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The Citric Acid Cycle II and the

Pentose Phosphate Pathway4/22/2003

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The Citric acid cycle

3NAD+ + FAD + GDP + Pi + acetylCoA

3NAD! + FAD! + GTP + CoA + 2C"2

Overall reaction

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"#er#iew

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24 E2 subunits 24 E1 orange a and b together

12 E3 Red

$% &ased i'a(e o) the core $2)ro' yeast pyr*#ate dh

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Do'ain str*ct*re o) dihydrolipoyl

transacetylase $2

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SS

E2

HSS

E2

SSH

E2

SS

E2

SS

E2

SSH

E2

HSS

E2

SS

E2

CH3OCH3O

CH3OCH3O

Acetyl reaction center trans)eres tho*(h the

$2 dihydrolipoyl coeny'e repeats

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Citrate ,ynthase

HO

CH2

O

C

HO O

O

H3C C SCoA

O

+

HO

CH2

O

C

OH

O

HO

CH2

HO O

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Ind*ced )it needs &indin( o) o-aloacetate

&e)ore Acetyl CoA can &ind.

CoAS C

OH

CH2

CH3CCoAS

O

CoAS CoAS

CH3

C

O OH

CH2

O

CH2

Proposed intermediateAcetyl-oA

Acetonly oA arbo!ymethyl-oA

"ground-state analog# "transition state analog#

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Aconitase

HO

CH2

O

C

OH

O

HO

CH2

HO O

HO

CH2

O

CH

OH

O

CH

HO O

Citrate CisAconitate

HO

CH2

O

HC

OH

O

C

HO O

HHO

Isocitrate

The do*&le &ond is placed on the Pro. ar'

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NAD+ Dependent Isocitrate

dehydro(enase

NAD+ NAD!

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-$etoglutarate dehydrogenase

HO

CH2

O

H2C

C

HO O

O

CoAS O

HO

CH2

O

CH2

CO2

This eny'e is *st lie pyr*#ate dehydro(enase1 a '*lti

eny'e co'ple- that is speci)ic )or lon(er CoA deri#ati#es

NAD+

NAD!

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,*ccinylCoA ,ynthetase or

s*ccinate thioinase

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,*ccinate dehydro(enase

HO O

HO

CH2

O

CH2

HO O

HO

CH

O

CH

+ 2e- + 2H+

The FAD on the

eny'e itsel) is

red*ced

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,*ccinate dehydro(enase is the only

'e'&rane &o*nd eny'e in the citrate cycleO

O

H3CO

H3CO

CH3

CH2

CH3

n n = 6-10

,*ccdh--FADH2

+

OH

OH

H3CO

H3CO CH3

CH2

CH3

n

&i*inone or

Coeny'e O!idi%ed

&orm

Reduced

&orm

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F*'arase

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%alate dehydro(enase

HO O

HO

H2C

O

C OHH O

HO O

HO

H2C

O

C

NAD+

NAD!

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.e(*lation o) the citric acid cycle

,tandard )ree ener(y chan(es in the citric acid cycle.eaction $ny'e G5 G5

6 Citrate synthase 3678 Ne(ati#e

2 Aconitase 98 90

3 Isocitrate dh 26 Ne(ati#e

4 :G dh 33 Ne(ati#e

8 ,*ccinylCoA synthase 2076 90

; ,*ccinate dh +; 90

< F*'arase 374 90

= %alate dh +2>7< 90

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The points o) re(*lation o) the cycle

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Citric acid cycle inter'ediates are

always in )l*-

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A sin(le 'olec*le o) (l*cose can potentially

yield 93= 'olec*les o) ATP

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Phosphopentose pathway

Prod*ces NADP! and ri&ose8phosphate

NAD! and NADP! altho*(h che'ically si'ilar they

are not 'eta&olically e-chan(ea&le7

%any ana&olic pathways re*ire the red*cin( power

o) NADP! )or synthesis incl*din( Fatty acid

synthesis and the synthesis o) cholesterol73G;P + ;NADP++ 3!2" ;NADP! + ;!+

3C"2+ 2F;P + GAP

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The pathway consists o) three parts

67 "-idati#e reactions?

3G;P + ;NADP++ 3!2" ;NADP! + 3C"2+

3.i&*lose8P"4

27 Iso'eriation and epi'eriation reactions?

3.i&*lose8P"4 .i&ose 8P"4+ 2@yl*lose8P"4

37 A series o) CC &ond clea#a(e and )or'ations?

.i&ose8P"4+ 2@yl*ose8P"4 2F;P + GAP

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Gl*cose; phosphate dehydro(enase

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Phospho(l*conate dehydro(enase

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.i&*lose8P"4iso'erase

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Two eny'es control the rearran(e'ent o)

car&on seletons which res*lt in theprod*ction o) Glyceraldehyde3phosphate

and Fr*ctose;phosphate7

Transetolasetrans)ers C2 *nits? TPPre*irin( eny'e lie pyr*#ate

dehydro(enase

Transaldolasetrans)ers C3 *nits? *ses a shi))s&ase with an acti#e lysine (ro*p

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Transetolase re*ires

TPP

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The transition o) car&on seletons in the Phosphopentose pathway

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The pentose pathway control

'he need &or (A)P* is controlled by glucose

dehydrogenase+ ho,ever+ ,hen ribose --

phosphate is needed ")(A and R(A synthesis# itcan be made &rom the reverse o& the transaldolase

and transetolase reactions &rom /ructose-0-PO4

and AP

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NADP! is needed )or (l*tathione red*ctase

.ed*ced (l*tathione is needed )or (l*tathionepero-idase1 which destroy hydro(en pero-ide and

or(anic pero-ides7 This eny'e re*ires seleni*' as

a co)actor7

H3+N CH

COO-

CH2 CH2 C NH

O

CH

CH2

C

O

NH CH2 COO-

H3+N CH

COO-

CH2 CH2 C NH

O

CH

CH2

C

O

NH CH2 COO-

S

S

H3+N CH

COO-

CH2 CH2 C NH

O

CH

CH2

C

O

NH CH2 COO-

SH

2

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Gl*tathione eeps proteins with red*ced s*l)hydryls

,! )ro' o-idiin( to . , , .

P,! + P,! + "2 P,,P + !2"

P,,P

G,!

P,! + G,,P

G,!

G,,G + !,P

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Gl*tathione red*ctase contains FAD

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.eaction o) (l*tathione with pero-ides

2G,! + .A""! G,,! + ."! + !2"

A steady s*pply o) (l*tathione is re*ired )or

erythrocyte inte(rity

9 40010001000 indi#id*als are de)icient in (l*cose

dehydro(enaseB

itho*t a )*lly )*nctionin( (l*cose dehydro(enase1

(l*tathione concentrations !e'olytic Ane'ia can

occ*r i) certain dr*(s are *sed7

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Pri'a*ine1 an anti'alarial dr*( is

pro&le'atic with indi#id*als with (l*cose

dehydro(enase de)iciencies

N

H3CO

NH CH

CH3

CH2 CH2 CH2 NH2

Primauine

imilar e&&ects are seen ,hen people eat /ava beans. /ava beansstimulate pero!ide &ormation and the demand &or (A)P* can not

be met.

ature red blood cells lac a nucleus and the ability to mae ne,

proteins and membranes. )amage cannot be repaired so cells lyse.

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A de)ecti#e G;P dh con)ers a selecti#e ad#anta(e

on indi#id*als li#in( where 'alaria is ende'ic7

!owe#er1 only heteroy(otic )e'ales are resistantto 'alaria1 not 'ales7 Plasmodium falciparumcan

adopt to a cell with decreased le#els o)

phosphopentose prod*cts7 This eny'e is in the @

chro'oso'e and )e'ales with two - chro'oso'es

prod*ce hal) (ood and hal) &ad &lood cells7

Plas'odi*' cannot adapt to the G;P dh

de)iciency i) it is sporadic or rando'7