d) NADP. precursor, capable of supplying a huge array of metabolic internediates for
1 ) 1uite ith *1(irh contnbuting to the acidity
biosynthetic reactions. A bacterium such as Eschuerichin coli can obtain Ribose5-phosphate Pyru
22. Direction of 0xidation-Reduction Reactious
f p u
H10) Calculate thefree en:rgy re- Uhich of the following reactions would you expeci l
from glucose the carbon skeletorns for every nirno acid, nw:leotide, co-
figure 15-1
r a l t 1T,4H1 mal of hydrogen jons ihrough enzyrne, fatty acid, or other metabolic intermediate needed for growth.
proceed in the direction shiown under standard cou Major pathways of glucose utilizalion in colls
tl nj t
Se apter 13.) Assume a tem tions, assuming that the appropriate enzynes are pr
comprehensive studs of the metabolic fates of glrose woutd encompass planls and animals. A"hough 'net the only pos
hundreds or thousands of transfomations. Iu ighuer plants and animals, 1or glucose, tiese three patiways ire tne fnost
sent to catalyze then? in terms of the amount of glscose that fors
IN tandard Heduction Potentials The standard
(a) Malate + NAD"
glucose has three major fates: it may be stored (as a polksarchuuride or as thern iri riost celis.
thr
i l jodeital. t* of any redox pair is defined sucrose), oxidized to a three-carbon compound (pynivate) via glycolysis, or
ialf cell arthn. Oxnloacetate + NADH + H oxidized to pentoses via the pentose phosphale (phosphuogluconate) path-
ubouup nge ut n electrona reducinß agent (b) Acetoacetate + NADH +H°- way (Fig. 15-1).
This chapter deseribes the individual reactioIs of glyeolysis and the en
B-hydroxybutyrate + NAD
ali f il NADNADH and pyruvate/ of glycolysis under
zymes that catalyze them, fermentatíon, the operatio1
Hif'at hoy -0.19 V,
purs are -0.32 and (c) Pyruvate + NADH + H' anaerobic conditions: and the pathways that produre thee starting material
il
lactate r NAD for glycoly'sis fron1 nonghucose hexoses, disaccharides, and polysaccharides.
)Wh oupatr pair has the greater tendency Using gycolysis as an exatnple of a metabolic patliway nder tight regula
(d) Pyruvate + 6-hydroxybutyrate
We conclude
Lion, we cdiscuss the general principles of metabolir conlrol
Jactate + acetoacet.ilr
with a brict description of the calabolic pathway thul leals to rentoses.
Whi i Ihetoger oxidizing agent? Explain. (e) Malale t pyruvate> oxaloacetate + lactzat
eyuunyg wih l M concentrations of eich re- () Acetaldehyde + succinate
aul juvct al pH 7, in which direction will the
ethanol + fumart
Glycolysis and
T l t i f ! ratin prorerd
Jn glycolysis (fron1 tthe Greck glykys, meaning "sweet," !ysis, meaning
of enzy!ne-
T'uvatrNADII+ JI'=lactate + NAD' "splitting") a molecule of glucose is degraded in a series
carbon conyound
Wal t t Standard ree-energy change
catalyzed reactions to yield two molecules of the three
sone of the free en-
pyruvate. During the sequential reactions of glycolysis, Fritz Lipmann
) a t 1,fr l convesion of pyruvale to lactate? form of ATP and NADH. Gly
ergy released from glycose is conserved in the 1899-1926
and is probably the
(W tquilibrium constant (hg) lor thus colysis was the firstsnetabolic pathway to be elucidated
best understoodFrom the discovery by Eduard Büclrer (in 1897)
of fer-
in bro ortracts of i0ast cells 1t.il the clear recagution by
 ol t e (a) Gluco:e 110 0.
and seco8itiofi m figure 15-2
the liseovery
ithols l eniym punieation, for cach
d the discovery of the pivotal ineta- The two phases of glycolysis. Her
such as NAD, through
ortance out of molecule of glucose that passes (1
of cocnzynes conpounds al cane prining
rs (1)
aud other phosplhorylatcd phase (a), two molecules
olc role of ATP of many species have long the preparetory reaction NG ADP
enzyines aro formed;
studes of glycolys.s. The glycolytic of elyceraldehyde 3-phosphale
and thoroughly studied (b). Glucose 6-phosphate -0
since been purned both pass through the payoíf phase
catabulis1n, of the second
universal central patl1way of glucose - Pyrurate is the end product phespho-
Glycolysis is an ainost cells. The glycolytie each glucose rna
Mux of carbon in most phase of g'ycolysis, For
the pathway with the lirgest consumed in the hexo5e
source of netabolic energy
in sorne
tnan ecule, to ATP are
breakdown of glucose is the sole and four ATP are pro MO||7s0nerase
renal medulla, braii, and preparatony phae OH
a ner
malan issues and cel types (erythrocytes, duced in thc payolfphase, yving O ¢lh
to store starch -0-CH
Some plant tissues that are modified molecule of gluCOse Fructose 6-phosphate
sperm, for example) yield of two ATP per
(watercress, for exaruple) number beside
(stuch as potato tubers) and some aquitic plants Converted 'o pyruvate. The
react on slep coresfonds
to Its nurn- Decond
hospho
derive mst of theit e'tie lrom glycoly sis; miny aaerobic meroora each Tuefo
bercd headirng in the teA discussion, Kcep Priping.YI k n a s e
t0
IS1S are nlirely dopendent on glycolysis. ADP
anaerobic degradatioII OI glu in rmind that each phosphoryl grcup, rep- rartion ,
Fermentation is a general term lor the negative
Becase recnled here as (P). ha% two Fructose 1,6-bisphosphate
cOSe or other organic
nutnents to obtain energy, conserved as ATP charges (--POS )
anaerobe
arose il an atniospBhere witlhout oxygen,
liing organsns li st mechanisu for deavago Aldolase
s the most arncient biological f Genrton
brakdown of glucose probably
orgauc fuel nolccules. In tlhe
course of evolitioi Ugur (
obtaining energy fron phosphs
conserved, u o 3-casln
the chemistry of this reaction
sequence has been completely thu
amino acld set )
are closely sinilar, in
Blycolytic enzynies of vertelbrates phosphabes
to their honologs in yeast and
(quence and three dinmensional structure, Glyceraldehyde 3 pho plhate
ir. the details of its regulatjon
spinacl. Glycolysis differs among specles only
atd in the sulbsequ.et nietabolle fale of the pyruvate forrned. The thermo Dihydroxyncelune phosphnto
ire
dynnmie principles and the types of regulatory mechanisms in glycoly'sis
can ther
common to all pattiways of
cell metabolism. A study of glycolysis (5)
diseussd later im
Payoff phaso
fore serve as a model lor nany spects of the pathways h o s phdte
(b) Oridativo cofursinn tl
his book. I30nease
In sone detail, we will take glvceraldohydn 3 ph0aph
Before examining each step of he pathway -0-1, (-
a look at glycolysis as a wlole
Cilyceraldeliy de 3 phorphale (2) the cuuplor
tiou
J U J E s c a l l e b
yfor ruvnte nnul
of ATP a1d N
r
Overview: Glycolysis Has Two Phases 2AD3-phoshoBe
p idaton nodA6) 2 dehrlrtog*nose
molecules of the threw
h e brenkdown of tlie six-carbon glucose into two
carbon pyruvate occurs n ten sleps, the first live of which constjtute thu
peparatory phase (Fig. 15-2a). In these reactlons, glucose is lrst phor, 1,3-Binphosphoglycerale(2)
The D-glucose G-plu:, zAID hospho
phorylated at the hydroxyl group on C-6 (step 0). wlurl
thus fonned is converted tu D-Iructose 0-phosplhuate (step ) , rming reu (i)
phate iaatiJiel
isagain phosphorylated, this tine at C-1, to yield D-fructose 1,6-bisplor Kinos0 P-9-H,11C
'
NTP is the phosphoryl gro 3 Phinphoglycerue 2)
phate (step O). For oth plosphorylations, phosphog/see -, ut
donor. As all sugar derivatives in tle glycolytic pathway are the D isou:
we will omit tte p designation except
when emphasizing stereocherntu )rta1e rnutos e
Prictose 1,0-splhosplate is next split to yield two three-ratlu
2-1'hsphyl, cerate 12)
molecules, dihydroxyacetone phusplate and glyceraldehyde 3-ph0phat
its name. The il
(step ) , this is tle "lysis" step ihat gives the pathway Enolase
a second molecule
of glyy )21,
liydroxyacetone phosplhate is isonierized to
the liu st phase of glycolys:Al
alclebyde 3-phosplale (step 5), elding Phosphnnl; ruvate (2)
invesled to activate the glucose n
a t Lwo noleculei of ATP uu:t be 2ADP P UNoe
into two thr:e-carbon pieces; later lhere will be: a stn
cule for its clenvage
To sun up: in thé preparatory phase of plyul, ,
return on this investnent.
the free-energy content of the
SIS the energy of ATP 1s invest el, raising C
the metabolized liexoses t Pyruvate (2
and Lhe carbon chains oI all
Ternediu;es,
glyceral1deuycde 3-phosplhate.
vrlemto a cominon prodhu:t, T
VThe energy gain c O u s in
Ihe payoI phuse ol glycolysis (F'18.

Each nolecule 3-phosphate is oxidized and plerjdu

of glyceraldelayde Lo fornn 1,3-bisplospBuop:lystl
ald hy inorganic phosphate (not by ATP)
Fnergy is then releasel as the Lwo nolecules of 1,3-brl jl
(:.te (). TOYiy 1o Wo ftolecules of pyruvile (stepsOthryi io
 e rgtics and Mctabolisn
Chapter 15 Glycolysis and the atabolism of Hexoses
531
Much of this energy is conserved
by the coupled phosphorylation of four
nolecules of ADP to ATP The ATP Fomation Coupled te Glycolysis During slycolysis some of the energy
net
cule of glucose used, because two
yield is Lwo molecules of NTP per mole-
molecules of ATP were invested in the ne glucose molecule is conseryed in ATP, while much remains in the
preparatory phase. Energy is also conserved in Lhe payoff product, pyrurate. The overall equation for glscolysis is
nation of two rnolecules of NADH
per molecule of
phase irn the for
In the sequential reactions of glucose. \ Gucose + 2NAD" -
2ADP +
2P,
glycolysis, three types of chenical trans 2 pyruvate + 2NADH + 2H" + 2ATP + 2H,0 (15-1)
formations ate particularly noteworthy: (1) degradationof the carbon
skeleton of glucose to yicld pyruvate, (2) P'or each inolecule of lucose degraded to pNTIvate, two molecules of ATP
by high energ phosphate compounds
phosphorylation of ADP to ATP
the of
transfer
forrued during glycolysis, and
(3)
are generated from ADP and
P, We can now resolve
yS15 Inio Lwo pro:esse3: (1) the conversion of glucose to p\Tuvate, which is
equation giycol-
ofalydnde ion with its electrons to NAD", forming NADH. Ttue fate
of the
pyruvate cepends CXergoniC
the cell type and
on
the metabolic circunstances.
Undert Atno sCand Anae rio6i c Cormd1
Vfates of PyruvalenBarring some interesting variations in the s Glu:ose +
2NAD'-2 pyruvate 2X.ADH- 2H° (15-2)
bacterial sG -146 kJ/mol
realn, the pyruv ite forined by glycolysis is further metabolized via one of
nd (2) the formation of ATP fro:n ADP and , which is endergoni.:
three catabolhc
routes. ln aerobic organisns or tissues, linder aerobic
diuos, glycoly sis is ouly tle first stage in the coinplete degradation of con
glu 2 ADP 2P, 2ATP 2H,0 (15-3)
Cose (Fig
15-3). Pyruvate is oxidized, with loss of its carboxyl group as SG 2130.5 kJ/mol) 61 kJ/mol
CO,, to yield the acetyl group of acetyl-coenzyine A, the acetyl group is then
The surn of Equations 15-2 and 15-3 gives the overall standard free-energy
oxidized completely to CO, by the citric acid cycle (Chapter 16). The
trons fron these oxidation:; are passed to O,
elcc. change of glycolysis, AG
through a chain of carriers in
the mitochondrion, forming 11,0. The energy Irom the electron trunsfer
re J AG +AG-146 kJ/mol 61 kJ'nol
+
-85 kJ/mol
actions drives tl syntlesis of ATP in tlhe nutochondrion
(Chapter 19). Urder stndard conditions and in the cel, glycolysis is an essentially irre
The serond rOute for pyruvate is its reduction to lactate via lactic actd Versible process, driven to coumpletion by a large net decrease in ree en
fermentauon. . hen vigorously contracting skeletal muscle must funetion of ATP, ADI, P, (see anc:
ergy. At the actual intraceilular conce:tretions
under low-0N gen couiticons (hypoxin), NADH cannot be reoxidized to Box 14-2) and c gluco% arnd pyruvate, the energy releasedd in gl;colysis
NAD, and NAD' 1s requred an electron acceptor for the further oxida
tion of
as
Cnder these conditions pyruvale is reduced to lactate, (Witn pruvate as the end product) as ATP with
:s recovercd an cfficiency
pyruvate. ac of over G0%,
Cepting clectroris from NADU und thereby regenerating tne NAD neces
Sary for glycolysis to continue, Crtain tissues and cell types (retina, brain, Energy Remaining in Pyruvate Glycolysis releases only a smuall roction
erythrocytes) corvert1 glucose to lactate evetu under aerobic condittons, and of the total avail: ble energy of he g'ucose mo.ecule, WTen glucose is oxi-
lactate is also the product ofglycolysis under anaerobic conditions in
son dized cormpletely CO, ard H,0, the total standard free- energy change
to 1s
nlcroorganisms (Fig. 15-3). 2,840 k.l/raol. Glycclytic degradasion of glucose to two rnoleciles of pyz
The third nmaor route of pyruvate catabolisrn leads to ethanol. Iu sone
plant tisses and in certain invertebrates, prclists, and tuicroorg,uisn
vate (aG" -116 kJ/ruol) tierefore yiclds ondly (146/2,40)100 52% of
Lie total ernergy ilut Can be releasei fron glucose by conplete oxidation,
SI1ch as brewers yeast, pyruvale is ecorverted uneder hypoie or anaeruie The two nolecules of pyruvate lurned ty glycolysis still contain inost of te
conditions into ethunol and CO, a process called nlcohol (or ethanol) fer. lhernical poteriliad energy of the givcose molecule, energy ttat can be ex-
tracted by oxidat.ve reactions in the citric acid cycle (Chapter l6) invt ox-
mentation (Fig. 15-3)
The focus of this chapter is calabolisrn, but pyruvate has anuboli: fate idative phospthorylation (Chapter 19
is well lt can, for example, provide the carbon skeletan for the syTiuhesis t
*AIP
he amino acid alonine. We relurn to these anabolic reactiors of ps ruvate i Importance of Plhosphorylated Intermediates Cach of the úne plycolyti
later chapters. internediates between glucose and pyrurate is phosphorylatd (Fig. 15-2)
Fra trs 7+ans nemben uf prrl
The phosphoryl groups appear to have three furictions.
ierub0
1'yale njuon
1. Trcy are ioni.ed plH 7, giving cach glycolytic intermedate 1 net
Ckingdom CompusIng boeleq* at
isirrpermcableto
li
charge. Hecausethe plasrca muebrane
o020gatve nolecules, the phosphorylated
1etata aJae, slme mo (ds, u n g i , " * ' cthurged inteTnediates cannot. ifuse
'
F'ontation to
lactete In vigoroualy i elude s all Single - C«ll
* i*"9 «sat
of the cel. After the iritial phosphorylation, no further cne2y
15 eCessary to retain phosphorylnted inteTncdistes in tiv; cel),
n c t n g niunclo, difference in their intracellular and zlracelular
espite die large
rylrrylen, none 5ms) concentrations.
2. lhosphoryl groups are essential conponenis in tie enzyin3l1¢ Conser
alion of nietatbolic: erei:y. EnerEy released in the breakage of phO
conserved
pionydride bonds (Such as those in ATP) is .jartially
n
he forrnation of phosphate est:rs such as 2lucose 5-phspriate. HIg
flgure 15 3 IM:rY phosp1ate conpounds forined in colysis (1,3-bisphospho-
ralatelic fates ol thhe pyruvate formed in donate phosphicryl groups to
Thiee ponible erate and phosphioenolpyruvate)
d i o n s ADPo fortm ATP
 Ol n s e D or
3. Bndngs energy restult
yfrom the
bindng phs glucokinase, whicn is ore specine tor giucose
actuve sites of enzyTmes lowers the activation energy
and increases the DLJhCrforms of hexokinase in kimetic and regulatory' properties (p. b55)
The phosphale
Speeihcity of the enzJmatie reactions (sce p. 251). LIKe the other nine enzymes of glycolysis, herokinase is a soluble, cy
form compiexts
SrouS of ADT, AT?, and the glycolytic irtenediates Osolic protein, although, as we note later, there may beorganized com
wlh Mg and the substrate bindung sites of many glycolytic enzyTnes plexes of several glycolytic enzymes (see Fig. l5-3)
require
these Mg" complexes. Most glycolytic enzyTnes
are specife for
Mg for activnty 2 Conversion of Clucose 6-Phosphate to Fructose 6-Phosphate The en
The Preparatory Phase of Glycolysis Requires ATP
y e phosphohexose isomerase (phosphoglucose isomerase) cat
the reversible isomerization of
ATP are invested uyzes glucose 6-phosphate, an aldose, o
In the preparatory phase of glycolysis, two molecules of fructose 6-phosphate, a ketose
The reallzauon
ana the hexase chan is cleaved nto two triose phosphates.
carne slowly
that phosphorglatod hexoses were intermediates in glycolysis
tested their
and serendipitously. In 1906, Arthur Harden and William Yourng 0-P-0-H2
stabilize the glucose-
hypothesis that inhibitors of proteolytic enzymes would ..
blood serun (knowTi to
ermening enzymes in yeast extract. They added
extracts and observed H \H N 0-P-0- 0 CH,0H
inubitors of proteolytic enzymes) yeast
to
contan
the predicted stinmulation of glucose metabolism. However, in a control ex
HOOH H phospholhexose
I50omerase
the stimulatory
perinent intended to show that boiling the serum destroyed
effective at stimulal- OH OH
activity, they discovered that boiled serum was just as
of the contents of the boiled Glucose 6-phosphate
ing glycolysis. Carcful examination and testing Fructose 6-phosphate
s e n i m revealed that inorganie phosphate was responsible
for the stimula-
added to their yeast
tion. Harden and Young socn discovered that glucose AG° 1.7 kJ/mol
extract was converted into a hexose bisphosphate (the "Ilarden-10urng e5
ter," evetually identitied as fnuctose 1,6-bisphosphate). This was the be This reaction proc>eds
Wiham YOung readily in either direction, as predicted fron the rela-
1978 1942 ginning of a long senies of investigations on the role of organic esters of fively small change in standard free energy. Phosphohexose isomerase re-
ol ires Mg and is specific for glucose 6-phosplhate and fructose 6-phosphate.
phosphate in biochemistry, which has led to our current understanding
role of plhosphoryl group transfer in biology.
the gentral Phosphorylation Fructose 6-Phos
of Fructose 1,6-Bisphosphate
glucose is In the secosid of the Lwo priming reactions of
OPhosphorylation of Glucose In the first step glycolysis, to ield glycolysis, phosphofructo-
of
klnase-1 catalyzes the transfer of a phosphoryl group froru ATP to fructose
activated for subsequent reactions by its phosphorylation at C-6
donor: Gphosphat e to yield fructose 1,6-bisphosphate
glucose 6-phosphate, with AT as the plosplhoryl
ATP ADP 0-P-0-CH
Mg
H-CH O phosphofructok inase-1
N
-O ATP ADP
Mg OH
HO
hesokinane
HO OH Fructose 6-phosphate Fructose 1,5- bisphosph
ate
2
OH
Glucose Glucose 6-phosphate AG-142 kJ/nol
Tie reaction is essentially irreversible nder celhlar conditiors. (This en-
VIu: is called phosphofructokinase-1 (PFK-1) to distinguish it from a
AG -16.7 kJ md sec
fu enzyme (PFK-2) that calalyzes the formation 9fAuctose 2,6-bispho
under intracellular conditions, is car dule from fructose 6-phosphate, see Fig. 20-8.
This reaction, which is ireversible
that kinases are enzy1nes thatl catalyze tu Soue bacteria and protists and perhaps all plants have a phosphofruc
alyzed by hexokinase. Recall okhase that uses pyrophosphate (PP), not ATP, as the phosphoryl group
fror1 ATP to sonme acceptor n
transfer of the terminal phosphoryl group
Kinases are a subclass of transferases (see Tall donor in the synthesis of fructose 1,6-bisphosphate
cleophile (see Fig. 14-10). normaly
case of hexokinase
is a hexose, i
8-3). The acceptor in the of otl Fructose G-phosphate + PP fructose 1,6-bisphosphate+P
also catalyzes the phosphorylation
glucose, although hexokinase 14 kJ/nol
as D-fiuctose and
D-mannose.
c o m m o n hexoses, such
requires Mg* for its açtivity, » Plosphofructokiiase-1 is a regulatory enzyme (Chapter 8), one of tle
Hexokinase, like many other kinases, the MgATP Cun
cause the true substrate of
the enzyrne is not ATP but 11 COplex knowTu. It is the major point of reguation in glycolysis. The
inexokinase have shown lhai
ivity of PFK-1 is ir.creased whenever the cell's ATP supply is depleted
or
Detailed studies of yeast
plex (sce Fig. 14-2). in shape, an induced fit,
when l
wlion the ATP breakdown products-ADP and AMP, particularly the
a profound change
the enzyme undergoes
se molecnle see Fig. 8-21). Hexokinase is present in all cer.
ho bo
 Chapter 15 Glycolysis and the Catabolism of Hexoses
53
taller-2re in èxrss. The enzme is inhibited whenever the cell has ample
AT and is well supplied by other fuels such as tatiy acids. In some organ
isnis, Ínuctose 2,1-bisphosphate (not to be condused with the PFK-I reac
tion product, fructose 1,6 bisphosphate) is a potent allosteric activator of
phosphofructokinase-l,. The regulation of this st:p in glycolysis is discussed
in goyer detail later in the chapter. Fructose 1,6-bisphosplbate
-OH
Cleavage of Fructose 1,6-Bisphosphate The enzyme fructose 1,6-
bisphosphate aldolase, often called simply aldolase, catalyzes a re- HS-OH
versible aldol condensation Fructase 1,6-bisphosphate is cleaved to yield CH-0-D
two different triose phosphates, glyceraldehyde
3-phosphate, aldose, an
Derived from ldolare
and dihydroxyacetone phosphate, a ketose: Derived from
glucose curbon glucore carbon
Derived from
H--C-0 glucose carbons
A or 3
H--OH Hc-O D-Glyceraldehyde
0P-0CH_0 CH-0--0 H,--0 CH-0-D 5 or 2
H2c-OH 3-phosphete
aldola e
HCOH Dihydroxyacetone Clyceraldehyde
or 1
CH-0-¬
CH,OH CIl2-0 P-0 phosphate -phosphate
OH H
Fructnae 1,6-bsphosphate T.4e phophatr i0nrrane
Subsequent reactions
Dihydroxyncetone Glyceraldehyde of glycolysis
phosphate 3-phosphate
(a)
(b)
AG 23.8 kJ/mol 1igure 15-4
The aldolase of vertebrate uurnal Lissues does F'ate of the carbon atoms of glucose in the formation of
not requir a divalent The Payoff Phase of Glycolysis Produces ATP and NADH glyceraldchyde 3-phosphate. (a) The origin of the
cation, but in many mucroorganisins aldolase is a Zn-containing enzyTne carbons in the two three-carbon
Although the aldolase reaction has a strongly positive slandard h e payoff phase products of the aldolase
free-energ cf gly coly sis (Fig. 15-21) includes ihe energs-conseving ind triose phosphate isomerase
reactions. The end
change in the direction of fnuctose 1,6-bisphosphate cleavage, in cells it can phosphorylation steps in which sone of the free energy of tle glucose mol- product of the two reactions is tvo molecules of
proceed readily in either direciiOn. During glycolysis the reaction (cule is conserved in the forim of ATP Remernber glycer
product that one fnolecile ol 2Idchyde 3-phosphate. Each carbon of elyceraldefiyde
(two triose phosphates) are removed quickly by the next two cOse yields two molecules of glu 3phosphate is derved from either of two specific
the reaction in the direction of cleavage.
steps, julling glyceraldehyde 3-phosphate; both halves of Carbons of glucose (b). Note that the
the gluco5e molecule follow te same numbering of
pathway in he second pluse of gly Carbon atoms of glyceraldenyde +phocphate dffers the
frorn
colysis. The conversion of two molecules of that af the glucose from which t
V Interconversion of the Triose Phosphates Only one of the two LWO molecules of glyceraldehyde 3-plhosphuate to is derived In glyceralde-
fSTUvale is accompanied yde 3-phosphate, tie most comnplex functional group
phosphates formed by aldokase--glyceraldehydc 3-phosphate-can trios
by the fommation of four mole-
be di cules of ATP from ADP
However, the (he cartofiyl) is
specified as C-1. This nurnbering
net yield of ATP per molecule of glu
rectly degraded in the subsequet steps of glycolysis. The other product. cose degraded is only two, because two ATP were chanpe is inportant for interpreting with
dihydroxyacetone phosphate. is rapidly and reversibly comverted to glycer ory phas0 of
invested in thee prepra- glucose ir whiich a single catbon is laerperirrients
beled witi a
8ly(:oly'sis to phosphorylate the two ends of ilie hexose 1.3dioisotope. (See Problems 3 and 5 at the end of this
aldehyde 3-phosplhate by the fiftlh enzyme of the glycolytic sequence 1olecule. chapler )
triose phosphate isomerase:
Oxidation of Glyceraldehyde 3-Phosphate to
1,3-6isphosphoglycerate
The first step in the payolf phase is the
oxidation of glyceraldehyde
3-phosphate to 1,3-bisphosphoglycerate, catalyzed by glyceraldelyde
3-phosphate dehydrogennse:
CH-0--0 H-0-o
Dihydrxyacet one
phcsphate
Glyceraldehyde C NAD NADH + H*
hate
ncOH +H elyceraldehyde ICO
AG°= 7.5 kil/mol H,OPO 3phasphate
dehydrogenase CH2OPO
By this reaction C-1, C-2, and C-3 of the starting glucose now become chom (ityceraldehyde Inorganic
ically indistinguishable fron1 C-6, C-6, and C-4, respectively (Pig. 15-4). 1phosphate phosphate 1,3-Birphorphoglycerate
This reaction completes thhe preparalory plase of glycolysis. The les
iolecule has been phosphorylated at C-1 and C-6 and then cleaved
forn two rnolecules of glyceraldehyde 3-phosplhate. Other hexoses, such n.
t.
11is is the first of the two
AC' = 6.3 kJ/mol
Iructo, D-11annose, and D-galactose, can also be converled into glycrr eventally
energy-conserving reactions of gdycolysis that
lead to the formation of ATP. The
aleycd 3plhosplhate, as r e shall see later aldel1yde group of alde-
 and the Catabolism of Hexoses
Chapter 15 Glycolysis
CH,OPO3
Bioe ergetics and Metabolism
H-Ol
-0 Phosphoryl, Transter from 1,3-8isphosphoglycerate to ADP The en
yne phosphoglfeerate kinase transfers the high-energ phospno
to ADP, 1ormung
KOp irom the carboxyl group of 1,3-bisphosphoglycerate
ATT and 3-phosphoglycerate:
1,3-Bisphospho-
CH,OPO NAD NADH+ H* gyeerale
CH,OPO 0- C
Mg
H--OH H-C-OH plhnphoy:l ceratr ICOH
C-O HCOH kin 1
CH,OPO
Rib- Adenine H,OPO
NADH NAD RibAdenine
ATP
1,3-Bisphosphogly cera:e ADP 3-Phosphoglycerate
.e e 1al Thioester G= -18.5 kJ 'mol
NAD SH Notice that phosphcglycerate kinase is rarned for he reverse reaction Lae
null enzymes, it catalyzes the reaction in both directions. This enzyrne acts in
the direction sugaesued by its name during photosymthetie CO, fixation (see
Glyceraldehydrogen.a
deho phale P'ig. 20-25) W
e e d g t n a t e 1 at tion: aa Steps and ( 1ogether constitute an energy-coupling process n
which 1,3-bisphospl0glycerate is the cormnon intermediate; it is formed in
lrluale of hydro he first reaction (which would be endergonic in iísolation), and its aryi
called an acyl pliosphate, has a very húgh standard free energs
Much of the free hosphate group is transferred to ADP in the second reaction (which
is
lysis (AG
=
19.3 kJ/mol; see Fig. 11-4, 'Table 14-6).
-
1s
energy of oxidatinn of the aldehyle group of glyceraldehyele 3-phosphate Mrongly exergonie) The surn of these two reactionis is
at C-1 of 1,3-bisplios-
conserved by fornation of thu: acyl phosphate group lyeeraldchyde 3-phosphate - ADP P,+ NAD
.n'A (ep (9) phoglycerate
-phosphoglycerate + ATP + NADII - H
dehydro
The acceptor of hyidrogen in the glyceraldehyde 3-phosptate AG -12.5kJ/mo)
The reduction of NAD procceds
nhrol genase reaction is NAD" (scc F'ig. 14-15). Thus the overall reaction is exergonic,
from the aldehyde group
a n d an acyl by the enzyTnatic transfer of a hydrile ion (:H) Recall frOn Clhapter 14 that the actual free-eiergy change, AG. 1s de
nicotinanide ring of NAD", yielding
of glyceraldehyde 3-phosphate to the substrate termined by thhe stardard free-energy change, AG", and the nass-action r
ale
the coenzyTIe NADIT
The other hydrogen alom of the
v etolrlotiyrde reduced to, which is the ratio [products|/rcactants| (see Eqn 14-3). For step
molecule is réieased to solution ias Il'.
bound to the enzyine during
Glyceraldehyde 3-pliosphate is covalently
dehydrogenase (Fg ACG +RT [1,3-bisphosphoglycerate)]NADHJ
the reaction catalyzed by plyceralelehiyde 3-phosphate
reacls witlh
AG glyceraldehyde 3-phosphate|[PJINAD"
of glyceraldehyde 3-phosphate
l5-5). The aldebycd» group active site, in a reaction
Notire that [!l"J is not included in the mass-action ratio. In biochenical cal
essential Cys residue in the
the -SH group of i n to be a constant (10" M), and this constunt
is in
lienacctal (see Fig. 9-5). in
this c s e pro lations, []is assurned
analogous to the foralin of a uded in the definition of AG" (see p. 494).
that glycerallehyde 3-pliosphal
ducing a thiolheritacetal. The discovery in step G.
jocloace:tate was irnportaiit
in the hustory t Step O, by consurming the 1,3-bisphosphoglycerate produced
dehydrogenase is inhibited y 4ces [,3-bisphosphoglycerate) and thereby reduces the mass-aci ioiI ta
inhibitor to crude
x
udditlion of this enzynme
research on glycoly'SIS; the When this ratio is less than 1.0,
hexo3e plhosplilr", o for the overall energy-coupling process.
caused the acciumulation of the
tracts
ofyeast or nmuscle ihem Lo be isolated and identified. iln uatural logarithra has a negative sign. If the
mass-action ratio is very
produced in glycolysis, allowiy term can make AG strongly uega
() ual, the contribution of the logarithnic
v , This is sinply another way of showing
that the two reactions, steps )
CH -C a cornmon internediate.
IN r e coupled through both reversible under cellular
NAD" SH III NAD o u t e o m e of these coupled reactions,
an aldehyde to a car
the energy released o r oxidatior. of
ICH-
f litions, is that coILSErved the coupled fornatinn of ATP froia
DP and
xyate group is by
a substrate
iv it', O group transfer from
Inactive enzyie Thu: formation of ATP By phosphoryl
lodoacetate 1,3-bisphosph:gycerate is referred to
as a substrate-level phos
id Ih a this mecharisn from respiration-linked
limitecd a m o u n t s of NAD", gycolysis would an plhurylation lo diztinguish involve soluble
Because cels contai1 of glyroly Sugstrate-level plhosphorylations en
NADH formecd in this step phophorylation.
in this
for lack of NAD if the internediates (1,3-bisphospBoglycerate case)
co to a lhalt The reactions in
reoxiclized.
wluch N.\ID' :: sys and chemical
Fand, involve Membrane
the other
nol continuously on
W are described in detail later,in
connection wittu
l lI1-lirikei phio:phorylations,
drarlionts ní nritnns [C'hartor 19)
ealed anaerobically 17Vmoc and rrancnomhrano
 Chapter 15 Glycolysis and the Catabolism of Hexoses 539
N n d Metabolism
8 Conversion of 3-Phosphoglycerate to 2-Phosphoglycerate The enzyme
phosphoglycerate mutasc catalyzcs a reversible sh ft of the phosphoryl
Dehydration of 2-Phosphoglycerate to Phosphoenolpyruvate In the
with high
phospho
SICup between C-2 and C-3 of glycerate, Mg" is csser tial for this reaction: d 8ycolytic reaction that generates a compound
reversible removal of a mol-
y Rroup transfer potential, enolase promotes phosphoenolpyruvate:
uC water from 2-phosphoglycerate to yield
HÇ-OH
phes ptogtyerrate HÇ-0-
CH-0 utase
CH-CH --0-P -0
enolase
C-0-P-0
CH
2-Phosphoglyoerate PhosphoenolpyTuvate
3-Phosphoglycer ate 2-Phosphoglycerate
AG" 7.6 kJ/mol
AG°= 44 kJInol
change of this reaction.
The reaction occurs in two steps (Fig 15-6) A phosphoryl group initially espite the relatively small standard free-energy ot
attached to a His residur of the mutase is transfcrred to the hydroxyl group standard free energs of hydroly'sis
The iere ls a very large diffprence in the and product: -17.6 kJ/mol for 2-phos
at C-2 of 3 phosphoplycrate, forming 2,3-bisphosphoglycerate (BPG). the phosphate groups of the reactant kJ/mol for phos-
is then transfered to ester) and -61.9
phosphoryl group at C3 of 2,3-bisphosphoglycerate OBycerate (a low-energy phosphate compound) (pee Fig. 14-3
and regeneraling the
the s a m e His resiclue, producing 2-phosphoglycerate hoenolpyruvate (a super high-energY phosphateand phosphoenolpyruvate con
hosphorylatrd enzyne. Phosphoglycerate rautase is initially phosphory- able 14-6). Although 2-phosphoglycerate the water molecule
the loss of
which thus unctions as a coen- energy, of
lated by pho:phoryl trensfer from BPG,
and is an nearly the sane total causès
amount
a redistribution of energy
within the no
small quantities to iírutiate the catalytic cycle
3 e , it is required in
BPG is pres- rom 2-phosphoglyceratethe standard free energy of hydro.ysis of the phos-
outinuously yegenoratr d by that cycle. Although nost cells
in
Cule, greatly increasing
a inajor cornponent (5 nmu) of erythrocytes,
ent in only trace atnounts, it is
Ior oxygen (see Fig. 7-16).
phate group.
w here regulates the afinity of hemoglobin
It Phosphoenolpyruvate to ADP
employs essentially the Transfer of the Phosphoryl Group from
The enzyTIe plhosp hoglucomitase (p. 518) ( of the phOsphoryl group from phos
mutase. Phosphoglucomutase con The last step in glycolysis is the transfer
Same mechanism aS phosphoglycerate which requires
pyruvate kinase.
epts glucose 1 phosplhate into glucose
6-phosphate, with glucose 1,5-bis phoenolpyruvate to ADP, catalyzed by
is given to
The general name mutnse R and either Mg*" or Mn*":
ospate serving as the roenzyTie.
a [unctional group frorn one position
yaes that catalyze te transler of
toanother in the sane molecle. Mutases
are a subclass of isomerases, en
stereoisomers or structural cr positional isonmers
ynes that interconvert
C=0 +
(see Table 8-3) o- +P) yruvate
kinae
CH3
CH
RibAdenine
Pyruvate
'hoaphoenolpyruvate ADP RibAdenne x
FnzyTme latod
pnosphorylated
ATP
tlis resiaue ADP ATP
e mdase teaclion. AG°= -31.4 k/mol
2,3-Bisphosphoglycerate 3-Phosphoglycerate
kindve
inial
phoapharylatíon
ofenryme 3-Phosphoglycerate phosphorylation, the product
pyruvate fîrst appears
In tdis substrate-level nonenzymatícally to its
keto
tautomerizes rapidly and
lL:i cnol form, then reaction has a large,nega
at pH 7. The overal
O~P 0
, which predominates spontaneous con
change, duein large part to the
ive nandard free-energy 14-3). The
to the keto form (see Fig.
Pho:plhnenzyune form of pyruvate abou: half of this
vTon of the enol
hydrolysis is -61.9 kJ/mol; aumerization
A " of
phosphoenolpyruvate
phosphoanhydride
bond of ATP
fcrmation of the
conserved in the
phoaphoglcerale TRy is
and the rest (-31.4 kJ/mol)
dr.
constitutcs a lurge
Pyruvat
mutaie ( A = -30.5 kJ/mol) 1The pyruvau:
kinase Pyruvate keto orm
toward ATP synthesis. (engl 1orn)
the reaction concitions and is
en
(D2,3-Bisphos-2 elug lorre pushing i r r e v e r s i b l e under
intracellular
tion is essentialy
phoglycerate Fr regulation, as
described later
nriant site ol
 and the Catabolism of Hexoses 539
Chapter 15 Glycolysis
Metabolism
3nd
rt h
The enzyme Phosphoenolpyruvate In the
Conversion of 3-Phosphoglycerate to 2-Phosphoglyceratethe Dehydration of 2-Phosphoglycerate to with high phospho-
sh t of phosphoryl a compound
phosphogycerate mutasc catalyzes reversible COnd &ycolytic reaction that generates
a
reaction: reversible removal of a mol-
C2 and C3 of dyvcerate, Ms' is esser tinl for this enolase promotes
Soup
belwren
y Rroup transfer potential, to yield
phosphoenolpyruvate
Cule of water from 2-phosphoglycerate
0
HC OH
phesphogtyerrate HC-0 C-0-P-0
H-0 - -0-P enolase
CH-OH
O-CH,
Phosphoenolpyruvate
2-Phosphaglycerate 2-Phosphog'ycerate
3-Phasphoglycerate
S0"° =7.6 kJ/mol
AG 4.4 kJ/inol
initially standard free-energy change
of reaction.
this
The Teaction occurs in !wo steps (Fig 15-f) A phosphoryl group espite the relatively snall in the standard free cnergs of hydrolysis or
transferred to the hydroxyl group
a:tached to a His residur of the mutase is there is a very large difforence kJ/mol for 2-phos-
(BPG). The the reactant and product: -17.6
at C-2 of 3-phosphoglyceTate, forming 2,3-bisphosphoglycerate
is then transferred to
the phosphate groups of phosphate ester) and
-61.9 kJ/mol for phos
phosphoryl group at C3 of 2,3-bisphosphoglycerate DOgycerate (a low-energy 14-3,
phosphate compound) (see Fig. con-
and regenerating the
the same His residue, producing 2-phosphoglycerate oenolpyTuvate (a super high-energy and phosphoenolpyruvate
Inutase is initially phosphory Table 14-6). Although 2-phosphoglycerate
phosphorylated enzyrne. Phosphoglycerate the loss of the water
molecule
which thus unctions as a coen- the sane total amournt of energy,
lated by phosphoryl tr:nsfer from BPG, nearly
in
within the no!
initiate the catalytíc cycle and is causes a redistributiorn of energ
7y e , it is Tequired
in small quantities to ron 2-phosphoglyceratethe standard free energy of hydro.ysis of the phos-
that cycle. Although in most cells BPG is pres- ele, greatuly increasing
Continuously regeneiati d by
is a inajor cornponent (~5 m)
of erythrocytes,
ent in ondy Lrace anounts, il
for oxygen (see Fig. 7-16).
phategrouD.
uhere it regulates the afinity of hemoglobin Phosphoenolpyruvate to ADP
employs essentially the 9 Transfer of the Phosphoryl Group from
The enzyme phosp hoglucomutase (p. 548) transier of the phOsphoryl group
frorn plios
Phosphoglucomutase con 1'he last step in glycolysis is the
same mechanisn a s
phasphoglycerate mutase. which requires
into glicose 6-phosphate, with glucose 1,6-bis- phoenolpyruvate to ADP, catalyzed by pyruvate kinase,
veris glucose 1-phosphate
to
The general name mutase is given K and either Mg** or Mn**:
phosphale serving as the coenzyine. frorm one position
1e transfer of a functional group
rnzyTaes that catalyze
Mutases are a subclass ofisomerases, en
o another in the s a n e molecule. isomcrs
stereoisomers or structural cr positional
7ymes that interconvert
(sce Table 8-3) pyruvale
kinone
H3
CH
donine
RibAdenine
Pyruvate
Phoaphoenolpyruvate
ADP
RibAdenine
Enzyme with ATP
unphosphorylated
te muase racion
His resiaue ADPAATP
initial 2,3-Bisph0sphoglycerate -3Phosphoglycerute AG°= -31.4 kJ/mol
kindue
tpslho phosphorylation
ofenryme 3-Phosphoglycerate the product pyruvate first appears
Iu tdis substrate-level phosphorylatíion, nonenzynalícally to its keto
then tautomerizes rapidly and
t enol form, 7. The overall reaction has large, nega-
a
fun, which predominates pH
at
-0-P-0 to the spontaneous con
change, due in large part
Pho:phocnzyne v ilaundard free-energy of pyruvate to the keto
form (see Fig. 14-3). The
wlon of the enol form abou: half of this
hydrolysis is -61.9 kJ/nol; Lautonerization
A of phosphoenolpyruvate
in the fcrmation of the
phosphoanhydride bond of
ATP
phosphoglcerate
TKY is conserved dr-
kJ/mol) constitutes large
a
=-30.5 kJ/mol) and the rest (-31.4 Pyruvat
N the reaction towardl ATP synthesis.
The pyruvate kinase Pyruvae
(enol forn) (koto form)
(O2,3-Bisshos- lg orce pushing under intracellular
concitions and is an
phoglycerate Tl i o n is essentialy irreversible
as described later.
luprlant site of regulation,
 Gnapter L d
Glyceraldehyde 3-phosphate
Part 11 Bioenergetics and Metabolism
form specific corn
noncovalent NAD,P
urhermore, some glycolytic eruyines whlch may organize reacuon
NAD 1,3-Bisphospho-
The OveralI Balance Sheet Shows a Net Gain of ATP A Land structural components of theofcel,
intermediates between cemiar
Eycerato NADH
nces assure effcient uransfer NADH
We can now construct a balance sheet for glycolysis to account for () the and aldolase, for example,
bnd
to
fate of mpartments. Phosphofructokinuse-1 nto close assoCiation ad
the carbon skeleton of glucose, (2) the input of Pi and ADP and ihe
output of ATP, and (3) the pathway of electrons in the oxidation-reducion ucrOnlaments, bringing the two enzynmes increase).
ilering the catalytic properties aldolase (both Km and Vmax
reactions. The left-hand side of the following equation shows al
the inputs leXokinase binds speciically to the outer nitochondrial membrane, per Slow Fast
of ATP, NAD", ADP, and P, (consult Fig. 15-2), and the right-hand move directiy to
side within the mitochondrion to
shows all the outputs (keep in mind that each molecule of gucose yields HAJS allowing ATP produced without enterins, and being diuted by. the
site of hexokinase
two molecues of glyceraldehyde 3-phosph:ate): e catalyticC channeling through muti- ADP
ylosol. There is strong evidence for substrate
Glucose+2ATP and many enzyTnes no
+
2NAD + 4ADP
+2P
4ATP+ 2H,0
yme cornplexes in other metinbolie pathways,
cell as lughly organized
2ADP +2NADH 2H" + as "soluble" probably function in the A TY
2 pyTUvate + +
tought of
that channel intermediates.
Canceling out common terms on both sides of the equation gives the over c(oplexes
all equation for glycolysis under aerobic conditions:
Glycolysis Is under Tight Regulatlon
Glucose +
2NAD +2ADP +2P, Louis Pasteur
2 pyruvate + 2NADH + 2H* + 2ATP + 2H,0
uring his studies on the fermentation of glucose by yeast,
discovered that both the rate and the total amount of glucose conisurnpP
anaerobic thar. aerobic conditions. ADP
The two molecules of NADH formed by glycolysis in the cytosol are, un- on were many tirnes grenter under
in the rates ot
ster studics of muscle showed the same large difference
der aerobic conditions, reoxidized to NAD' by transfer of their electrons to
the respiratory chain, which in eukaryotic cells is located in the mitochot BIMAerobíc and aerobic glyeolysis, The biochemical basis
of this Pasteur
"
ATP
"fect" is now clear. The ATP yield frcn gly colysis under anaerobic eon 3-Phosphoglyccraue
dna. The respiratory cluin passes these electrons to their ultimate destina
srnaller than that from
tion, Op: lltions (2 ATP per molecule of glucose) is much 8uhistrnte channclin
aerobic conditions (30 or Secuential action of.
2NADH+ 211 +O 2NAD* + 2H,0 ofglucose to CO, under tirnes as much glucose
Ine cornplete oxidatlonsee r enzyno hrouglha hunctional
'1able 19-5). About 18 ooupledt Lwo énzyTnes
APEr Bucose,
must therefore be consumed anaerobically as aerobically o yiera u e ohoevaratoy 3bigphosphoglycernto
Electrontrarsfer frorn NADH to 0, in mutochondria provides the energy for
syTthesis of ATP by respirntion-linked phosphorylation (Chapter 19). hine aunOunt of ATP. 1,binphoapnag nver relensed to the "
nover relensed
is regulated to onzyinerhgecond #i olvent2
in the giiicose through the glycolytic pathway
process, one molecule of glucose is
overall glycolytic
of pyruvate (the pathway of carbon). Two molecules of
converted nux o
ne constant
Achieve ATP levels (as well as adequate supplies of glycolytic in
totwo molectles lernediates that serve biosynthetic roles). The required adjustrdent
in the figure 15-8
ADP and two Pareroverted
of to two molecules of ATP (the pathway of
alosteric regulation of Lwo glycolytic Channeling of a substrate between two enzynes
in the
phosphoryl groups) F'oiur electrons, as two hydride ions, are transtered ate of glycolysis is achieved by the glycolytic pathway. V/hen glyceraldehyde
3-p11sphate
secod-to-
Irom two molecules of glyceraldehyde 3-phosphate to two of NAD" (th PVZyTnes-phosphofructokinase-l and pyTuvate kinase--by denydrogenase (blue) and 3.phosphoglycera'e
kinase
metabolites that rellect the
4econd luctuations in the concentration of key
pathway of electrons). 3t whicr they
(ye:llow) are combined in vitro, the rate
We retumm to a
(elular balance between ATP production and consunption.
atalyze the two-step conversign G Blyceralde"/de
-5
Intermediates Are Channeled between Glycolytic nes
Nore detailed discussion of the regulation
of 2ycclysis 1ater in une cnapter. pojthate to 3-phosphoglycerate (ee Fig3
15-6) exceeds the rate at whuch the lirststep13 Culyzed
Athough the enzynes of glycolysis are usually described as soluble co
1issue
Ir the presençe of the first enzyme orily ApCasnt"y
the
ponents of the cytosol, growing evidence suggests that within the coll Glucose Catabolis1n Is Deranged in Cancerous d rect transfer of 1,3-bisphosphoglyce ra:e frcn he
these ten times faster in nost solid danydrogenase to the kinase (right) occurs '25'er tr3n
enzyTnes exist as ultienzyTne complexes. The classic appruach Glncose uptake and glycolysis proceed about
Tumor cells comrnonly experience the dissociation of 1,3-blsphosphoglycerate i'ori tr:e
of individual proteins from extracts of brokrn
enzyTnolog-purification nnors than in nonicancerous tissues.
because they inútially lack an
extensive dehydrogenase into the surrounding nedium iet)
cels-was applicd vitlh great success to the enzymes of glycolysis. Hw liypoxia (linited oxygen supply) hysical studies show that the two enzymes can
form a
cancer cells
ever, the first casualty of cell breakage is higner-level organization witlun the tumor with oxygen. As résuit,
a
stable complex, as is requlred for substrate chnneling
1pyllary network to supply anaerobie
cell-the noncovalent, reversible interaction of one protein with anotlr t the nearest capillaries depend on
I1ore than 100 to 200 pem frorn
betvween trhen.
more glucose
of an enzynme with some structural component such as a membrane, niv ATP production. They take up
elyrolysis for much of their and then to lactate as they re
ibule, or microfilanent. When cells are broken open, their contents, tluan nornal cells, converting it to pyruvate frorn srnaller
cludng enzy1nes, are ciluted 100- or 1,000-fold (Fig. 1-7). rate may also result in part
rych: NADH. The high glyçolytic
in tunor cells; less ATP made by
nitochondnal
Wen the purified enzy1nes of glycolysis are cornbined in vitro al pnbers ol rnitochondria
tively high concentiations, they torn specilic. functional aggregales, needed from glycolysis. In addition,
wl Xlalive phosphorylation mearis more
severa. glycolytic enzyTnes, including an
Itay rellect their true stale inside cells. Several types of evidence sut e taurnor cells overproduce
associates with the cytosolic face
of the nito-
hit, in cells, slich complexes ensure efñcient passage of the produt
Iiuuyne of hexokinase that fe2dback inhibition by glu-
one enzyme reaction to the next enzyme in the pathway. Kinetic evilew and is insensitive to
tlundrial inner mesmbrane
, 0 t n by uller for the channeling of 1,3-bisphosphoglycerate from This enzyrne may ronopolize
the ATP pro-
l r
/yrri
euul rations glyceraldel1vl ( 6-plhosphate (p. 555).
to convert glucose to glucose
6-phosphate
1,2, ud 3, phosphate dehydrogenase to phosphoglycerate kinase without its entem idrrd in nitochondria, using it of
The protein products
sohut on (Fig. 15-8) is corroborated by physical evidence that thea tn 1l cOnitting th: cell to contirued giycolysis. e (digcussed in
 Fates of Pyruvate under Aerobic
and Anaerobic Conditions Concentrations of Uxygen: Athletes, Alligators, and Coelacanths
Limiting
wPynuvate represents an important junction in cartohydrate
catabolis1n (Fig. box15-1 Glycolysis at
15-3).tnder aerobic conditions pyruvate is oxidized acetate, which
to en-
aerobic organ- must be followed by long periods of recovery.
and NADH formed Most vertebrates are essentially
ters the citric acid ycle and is oxidized to CO, and H,0, to pyruvate by glycol- The last emergency movements require l&ctic
is reoxidized to isms; they convert glucose
by the dehydrogenation of glyceraldehyde 3-pliosphate completely to CO acid fermentation to generate ATP in skeletal
in mnitochondrial respiration. How. ysis, then oxidize the pITIvate
NAD by passage of its electrons O,
to Anaerobic c a muscles. The stores of muscle glycogèn are
such as in very active skeletal rmuscle, in
and H20 using molecular oxygen.
ever, under hypoxc conditions tabolism of glucose to lacate
occurs during short rapidly aspended in intense muScular acürity,
subnerged plant parts, or in lactie acid bacteria, NADH generated by gly- bursts of extreme muscular activity,
1or example and lactate reaches very high concentratio!:s in
NAD" would leave
colysis cannot be reoxidized by O,. Failure to regenerate in a 100 m sprint, during which oxygen
cannot be muscles and extracellular fAud. Whereas a trained
the cell with no acceptor for the oxidation of glyceraldehyde
electron
carried to the muscles fast enough
to oxidize athlete can recover froma 100 m sprint in 30 nin
would stop.
3-phosphate, and the energy yiclding reactions of glycolysis pyruvate. Instead. the
muscles use their stored or less, an alligator nay require many hoLrS of
therefore be regenerated in some otlier way. ATP by rest and extra osvgen consumption to clear the
NADThemust
earlest cels to arise during evolution lived in an atmosphere al glucose (glycogen) as fuel to generate
excess lactate from its blood and regenerate
end product. In
for deriving energy
fermentation, with iactare as the
most devoid of oxygen and had to develop strategies a sprint, lactate in
the blood builds up to high muscle glycogen after a burst of activity.
from fuei molecules under anaerobic conditions. Most modern organisins concentrations. It is slow:ly converted back
to Other large animals, such as the elephant and
NAD" during anaerobic (Chapter
liver rhinoceros. have similar metabolic probiems, as
have retained the zbilty to continually regenerate glucose by gluconeogenesis in the
NADH to form a reduced end prod- do diving mammals such as whales and seals. Di-
glycolysis by transfering electrons from 19) in the subsequent rest or recovery period, nosaurs and other huge, now-extinct ariials
lactate or ethanol. v at a gradually
uctsuch as during which oxygen is consumed
diminishing rate until the breathing
rate returns probabir had to depend on lactate fermenta:ion
in Lactic Acid Fermentation
Pyruvate Is the Te minal Electron Acceptor
to supply energr for nuscular activity, follawed
to normal. The excess oxygen consumed in the
with sulficient oxygen to support by' very long recovery periods during whuch they
When anumal tissurs cannot be supplicd NAD" recovery period represents a repayinent
of the
and NADH produced in glycolysis, amount of oxygen re. were vuinerable to attack by srmaller preda:ors
aerobic oxidalion of the pyruvate oxygen debt. This is the
to lactate. As better able to use oxygen and thus better adapted
is regenerated from
NADII by the reduction of pyruvate quired to supply ATP for gluconeogenesis during
and cell types (siuch as erythrocytes) pro- the Lo continuOUs, sustained muscular activity
mentioned earler, some tissues recovery respíration, in order to regenerate
even under aerobic
coriclitions. The reduction of to eep-sea explorations have revealed rian
duce lactate iron1 glucose
the L iso- glycogen "borrowed" fror liver and muscle
Inctate dehydrogenase, wBhich forms in the sprint. species of marine life at great cean dep:hs,
PyTUvate is catalyzrd by carry out intense muscular activity
reaction strongiy fa- where tie Oxygen concentration is near zero tor
mer of lactàte at pll7
The ovcrall equilibrium of this The cycle of reactions that includes glucose con
lactate forniat9n, as showIn by
the large negative standard free-energy version to lactate in muscle and lactate conver- exaraple the primitive coelacanth, a large thsh re-
VOrs
sion to glucose in liver is called the Cori cycle, for covered frorn depths of 4,000 m or more off the
change. ol the two mo ecules of glyceraldehyde coast of SOuth Africa, has an essentialy ana+ro
In glycolysis, deltydrogenation Carl and Gerty Cori, whose studies in the 1930s
converls two molecules and 1940s clarified the pathway and its role. bic rierabolisn in virtually all its tissues. lt con-
from each molecule of gucose
3-phosphate derived of pyru- verts carbohydrates to lactate and other prod
Iate B:cause the reduction of two molecules The circulato:y systems of most sTnall verte
of NAD' to two of N.ADH.
nolecules of NAD", the overall brates can carry oxygen to their muscles last ucts, Inost of wtuch must be excreted. Some
regeerales two
vate to two of laci.ate
enough to avoid having to use muscle glyc0gen marine vertebrates ferraert glucose to ethanol
process is balanced
and can coritinue indelinitely.
oxidation- and CO. in order to generate ATP
to lactale includes two anaerobically. For example, migrating birds
often
Although convrsion of glucose oxidation state of carbon; in
reduction steps, there is no
net change in the fly great distances at high speeds without rest
Cratio is the sanie. Nev
acid (CH,0,), the H: and without incurring an oxygen debt. Many r u -
glucose (C;H,0,) and lactic has been extractecd
níng aninals of moderate size also maintain
an
of the glucose.molecule
eftheless, some of 1he energy two molecules of
a net 1eld of
to lactate, enougi to give essentially aerob.c metabolsm in their skeletal
by ils conversion lactate foiNed by active
niolecule consumed. The muscle. However, the circulatory systens of
ATP for every glucose to the iver where
it is carried in the blood larger anirnals, including humanis, caniot com
skeletal muscles ca be recycled, strenuouS muscular ac
if is converled to glucose during
the recovery fronm
uscle
pletely sustain aerobic meabolism in skeletal
in large quantilies cluring vigorous muscles during long bursts of rmuscular activity.
ivity. When lactate ia produced cidilication that resiull: These anirnals generally are slo-moving under
O n t r a c t i o n (during a sprint,
for exain:ple), the
causes pain and linits the nornal circunstances and engage in intense
.tle acid in muscle and blood
IO ionization of la:tic The best-conditioned athletes cn sprint for u muscular activity orly in the gravest emergen
period of vigorous activity.
l5-1). cics, because such bursts of activity require long
n o r e than a ninute (Box hexoses to lactale
ferment ghucose and other recovery pericds to repay the oxygen debt.
Many microorg1nisims fermment he lkctose in
streptococci, for example, Alligators and crocodiles, for Cxample, are
(Crtain lactobacilli and to lactate and H'
in th normally sBuggish and torpid. Yet when provoked
dissociation of lactic acid
nilk to lactic acid. "The casein and other milk pro these anirtials are capable of lightrirng-fast
fermentation mixture lowers
the pH, denaturing
controlled codi charges and dangerous lashings of their powerfui
Under the correct,
them to precipitate.
1 u s and causing
cheese or yogurt, depencing
on
tl tails. Such intense oursts of activity are short and
curdhing produces
ios, the resultant
ticmoanisan. x 4. 12.
 -
-

POCO
SHOT ON POCO X2
 i s 3nd Metabolism
Crapter 15 Glycolysls and the Lataouuun
15-1
Some TPP. Dependent Reactions
Feeder Pathways for Glycolysis lu tho Hly
Entyme glucos2 ineet their catzbolic ale
Pathway Bond cleaved Mary carbohydrates besides the glycolytle lnternmecll.
Bond formed translormed to one of
colytic pathway, after being polysacchariclcs glycogen und
are the storage
Pyruvate decarboxylase ates. Tte inost significant and tlhe
Alcchol fermentation lactose, trehalose, aml tucroA0,
R-- Starch, the clisaccharides maltose,
R-C monosucharides fructose, mannose, and galactose
(Fig. Ih-11)
Pyruvate dehydrogenase Synthesis of acetyl-CoA
a-Ketoglutarate dehydrogenase Citric acid cycle R2-C trehaluso Jactase
SCoA
OH
Transketolase Carbon-fixation reactions of OH Rbesgenatar
photosynthesis --R* R-C-C-" P
phosphorylas0 UDP-galactese
O Sucrose UDP-glucose
Acetolactate synthetase Valine, leucine biosynthesis Glucbse
R-C-C 5UTAS0
47P
1-phosphate ETCEOiL
7exokinase
pkosphogluco
matase
Gtcuse HO o7oH
n Pphate
Microbial Fermentations Yield Other End Products 2 hospho
of Commercial Value
Mant
Lactate and ethanol are common products
nexokinase Abeokinas
Mannose 6-phosphate
of microbial
they are by no means the only possible ones. In 1910fermental ATPru n h v i n ) Fructose
Chaim Wi n b:phphate
Mo ATP phos - hoiomanose
(later tc become the first president of Israel) discovered that the hn Pructose I plhosphat
Clostridium acctobutyricum ferrnents starch to Aop ho
butanol and acel 1uctos0 1.
phosphate Wresetolks nas e
discovery opened the field of industrial fer+nentatlons, in
wii hldolaso
readily available material rich in carbohydrate (corn starch or mola Fructoze 1.6.
example) is supplied to a pure culture oÍ a specific microorganis, n bisptosphate figure 15-11
Glyceraldehyde + Dihydroxyacetone
fernents it into a product of greater value. The nethanol use:1
phosphate
Aldolas e starch, disaccharides, and
"gasohol" is produced by nucrobial fermentation, as are formic, iarrl Entrytheof glycogen,
into pieparatory stage of gl'ycolysis.
pionic, butyric, and succinic acids, and gycerol, cthanol, isopr ATPoue uriose phosphate
i50merabe Glyceraldehyd
Lanol, and butanediol. These fermmentations are generally carT
3-ploaphote
huge, closed vats in which tenperature and access to air are aljurt t . f
vor the muliplication of the desired nmicroorganism and to exehwh d
ADP
-
The
ninating
that
organisms (Pig l5-10) beauty ofindustrial f r r t Glycogen and Starch Are Degraded by Phosphoro'ysis
conplicated, nultistep
chenucal transformations are
. and s'arch1 enter the
The ghicose nits of thc outer branclhes of glycogea
higli yieldsand with few side products by chemical factories ulhat actiwn of w o enzyu4:5: glycogen
themselves-microbial cells In
some cases iw
it is possible to dus ghycolyic pathway through the sequential
cells in an inert support, to pass the starting material corntinnn, t.. plusptorylase or lho simihr starch ohosp!horylase 1 pl.unts, and pliospho-
t e tea: ioJ ii w)ich an
a bed of irnnuobilized glucni.tse. ilycoyt1 pluosplorylase catalyze:
cells,and to collect the desired pronlrl two glirose r : i e s in glycogen
nder
entan engineer's drean! (el-i) giyrosili: linka" joning
te trrunal glicose resirlue
goes allack by inorune phosplhate, cenoving
This phosp ornlysis reaction is
as a-D-gliicose 1 phos1pl:te (Pig. 15-12)
figure 15-10 clifferent from the hydiolysis of glycosilic bods by anylase during in
lestina! degradation of glycogen or starcI. In phosphorolysis, SOne of the
Industrial-Scale fermentation. Microorganisms are cul. C
lured in a slerilizable vessel containing thousands of liters is preserved in the lornatjon of"he piosphat
energ of the glycosidic bond 0-P-OCH1
of growth nedurn-an
inexpensive source of both
Carbon and eriergy-under carefully controlled condi-
ester, glucose 1-plh0sphate.
the glycogen phosph9
tio's, includirig low Oxygen concentration and constant Pyridoxal phosphate is aii essential cofactor u CH,
acirl catalyst, proniot
emwtture, Afler centrilugal separation of the cells from rylase rection, its phosphate group acts as a gereral
different rolc of pyridoxal
t rowtt nwdaun, the vakuable products of the fermen ing attack by P, on the glycosidic bond. (A quite Ptu ,plite
hn oalle or trom Ijp Siuner- netatolsn is desc nitei in det:il in
phospiate as a cofactor in amiro acid
 at 1 ixnergetics and Metabolism
Several Points
Patliway at
Enter tho Glycolytic ial'tr
Uther
Monosaccharides
can undergo glyeolysis
utlher tlun glucos( trée 1otin
ost orgHapisms,
huex»Ss
I-Pructos, presel n
i derlvntivo. ye ot
s t sidue trom the plhoaplhorylated sinall ntest
CH,OH Coversiot Lo a
of sucrose in th
SYOn cain by syEen CHOH fruils and forned by hydrolyals
n ny
H Is pluonphorylated by wxokinuse
Vortebratn,
ADI
OH H OH Lo- F r u e r e A T P , fruetue -phuuphato
1
the muscles
and
fructoso entry
nto glycolysls in Ihe
OH Ol Glycogen chain pathway of clifferent pathway.
glucose' This Is alnnnjor
tho liver, however, ructose
enters by a
phosphorylation
ol Iructose a
sg en djry. ructoklnase cutalyzes the
phos phor 1ase cAyTO
AvOr
rather tlan C-6
Yonrduc Fructono NTP fructose 1-phosphate +ADP
CHOH clL,OH and dhydrcxy Galactose
cleavecd to gyceraldehyde
hee fruetoe 1-plwiphat s then l-phosphate aldolase:
AT
H
H/i H etone phsphato by
fructose
galactokinase ME
HoH -0-P-0 0 A
CHa-0-P-0
H OH H OH CH,OH
Dihydroxyacetone
Glucose 1 pho»faate Glycogen shortened CIla-0P-0 phosphate
by one residue CH,OH
glucose'-1
HOCH
OP -D Galactose 1-phosphate
Iructoe -phosphale OH
(al-6) Glycegen pihasphory lase (or starch phosphorylase) acts repetitively on HCOH C Clyce raldehyde CDP-glLcote--(alactose l
linkage the nonreiuczg ends of glycogen (or amylopectin) brarnches until
reaches a point four glucose rusidues away from an (al->6) branch
FcOH HCOH
UDr phosphate undyltrisirr33*
glucose
poin CH,OH CHOH Glucose 1-phosphate
(see Fig. 8-15) where its ction stops. Further degradation can occurons Fructone 1-phosphate
after the debranching enzyme, formerly knowT as oligo (al->6) to
3-jphosphate CH,OH
(l-4) glucantransferase, catalyzes two successive reactions that re- converted to glyceraldehyae
Dilydroxyacetone phospluite is Glyreraldelyle is
-0
move brenches (Fig 13-13). phosphate isornerase.
glycolytic enzyine triose hte
by
toglyceraldeliyilhe3-phni
Glucese 1-phosphate, the end product of the glycogen and starch phos- the
and triose kinase
phorylase react:ons, is converted to glucose 6-phosphate by phosphoglu uosphorylaled by ATT
ADP
comutase, whuc1 catalyzes tlie reversible reaction
ATP Klyceraldehyde 3.phosphhnt IHO
FIN
Cyceraldehyde
1-phosphate hydrolysis
enter th giycvi 0--
Glucose 1phosphate glucose 6-phosphate Thus both produets ofirue
tose
Phosphogucomtase requires as a cofactor glucose 1,6-bisphosphate, paliway as glyceraldelyde
3 phosphate.
the disaccharide lactus
(1uk oCH
the of hydrolysis of UDP-galactose
a role analogous to that of
which has 2,3-bisph
phoglycerate mutase reaction (Fig 15-6). In phosphoglucomutase, how
osphoglycerate in phos D-Galactose, a product
is lirst phospliorylated
at G-1 at the expense
of ATP uy the y 7 e
ugar),
ever,the hydrosyl group of a Ser residue (rather than a His residue as in galuctolklnase:
phosphoglycerate mutase) undergoes phosphorylation and dephosphoryla- ADP AD
pm r e
Galactose ATP * galactose 1-phosphate
tion in the catalytic cycle.
to its epiner al hcos (-1.
is then converted
1-phoslhate diphosphate (t'DP)
Thegalactose reactions in vhich uridine
CH,OH
by a set it
1-phosphale, l5-14).
functions as a
coenzyme-like carrier of hexose groups (Fig. H
4- figure 15-13 figure 15-14
Glycogen breakdowin near an (al->6) branch point. to o-2lucOs2
1-phosphate
Following ire SEqLEnial rernoval of terminal Blucose Conversion of D-galactose
The prGcecds
conversion
through a
sugr
esidues by gIycogri phosphoryiase (see ' 8 . 15-12
Blucose res iues near a
branch in a lwO-
are removed

1-phosphate.
nucleotide derivative,
UDP-galactose,
wren galactosee I-pn05pnale displaces

wich s
g'uco0
torried
1, 0-P-O
lucoas
Siep process trat zq uires a bifunctional "debranching
enzyne,st, hE ('anslerase aclivity of the enzyme -phosphate from
UDP-glucose. UDP g3lactce
Converted by UOP-glucose 4
Cpimerase to

te
is
JDP-gluOSe -CHo
nfts 2 blo: of tnre? glucose residues from the branch
is rccycled through
aother rourd of
the
UDPglurc4
to i i : a t y n>rre: Jcing end, to whicth they are re- The UDP-glucose the coverson
effect of this cycle is
allached r. (ul--4) linkage. The single glucose residue sa ne reaclion.
The net to glucose 1-phcsphate,
trere is
t
t : Dräich point, in then
(al>6) linkäge, IS ofgalactose 1-phosphateconsurnption of UDP ga actose
or
remainin prouclion or
p'C5e by the debranching enzyme's rc net
eear ot iree
h e plucose residues are UDP g'ucose
(xl) os cEs2 ar wily.
 15 Glycolysls and the Catabolism of Hexoses
Chapter
KKA
Several human genetic diseases result in disordered galactose
in the most common form of metabolism. countries. In
galactosemia, the enzyne
UDP-glucose- with lactiuse are conimercialy avallable in sonie
galactose 1 phosphate uridylyltransferase is genetically defective, predigest:d
several or all of the
intestinal disciccluuiluses are
ing the overall conversion of prevent Certain hurman disorders, disturbances triggered by dieraryi-
galactose to glucose. Other forms of the cllgeative
tosemia res lt when eicher galac- TUSsing. In these case:s, controlled diet.
galactokinase or UDP-gucose 4-epimerase is ge- Saccharides can aometlnes
be mlnlmized by a
netically delective.
D-Mannose, released in the digestion of various polysaccharides and
sly coproteuns of foods,
can be
phosphorylated at C-6 by hexokinase: Catabolism
Mannose+ ATP
Regulation of Carbohydrate bo:h ATP and a variety
of precursors for
mannose 6-phosphate +ADP Carbohydrato catabollam provldos
to maintain the
concertration
It Is cruclal for a cell
Manese 6-ohosphate is isornerizcd by phosphomannose blosynthetic procesoes.
of which fuel is used
to pro-
i i fnictose 6 phosphate, an internediate of slycolysis. IsomgrAse to
of ATP ht a ncarly constnnt level-regardless
ATP is consumed. Similarly,
biosyn-
the rate at whiçh'
duce the ATP andderlved from carbohydrate catabolism (for exampe, fruc
tlhetle precursors or 3-phosphqglycerate
for
Dietary Polysaccharides and Disaccharides tose 6 phosphuate for
glurosamine synthesis,
amounts. An orgarism
in adequate
Are Hydrolyzed to Monosaccharides unino
must be provided
acld syntlesis) muscular increased ac
circumstances, such as
For most humans, starch is the major source of carbohydrates in the that undergoes a change in intake of car
diet. or decreased dietary
availubility of oxygen, catabolic pathways and
Digestioh begins in the mouth, where salivary a-amylase hydrolyzes the in tivity, decreased
ux through its
ternal glycosidic linkages of starch, producing short polysaccharide bolydr ite, nust aljust the rate of reserves mobi-
frag- turning to fuel
source of fuel as well, perhaps
ments or oligosaccharides. In the stornach, salivary a-amylase is inactivated possthe These changes in
catabolic patterns are accom
by the low pH, but a second form of a-amylase, secreted by the pancreas llzed ondy in tine of nced. the catabolic pathways.
In gly-
of key enzymes in
into the small intestine, coritinues the breakdown process. Pancreatie pllsted by the regulation play a regulatory
role:
liver tissue, four enzyznes
coly sis in muscle and hexokinase, phosphofructokinase-1, and pyTuvate
a-amylase yields rnainly maltose (the disaccharide a(1-4)
of glucose) and glycogen phosphorylase, necessarily involves
oligosacchandes called dextrins, fragnents of amylopect.n containing the regulation of glrcolysis
in.ase Our discussion of synthesis (glu
a(l6) brarnch points. Maltose and dextrins are degraded by enzymes of
s o e details of the
reciprocally regulated process ofgluco3e
20.
the intestinal brush border (the fingerlike microvili of intestinal epithelial cliscussed in Chapter
n c r e fully
coeogensis), which is we conSider
cells, which greatly increase the area of the intestinal surface). Dietary of gucose catabolisiu,
Before describing the regulation of all biochemical
glrcogen has essentially the same structure as starch, and its digestion pro- that apply o the rezuiation
some general principles
ceeds by the same pathway.
pathwas.
Disaccharides must be hydrolyzed to manosaccharides before entering
cells. Intestinal disaccharides and dextrins are hydrolyzed by enzy1nes at Metabolic Valves
Regulatory Enzymes Act as adult orgausms gen-
tached to the outer surface of the intestinal epíthelial cells: with their surroundings,
Althougih not at equilibrium constait irnllux
of enerty and
state. By managing a
Dextnn t nti0 D-giucose eraly exist in a steady tle organistu antains
dextnnase relcase of waste products,
ntifrients a d a constant
dist turbed by s o I e tharnge
1 CorLStaat cOuposilion.
When the steady state is fiuxes
Maltose + H,0 2 D-glucose the teimporarily altered
circumstances c r energy suppiy,
tanltase in external mechanisms in
netabol.c pathways trigger regulatoiy
through inlivicdual adjustineits 1s to teturn
Lactose t H20- D-galactose + D-giucose The uet elfect of all these
ACLase tr:s to each patlway:. s t a t e - t o achieve
h o m e o s t a s i s . ATP has thhe
the org:nisIu to the steady organisns
and under selective pressure
Sucrose + H2O D-fructose t D-glucose centr.al ule in cellular activities, with reg-
ncras ne'work of catabolic enzyines
ave developed a hugihly integrated concentralion of ATP
ensure a high steady-state
Trehalose + H20 2 D-glucose ulat.ory properties that
trehnlaso breakdown products ADP and AMP).
(high relative to the depends on the
activities of
the epithelial ««ll, biochemical pathway
ostlnal ephlhellal cells. Although The monosaccharides so formed are transported into The lux through a
in a pathway such
then pass into the blood to be carried to various tissues where they a eacii reaction. For some steps
a l la: lasA, msl p l a teas0 to the enzy incs thal eat:alyz vilhin the cell, the
reartion is essentially at cquilibriurn
ltw i! and Th0otore are phosphorylated and funneled into the glycolstic sequence 1S JycoysIs, the substrate equilihrates
tolccted by trealinga Lactose intolerance, conon among adults of most human pojl. suffuciently highh that the
is
activity of the enzynie this step
Lilt
iath aitxly tal supplied. The flux through
sabstrate is
(1ons except those originating in Northerm Europe and some parts of Af 1with product as fast as the
etemined by the instantaneuus concen
is due to the disappearance after childhood of most or all of the lacta:a a is essentially substrale lmatel
vtu by lachi lo
Lactose cannot be completerly li tuation cf thhe substrale.
ivity of the intestinal cells (Fig. 15-15). are far fron equilibriun, The equilibriun con
and in the large intestile lh L cellular reactioIuS
Other
ested and absorbed in the small intestine, rcaction is about 250, but the rnass
l ye ly labl l e uole:lurn.l
tose is converted by bacteria into toxic products
that cause aboliuiu.l stut (F,) for the phosphofructokinase-I
1,6-bisphosphate}[ADPVlructose
-phosphatej[ATPI
i i t ( ) intestiai ratio [fructose
Cranps and diarrhea. In most parts of the world where lactose inloler.nn action
state is about 0 04. (The
intracelular concen
nilk is not used as a food by acults, although
inilk
prnlu!i 1n a typical cell in the steady
Iprevalent,
 exergonic reacijos, Co
rate-imiting steps are very thes0 exergm1C, Tate
conditions. Tho onzymos
that calalyzo
ahle 15-2 er celular motabolic regulati0n. very
Glycolytic Pathway commonly tho lurgols of of control in
cells. In
i n g steps
are
Intermediates of the
Oytosolic Concentrations of Enzymes and
regulatlon is a prlnary level
in Skeletal Muscle
Concentration (um)
rapid alosteric enzyma tho concentratlons of allosteric regulators may
Concentration ( ) Intermediate uicellular organlsms, hormonal control.
Hormone action alers tne
Enyme
Glucose 6-phesphate
3,900 themselves be under alower wlthin seconds or minutes,
allowing the
Al3 olase Si0
1,500 cCs
Of key enzymes, often coordinated (Onap
TrSe phosphate isoner ase 220 Fructose 6-phosphate dlfferent tissues and organs to be
Fructose 1,6-bisphosphate
30 netabollc uctivltles of clreumstances change over a longer time, as wnen a
Gyceraldeyde 3-phasphae external
1,400 Dihydroxyacetone phosphate 160 ter z3). When carbohydrate, TIUX
primarily, Sat to primarily the relative
dehydrogenzse
Phesphogycerste kinas 30 Glyceraidehyde 3-phosphate urnan'g dlet shints from can be changed by adjusting rates
240 1,3-8isphosphoglycerate
Chrough specllc pathways enzymes themselves, the
slow-
and degraclation of the regulatory
hsphogycerate mutz2
00 ynuncsis
Enalzse 540 3-Phosphogycerate 20
est level of control (Chapters 27 and 28).
PyTuvate knzse 70 2-Phosphog ycerate are situated at
critical branch points in me
Phosphenclpyruvate
65 Many regulatory enzymes the allocation of a metabolite to each
Lsctate dehydroge nase 20 380 abolisrn, ther activities cleternuning it
Pyruvate For example, glucose
Phosphoglucomutase
3,700 through wbich might pass.
of the several pathwaysmetabolized
Lactate -phosphate can be either by glycolysis or by the pentose
ATP 8,000 The first enzyme
600 phosphate pathway (described later in this chapter).
ADP and gucose 6-phosphate deny-
P 8,000 tinique to each of these pathways (PFK-1 "comnitted" step for its patnway.
NAD' 540 arogenase, respectively) catalyzes the control
50 Both are regulatory enzymes subject to by a variety oI allosternC
NADH
regulators that signal the need for the products of each pathway.
to out both t e ca-
Sourte: From Srivastzva, D.K. & Bernhar d. S.A 198/) Bophysical chemistry of metabolic Cells commonly have the enzymatic capacity carry
tabolism of a complex molecule into a símpler product and the anabolic con-
reacton seqUentes in concentrater solut on and
in the cell. Annu. Rev. Biophys. BiOphys.
Chen. 18, 175-204. version of that product back into the starting molecule. Glycolysis
degrades
converts pyruvate to glucose. Paired
Bucose to pJTUvate; gluconeogenesis
catabolic and anabolic pathways often employ many of the same enzyrues-
rarunn ((ar from trations of some glycolytic enzytnes and
intermediates are given in Table Lhose that catalyze readily reversible reactions. Phosptioglycerate
mutase,
qul.bnun 15-2) The reaction is so far froin equilibri:m
because the rate of conver for example, acts in both glycolysis and gluconeogenesis. However, paired
is limited by the dlirectiorn that
pathways invariably have at least one reaction in the catabolic
sion
of fructose 6-phosphate to fructose 1,6-bisphosphate
fructose 6-phosphate by Lhe pre ilfers froIn Ihe corTesponding step in the anabolic
direction and is cat-
activity of PEK-1. Increased production of of
netraie bmmted ceding enznes in the glycolytic pathway
does not íncrease the fux alyzed by a different enzyrne. These d:stinctive enzynes are th poiits
ihese
nrat eguhbrum through this step, biut to the accurnulation of
instead leads fructose 6-phos:
regulation of the two opposing pathways. The reactions calalyzed by
irteversible under
phate. Thus PFR-1 hnctions as a valve, regulating the
low oI
carbor
acti
path-specific enizýTnes are generally exergonic reactions,
cclular conditions and out of equilibriun in the stealy state, they
are
of this enzyme (by allosteric
through glycolysis, irncreasing the activity
overall lux through the pathway enzyme-linited, not substrate-linited. Havig one or not se arate eli
vation, for exanple) increases the
mass action (by ion ct the
iux through this pathway is determined not by
Metabolite zymes for catabolic and anabolic pathways allows separate regulal
extent of "opening" ol ux in each direction, avoiding the wasteful "rutle cyclir1g" that
would re-
product concentrations) but by the
substrate and
sult if the breaklown and energy-consuning resyrthesis of con1pound
a
this enzymatc valve.
one reaction that, in the cell,
is lu that con-
were allowved to proceed simultaneously. The regulatory enzyues
Every metabolic pathway has at least Fructose 6 phosphate
irom equilibrium because of Lhe relatively
low activity of the enzyme llil trol the rate of breakdown of carbohyirates via glycoly'sis
ilustrate these
reaction is not lirnited by substral general principles of metabolic regulation.
catalyzes it (Fig. 15-16). The rate of this
The reaction is said to ler t'a ATP
availability but by the activity of the enzyrne. P
zYme-limiled, and its rate imits the rate of the entire
because
reacleni a
Glycolysis and Gluconeogenesis Are Coordinately Regulated Glyoolysis Glucnaogoneis
such as PF6 1 FRPasm-T
quence, thestep is rate-limiling step in the pathway. In geriera, Ih
the Most organisms can synthesize glucose from sinpler precursors
called gluconeogenesis, oc
pyruvate or lactate. In marnmals this pricess,
curs priranly' in the iver, arid its
role is to provide gucose for export to ADP
other tissues when other of glucose are exhausted. Gluconeogene-
sources
gue 15 16 in but it is not
glycolysis.
sis enmploys most of the s a n e enzymes that act Fructose 1,6tisphosphato
pathway. Seven of the glycolyuc reactions arefreely
gulaton tof the fhx through multistep
a
sinply the reversal of glycolysis. figure 15-17
ulatr ( a leqs thaf àfe enzyme-lirnitea. At
',
these reactions also function in
reversible, and the enzymes that catalyze The reaction of gluconeogenesis that bypasses the irre-
lp. (o1,1ng0: arrows), wtich are gantrally are so exergonic as to be es
y t l .hwe t r l t , i t e
i, riol in cquillbruin with the gluconeogenesis. Three reactions of glycolysis versible phosphofructokinase-1 reaction of glycolysi5.
hexokinase, PFK-1, and pyruvate
t wt.0 feactiori Is felalively slow; Uie sub- sentialy irreversible: those catalyzed by Convers.on ot tructose 1,5 bisphcsphate to tructose
acumu- detours around each of these ireversible 6phosphate s caLalyled ty tructoSe 1,6-bisphosphatase
f r u',
lo art ate, JuA 3s tiver water kinase. Gluconeogenesis uses
alen alunlia rlan in lhe Aayliate-united feaclions conversion of fruclose 1,6-biSphospBiate to fructose (calied FBPase ) to distingush it trom astrnilar enzyrne
at. steps; for example, the Table 20-2).
ar ICd proiuci are esArtiäily that dcls in g'ucoiecgenesis;
see
ftW), lue
il,ltale
fructose 1,5-bisphosphatase (BPase-l)
( 6-phosphate is catalyzed by
 Toprevent a wastehul ckele in which glucose is to proruce lugher enzyne activ
simultaneously de- inhibition by ATP. Thesc ellects cofubine
and to lower ac
STaded by skcoysis and resyithesized by gluconeogenesis, the enzym when'fructose 6-plOsphate, AlDP,
or AMP accumulates
un:que to each pathway' are reciprocaly regiulated by common allosteric
Ity
ef- tIvity when ATP accunulalrs, intermediate ln the aer
Pruc:ose
fectors.
therefore
2,6-bisphosphate,a
potent activator of liver PFK-1 and Citrate (the lonlzeel forin
of cltric ucidl), a koy
regula-
16), also serves us allosteric
of dyeolys.s, inhibitor of
is an FBPase-l and therefore of an
guco- oble oxldation of pyruvate (Chuplor effiect of
neogenesis. concentrntion Iricreases the Inhlbitory
tor of TFK-1; hlgh cltrate
Glucagon, hormone released the
a
by pancreas to signal low blood of Uirough elycolysls. lai this case, as
lowers the level of fnuctose 2,6-bisphosphate in sugar ATP, Aurthor reduclng the low gucose citrate serves as an intracellular
-P-0 of glucose by dycolysis and liver, slowing the consumption ln several othors to bn encountered luter, mctabo-
stinulating the production of glucose by gluco- slgnal that the cell ls mcetlng lts
current needs for energy-yielding
neogenesis:; the lver releases the glucose into the blood. We will return to a lIsn and for blouynthetic intermedtes.
more complete cseussion of tus
coordinate regulation in The most slgrulfleant allosteric
regulator of PPK-1 is fructose 2,6
Fructose2i bisplosphate is found in all anúmals, in Chapter
20.
strongly actüivates the enzyne.
fungi, and in somne blsphosphate, whlch, s noted earlier,
plants, but not bactem It stimulates PFR-1 activity
yeast. In plants. inictose .5 bisphosphate in all arwmals and in Its Reaction Product
regulates carbehydrate metabo- Hexokinase Is Allostericaly Inhibited by
lism by actitairg ile I1', of free glucose into the glvcolytic
dependent phosplhofructokinase that is Hexokinase, wl1leh catulyzes the entry
ble for inuctose 1.G-bisplosplhate formatio11 in
responsi The hexokinase of myocytes has a
glycolysis (p. 533), but it pathway, Is another regulatory enzyme.
does not activate the ATP-dependent PFK-1 half-saturated at about 0.1 mM. Because glu-
plants.of Plant PFK-1 is,
how high alünity for glucose--it is concerntration
strong: inubited by phosphoenolpyTuvate,
ever, a
glycolytic intermediate from the blood (tn which the glucose
dewnstream fromm fructose 1,6-bisphosphate cose enterng myocytes an concentration high enough
Is 4to 6 mN) produces intracellular gucose
acts at its maximal rate. Mus-
to saturate hexokinase, the enzyrne normaly
Phosphofructokinase-1 Is under Complex Allosteric Regulation cle hexokinase is allosterically inhibited by
its product, gucose 6-phos-
Glucose 6-phosphate can tlow either into concentration of glucose 6-phosphate rises
glycolysis or through alternative phate. Whenever the cellular
oxidative pathuars described later in this and reversibly irhibited,
chapter. The irreversible reactiori above its normal lovel, hexokinase is temporarily'
catalyzed by PFK-1 is the fornation into balance with the
step that commits a cell to chaneling glucose bringing the rate of glucose 6-phosphate
into glycolysis. In addition to its substrate-binding sites, this rate of its utilizalios and recstablishung
he steady stale.
conplex en- which catalyze the
zyTme has severad regulatory stes at which allosteric activators or indhibitors lammals have seveial forns of hexokinasp all of
bind. Different proteins that cat-
Conversion ol glucose to glucose 6-phosphate.
The lifferent
ATP is nt only a substrate for PFK-1 but also an end
product of the gly alyze the sane reaction are called isozymes (Box 15-3). h
roles of these organs in
colytic pathway Wlrn hugh ATP levels in the cell signal that ATP is being isozy7nes of liver and muscle retlect the different
it for energy
produced faster than it is bemg consumed, ATP inhubits PFK-1 by binding carbohyirate metabolisn: Inuscle consurnes glicose, using
for cther tis-
to an allosteric site and
lowering the afinity of the enzyme for fructose production, whereas liver produces and distribites glucose
6-phosphate (Fig l5 18). ADP and AMP, which increase in concentration Sues. The predoninant hexokinase isozyrne of liver
is exokinas: D, also
as consumption of.\Tl
outpaces productiori, act allostencally to relieve this called glucokinase, which differs in Iwo inportant respects iron the hexo
Iinase isozymes of nuscle
irst, the glucose concentralion at whirl: gucokinas1 i hall
aliratel
the
(abont 19 uM) is hugher tliarn tlhe usial concentration ol uroe iI
figure 15-18
blcod. Because an ellicient glhucose transporter in hepatocyles maintais a
Phosphofructokinase- 1 and its regulation. (a) A ribbon diagram of E.
coll PFK-1, sho«i"g twa of its four identical subuni's. Each glicese concentration close to that in the blood. ihis property of glucoki
subunit nas
itsown catalyt1c site where ADP (blue) and fructose nase allows its lirect regulation by thhe level of blood glucose. When the
1,6-bisphosphate blood gluCose concentration is higl1, as it is after a meal rch in carbohy
yellow) are almost in contact, and its own binding sites lor the allostenc
rezulator ADP (5lue), located at the interface betwe an drats. eseess bloord glucose is transported inta tepata"yles, wlcTe gluco-
(6) Allosteric regulabon of muscle PFR-1 by ATP, shownsubunits.
by a substrate- kI rOiverts it to glucose G-phosphate
activity curve. At low {AP] the Kos (p. 281) for fructose 6-phosphate is Second, glucokinase is inhibited not by ts reacuon product glucose
relatively low, enabling the enzyme to function at a high rate at relatively
w ATP low concentrations of fructose
6-phosphate but by fructose G-phosphate. which 1s always in equilbrium
fructose 6-phosphate is greatly
6-phosphate. When [ATPJ is high, K;5 for with glucose 6-pliosphate through the action of pBosphoglucose isornerase.
increased, as indicated by the sigmoid
relationship betwean substrate concentration and enzYme activity. Partial indibition of ghcokias by fructoe -phtospBhate is mediated by an
(C)A summary of the regulators affecting PFK-1 aclivity. The symbo's additional protein, the glucukinase regulatory protein. This protein also
here are those used
throughout the book: ® for inhibition andfor
activation.
has an affinity for fructose 1-phosphate, whuclh competes with fructose
6-ptiosphate and cancels its inhibitory effect on ghucokinasr. Becuse fruc
1,1.iP 1ose 1-phosphate is present in liver only when fr1uctose is present in thue
ATP AMP, ADP blocd, tius property of the ghucokinase regulatory protein explai rthe ob-
servation that ingested fructose stirnulates the phosplorylation f glucose
in the lirer. 21craf
Fructose G- t ATP- Fructose 1,6- +ADP
Cells of the pancreas known as f cclls, which are responsible for the re
pinphalo bisphosphate
 i Subsuraue-Eve
pyruvate Kinasevia
affinity of result
tUfICentration
falls, the
the
formation ofATPrelatively low. T h e
Metamls is
a xnegeticsand the enzyme
to catalyze concentratior.
TP
tung though the
PEP of AlE.
even concenträãon
uon steady-state
maintenance of the and
Hormonally
Proteins, Same Reaction
1 Allosterically
and the rareo
sorymes: Different of Phosphorylase Is Regulated
production,
uycogerd is ATP demanding m o r e ATP. Tne
concentrations
of very low by glycolysis
Rpd reduction whereas
the end served Dy
of hexoinase found in mam to lactate inskeletal muscle,
lac muscle, works harder, of blood glucose
bNTms PTuvate oxidation of as
muscle
level
example of a a constant
common
ai u S 2P dut one
those of isozyme B, favoi rapid nereases
a clifferent role:
to maintaln
tissues
demand , andweu have
in thehea a VE as when the the diet.
As
of an tate to pyTUvate isozymes oI exporting glucose e x c e s s in
POaucng and
ma.ecular foTns
provided in
different
MOTE diiferent of
y The distribution
when about by 8ycog
forms, c l d isoYMES
These mulnDle reflec.s at least four lactors r n g glucoseof stored glycogen ls brought 1-phosphate (Fig.lb
DE
Lie aame StACTeS, Siven enzYTne
c mobilization
T
TS, May
occur n
cel. ihe iljerent seen, tne degrades glycogen
to glucose
instructive exarnpe o
ylaSe, whlch
the
patterns in ayere
even n sane
Cr
e Same hise, seneraly dffer 1. Diferent metabolic phosphorylase, o provides a n
especiálly
allosterically regu
oTms oi the ezyme the Gycogen phosphorylase of an
t Por glycogen have 4 Arst known exanple
n the cofac- organs muscle and liver regulatlon. It was the controled by reversioie
7nei r regiatoy propertues, ISOZYTNes in
skeletal
enzytne shown to be Lne
ar they use (NADH or NADPH or dehyiro e rellecting and the drst enzyme for which
iher subcel different
regulatory properties,b r e a k d o w n ated enzytne also one of the ffrst
allosteric enzyrmes weie
/CH-07 0 - C H
S I s , 0T erample), CT phosphorylatlon. It was
n
ro.es of glycogen inactive IOrins
r active and
structures of the
the different
ular distrbution (saluble or membrane-DOUnd)
in these wo tissues. deked threo-dimenslonal
have Smuar, but not ice nncal,
may and metabolic TOLes revealed by x-ray crystallographic
studies. exists in two
S mes and in many cases they 2. Diferent locations The isoci- isozyme of
skeletal muscle
auno acid sequences,
in the same cell. n e 8ycogen phosphorylase active, und Phosohorylase a
evolutonEr orcn. Jor is02ymes
of the cy- which is catalytically Alloateric
coumon forrns: phosphorylase a,
Phosphorylase b predominates n
E T shre a sites empty
One of he irst enzITmes found
to hs:e 150- trate dehydrogenase
isozy1nes
an exan-
nterconvertible
which is less active.
actave)
and the mitochondrion are
phoaphorylase b, the hormone epl-
vigorous muscular activity
tosol
dehydrogenase (LDH) (r 542).
3 e s a s hctate
uTuch n vertebrate tissues exdss as a: least ple (Chapter 16).
derelopment 1n resting muscle, but during
phosphorylation of a speciñc
Ser residue in phosphory 2 Glucose
e dilerent isozymies separable by electtophor 3. Diferent stages of adult nephhne triggers to phosphorylase a. The mechanistic details of prios
tissues and in it
esis Al LDH isozymes contain fow pokTeptide e m b r y o n i c orjetal
fetal liver has a lase , coriverting
activatíon by phosphorylation
are presented
on pages 282-284,
For exanple, the this type of
control.
chars (each of M, 33,500), each type containing (1SSues. of LDH, prorylase served as an example of
isozy+ne distribution where gycogen phosphorylase
a dlferent ratio of wo kinds of polypepudes. characteristic
develops into phosphorylase speeds glycogcn breakdo
wn,
and which changes as the organ The actuvated form of glycogen to power
The A chain (also designated M for musc e) of glucose ca- of the ATP required
Te en- its adult form. Some enzymes 5upplying glucose 1-phosphate for production responsible 1or
he B chan (also designated H for heart)
tabolism in malignant (cancer)
cells occur
qiscle contraction.
The enzyme (phosphorylase kinase)
b
its CIl CH
coded by wo different genes. n skeletal
muscle
as their fetal, not adult, jsozyTmes. transíerring a ph0sphoryl group to Ser
he predorinant isozyme contains four A chains, acuvating phosphorylase by a series of steps
shown in
residue is itself activated by epinephrine through
to
nd in heat the predominant is0z\Tne
contains 4. Diferent résponses of isozymes second enzyme (phos
This difference is muscle returns to rest, a
four B chains. LDH isozyTmes in other tissjes are
alosteric modulators.
Figure 13-15. When the from phosphory Gl Glo
rates. Hex- removes the phosphoryl groups
a Tuxture of the ffve possible forms, which may useful in fine-Luning metabolie a phosphatase)
okinase D (glucokinase) of liver and the ptiorylase
asc a, converting it to the inactive form phosphorylase b.
e designated Aq, AB, AB2, AB;. and B, The covalent inodil-
isozyrmes of other
tissues differ of phosphorylase by
differnt LDH isozyTmes have signuicantly differ hexokinase Superimp0sed on the regulation for muscle
to inhibition by glucose nechanisms. Ca", the signal phospht 2P
ent vaues of Vma and Kn particularly for pyTIU- in their sensitivity cation are two allosteric control promoting con-
activates phosphorylase b kinase,
Vite. The properties of LDH isoz\Tne A; favor 6-phosphate. contraction, binds to and which accu-
version of inactive phosphorylase
b to the active a form. AMP,
Ofl
binds to and activates phosphoryl-
mulates in vigorously contracting muscle,
ase. When ATP
levels are adequate, ATP blocks
the allosteric site Lo
wBuch
CHa CH
AMP binds, inactivating phosphorylase. hormone
is regulated by the
n the liver, glycogen phosphorylase level is too
mechanisms. When the blood glucose
gucagon and by allosteric converts inzctive
phosphorylase b knase, which I'hoaphorylaso b
low, glucagon activates release of glucose into
active a forn, iínitia:ing the
phosphorylase b to its ernters he
levcls return to normal, glucose
the blood. When blood glucose a (Pig. l5-19).
an allosteric site on phosphorylase
patocytes and binds to the phosphorylated
figure 15-19
conformational change that cxposes of liver as a glucse sensor
This produces a removes the phospho-
Glyccgen phosphorylase
a phosphatase, which Glucose oinding to r alksteric site d phsphory 2e
Ser residues to phosphorylase of theoe complex reg- har epOSes tne phes
phosphorylase. The details induces a Conlorrnational change
ryl groups and inactivates where we compare the reg. phoryated Ser rcsdues to the
action of phsprorytae I
discussed in Chapter 23, à
ulatory processes are in glyc0gen phosphoto%. This phosphatase
Converts phosphcrylase
with that of its counterpart
uation of glycogen phosphorylase under fincly tuned
to phosphorylase b, reduzirg the actrty of phosprorfa
These two enzymes are
synthesis, gycogen synthase.
in response to hign blooC glucose
and reciprocal regulation.
 -
1)CH3 *'2
C-o-<H=
Ac e hanel HC-
Ethyl a e eto
foenergetlesani Mrtll
+H20(waf.

Ihe Pentose Phosphate Pathway

of Glucose Oxidation
brezkdown to
themajor fate of glucoseacid
tissues,
is glycolytic
u
uul via the citric cycle-the main func-
pale, of which is
nos oxidized catabolic fates, liow.
Glucose does have other
m ng formation of ATP. needed by the cell.
Of particular
whuch le specialized products
id to
HCCH ,
perntose phosphates.
n g t a n c e 1s the synthesis of called the phosphoglu-
FOCH pathway, also
pentose phosphate 5-phosphate. Recall
fron
Th NADPH and ribosc
HCCH pathway, produces of re-
onate

:hat NADPH carries chenical energ in the form

haptrr 1 (p 519) as the
reductanu uI anabolic
used almost universally
power and is of the
NADPI1--and thus the activity
due
CH-OPOS In manutads this role of actively
atways.
ADPT pathway-is especially
prominent in tissues
t p s e phosphäte adrenal
acids and steroids,
such as the inaunary gland,
syullhesuzng farty reduce the
These tissues use
to
NADPH
ADPL iver, and adipose tissue. process
of intermediates in the synthetc
cortex,
double bonds and carbonyl groups such as skele
Tissues less active in synthcsizing
fatty acids,
C=0 (Chapter 21).
in the pentose phosphate pathway
lal muscle, are vitually lacking is to.generate
HCO of thhe pentose phosphate pathwar
A second unction nucleic of
D-ribose, necessary for the biosy7ithesis
ToCH pentoses, particularly o c c u r s at huigh
rate in grow
Nucleic acid biosynthesis
ICOH en luctone acids (Clapter 22).
tissues a1d in tumors.
and regenerating
ing pathwar (Fig. 15-20) is the
phosphate
The first reaction of thepentose 6-phosphate dehy-
CH ducose b-phosphate by glucose
dehydrogenation of intramolecular ester.
an
phosphoglucono-6-lactone,
drogenase to forn lar in the
and tie overall equilibrium lies
NADP' is the electro1 uCceptor, the frce acid
The lactone is hydrolyzetd 1o
direction of NADPH foruation.
6-phosphogluconate by,a spociic
lactonuse, then 6-phosphoguconate
6-phosphogluconate
and decarboxyation by
undergoes dekydrogenation This reac
t e ketopentose D-ribulose 5-phosphate.
dehydrogenase to forrn
second nolecule of NADPH.
Phosphopentose isomerase
6-Phospho- tion generates a In
Io its aldose isomer, D-ribose phosplate.
5
gluconate converts ribulose 5 plhosphate:
ICO phosph:ate pathway ends at
this point, and it
some tissues, the pntose
overall equation is

1OPOSi Glucose 6-phosfhate -2NADP

+ H,O
+ CO, + 2.NADPH 21
NADP ribose5-phosphate
NADPH, redurtant for biosynthetie n,
The net result is the production ol
a

precursor for
nucleotide syTIthesis. M
actions, and rilbose 5-phosphate,
a

NADPH rather than ribose 5-plu

In tissues tht requre prinarily
into glucose 6- phosphate in a
phate, pentose phosphates are recycled Fir
exanined in more detail in Chapter 20.
ofreactions (Fig. 15,21) to be 5-plwsphate. Then, in a
ribulose 5-phosphate is epimerized to xylulose
six five-carbon sugar in
Ralulose ries of rearrangenents of the carbon skeletons,
phpulhate six-carbon suga" phosphates, compleiiny
phates are corveried to five
6-phosphate wilit ir
cycle and allowing continued oxidation of glucose
NADPH produced by this Jathx
y

duction of NADPH. In erythrocytes, the i

oxidative darnage. A gene'ir
is essential in proiecting the cells fron
can have serious cons"
in glucose 6-phosphate dehydrogenase
POx 15-1)