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Hema 1

Hema 1

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Published by: Janine Victoria Cabitac on Jan 08, 2012
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08/04/2013

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C
-
Terminus
{
'
glg
-
TYR
-
LYS
CHAP
T=tr
10
HemoglobinMetabolism
to7
'IPHEGLU,.
120
lIS
G
ASf{
GLY
"-.
cys
'ffir,,
-
t
&e"-_--,-:
PHE
vA|T
ynsffi
Hrs-
uu
110VAI
+
N
*Terminus
-r-a
n,,
--@
Lys
-
ssp
tr90\
A|-l
'
619
-
cYS
-
n,'
TH;
Piir
tHaG
@@
-TS"-'@:,:)"histidine,
HIE.
l
$u
THR
1....
eruJ"-
Pno
lunf
4
-lsER
'
ALA.-
I
A
ViL.
i'--'THR
ALA
rgr---.-@,
r-Ys
-t-
GLY
g'
20
LEU
so
A$N
ASP
LEU
Hts
LYS
ALA
tY$Close spatialcontact
40
GLU
6e
oLY-AsP-r-Eu-ssa
I
,::.-i
Fxample ofaBglobinchain.
lt
is
apolypeptdechain shouringhelical andnonhelical segments.
(FrOm
--i.
SchrocierWA:Ney,,Aspects
of the
Structure,Functon,
and
Synthesrs
of
Hemoglobins.
Boca
Raion,
trress,.]971,
modifiecl
from
StamatoyannopoulousG:
The
Molecular
Basts
of
Bl00d
Diseases,2nd
ed,
:
Saunders,
l994.)
E7
(Distalhistidine
residue)
I
tti'W'
66
PBO.
q,.lffi
D
vnrJMrr
*sd.r
I
ASp
56
11.16
PRO
.:,ii'
of
llb,
alsocalied
a
tetrarneric
ir
noiecule.
The
complete
IIb
rnole'
.
hen-re
groups attached
to
four
pol-v-
rrrn'
lbur
molecules
of
oxygtrt"t.
lt
is
rin
chainsand
lwo
non-crglobitr
,.;r
has
a
lretne
gloup
attached.
I]ach
-:
..i
carrying
onerroleculeof
oxyrge
n.
-,
c
.1,
non-o
2
climericbondshold
'
:n.
'Ietram€r'ic
g
1,
non-o-
2 and
g
2,
non-o
1
bonds also
contribute
to
thestabilitvof the
structure(Fig.
10'4)."'i
BIOSYNTHESIS
fi**:c
Biosynthesis
of
heme occurs
in
thebonemarrow
in tlie
rnito-chondria
and
cfioplasm of'theerythroryle
precursors
frcrtlr the
pronoruoblast/proerythroblast
to
the
reticuloryte-Matue
 
108
PABT
Il
Hematopoiesis
t.".
,1,.t,,,
".,....]
,
::
I
'.,
.
r,'ll,t,...
...,'..
::!::,.'._l*,:
:
::i_I1........
ftofl-0,1
fill;r*
ill-,{
Complete
Hb
molecule.Heme
is
suspended
betri,ieen
the
E
anC
F
hellces
0f
thep0lypeptidechatn, Pinkrepresents a,
1
\lef4
artd
a.
2
\itghil,
yellori
represents
nan'a. 2
(lell)
and
non'
a.1
lright)
ery1hroc.\"tes
cannotrnake
Hb
because
tl-re.v
lose
their
niito-
chondria
ancl
the
capabilit-v
of
using
tl're
tricarbox-vlicacid
o'clell('cc\\Ara
iorHb:r
ntitesis.
Heme biosynthesisbegins
n'jth
tlre
conde
nsation
trl
glvcine
and surcinyl
coenzvme
A
(Co,'\)
catal-vzed
bvaminolevulinatesynthase
(AL,\S)
to
form
anrinoler.'r,rlinic
acicl(AI-A).
AI-A
dehvdratase
(AIA
deh.vdrase/porphobi
I
in
ogen
s.vnlhase
)in the
pr€sence
of
AL,\
catalvzes
the
tbrn-ration
of
porphobilinogen.Porpl-robilinogen
deaminase,
also
knor,vnas hyclrox,vmethyl-
bilane
synthase,
in
the
presence
ofporphobilinogen
catal1'zg5
the
formatiort
of
hyclrox,vl
methylbilane.
This
pathrva-v
cor-r'tinr"res
until, in
thefinal
step
ofproduction of
heme,
Fe-=
com-bines
with
protoporphvrin lX in
the
presence
of ferrocheiatase/herrrr
synth.rse
to
tnakt'
hemc(lig.iU
l
)
''
'[iansferrin,
a
plasma
prolein,
carries
iron
in
thel'erric
(l'eJ')
form
to
developing
tlllCs.
lron
goes
throu€lh
thefl[]C
ntenr-brane
to
the
nitocliondria
aud
is
uniledrvitir
protctporph.vrirrIX
to
make heme. Fleme
ieaves
the
mitochondriaand
is
joined
to
the
giobill
chains
in
thc
cyioplasm.
*{*bi*
Six
structurai
g,enes
control
the
s1'nthesis
of
the
six
globin
chains.
s
and
(
genes
ate
on
chromosonle
16;T,
0,
E,
and
e
genes.rre
linkedon
chromosome
11.h'r
the human
gc.-
there
is
one
cop,v
of
each
globin
gene
per
chronaticlfor .
oi
tr.vo
genes
per person
lvith
tl-re
exception
of
s.
and
^'
arc
1$ro ct-rpies
oithe
o
and
lgerres
perr
chrortl:rtid
foi
a
t-
four
genes
per person.
lhe
prorlr.rction
of
the
globin
ch:rins takesplace
fro::pronornroblast
to the
reticttlocvte.*
lhc
globiir
Proteii-.'
made
via
transcrip{ion
of
the
geneticcnde
lct
lness:
ribonucleic
acid
(ri-rRNA)
and translation
of
ntRNA
t:
globin
pol-vpeptide chain.A
slight
excess
of
u-globin
mR'.'
nr
present
in
erythroblasts;
hol,evetp-globinmRN,\
is
tran:
;more
elficientl,v
rhan
cl"-globin
nfu\A.
This results
1rr s€
:
'1
single
chainssvnthesized
in
approximarel-v
ec1ua1
alnoi
:
Whcn
slrnthesized,the chains
are
releasecl
from
the
ribosc
:
in
tire
cvloplasm.t
S*rx*g
1*f:!
I
3!s***:l.r[y
Afier their
release
lrom
ribosomes,
each
glcbin
chainbin.-'
a
hememolccule
antl
tltev
pairoff.r\u
s,
cl-rait-t
and
a
tlr
chain
cornbine
tc)
form
heterodir-ners.'l-woheterodimerss:
taneousl-v
combiire
to lbrm
tetramers.The tetrameric
tr,p
.-
a.p,
bonds
alsr:r
contributeio
th€ st.:bilitw
of
the
strrrcrut
c.
completesthe
llb
n'rolecule
(Fig.
10-5)."'7
 
CHAPTEP
10
HemoglobinMetabolism
109
-
.r:rion
of
two
tx
and
two
B
chainsalong
r,r';th
the
,
r :::iecules
forms
Hb A.
This
is
the
predominantHb.-:l.rral
life.
l'lb
A,
contains
two
G
and
two
6 chains.6
-
-.:
rre
inefficiently
expressecl;
only
smallamounts
of
i{b
A.
-.
:,und
in
the
RBCs.
Ifb
F
contains
two
cx
and
two
y
chains.
.
jults,
Fib
F
is
not
distributeclevenlv among
the
RBCs;
it
is
.(nt
in
a
few
RBCs
called
f
rails.:
,ee
various
globin
chains
of
l-lbdiffer
in
the
charge per
-
.ecule.
In
the
procedure
of
Hb
electrophoresis
under
the-
.:ence
of
an electric
field,
Hbs
exhibit
different nrobilities,
:rrirg
differentiation
of
subtype.
lt
mavbe
necessary
to
use
lrent
assay
procedures
(support
rnedia,
buffer,
pH)
for-efinitiveidenrification
(Chaprer26).
The
Hb composition
in
theerythrorytediffers,
clependinpi
ongestation
or
postnatal
age.
This
change is
due
to
changes
in
the
activation
and
inactivation
or
sr,r'itching
of
theglobin
genes,
progressing
from
the
(
to
the
c{.
gene
on chrornosome
1(r
and
from
the
e
to
the
1,
6,
or
B
genes
on chromosorne
ll.
The
(
and
t
genes
normallv
appear
only
duringthe
first
3
monthsof
embryonic
development.
These
t.r,r'o
chains
inaddition
to the
d
and
l
chains
are
constiruenrs
of errbryonicHbs (Fig.
10-6).
Ar
birth,
Hb
Ir
is
thepredominanr
Hb.
Norrnal
adult
flb
is
pre-
donrinatelyHb
A
(urB.)
with
smallamounrs
of Hb
A,
(a.6.)
and Hb
It
(cx.,yr).t'lable
10-2presents
adull
reference
intenais.
.,.l
Mitochondrion
Glycine ALAsynthase
+>
SuccinylCoAProtoporphyringogen
Cytosol
ALA
I
ALA
d"hudr"t"
I
v
Porphobilinogen
(PBG)
I
I
PBG
deaminase
v
Hydroxy
methylbilane
I
UioPorPhyrinogen
lll
synthase
t
Uroporphyrinogenlll
I
Uroporphyrinogendecarboxylase
*
Coproporphyrinogen
ll
I
IX
Protoporphvrinoqen
I
-l
oxroase
I
Y
.-T-
Coproporphyrinogen
oxrdase
Protoporphyrin
lX
Fe+2
Ferrochelatase
Heme
polypeptide
chain
I
Globinnon-upolypeptide
chain
 
@@@@
-
r'
r;}"i
Ribosomes
It'I
@-'J_
 
t;rFY
*'M
'lt"
non-{{'tetramer
F4ry*
Flgure
10-5
Hb
assembly

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