Citric Acid Cycles

7/27/2019 Citric Acid Cycles

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By : N uniek H erdyastuti P ebr u ar i - 20 13


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Org an ic fue l m olecu les g lucose,fa t t y ac i ds, and som e am i noac ids are ox id ized t o y ie ld t w o-c a r b o n f r a g m e n t s i n t h e f o r m o ft h e a c e t y l g r ou p o f ace ty l -coenzym e A ( ace ty l -C oA) .

The acety l g roup s a re fed i n toth e c it r i c a c id cyc le , wh ichenzym a t i ca l l y ox id i zes them toCO2 ; the energ y re leased i sconserved in t he redu cede l ec t ron ca r r ie rs N AD H andF A D H 2 .

These redu ced coenzym es are

th em selves ox id ized, g iv ing u pp ro t ons (H ) and e l ec t rons

CELLU LAR R ESPIR AT IO NO C CU RS IN T H REE M A JO R

STAGES :

PRODUCTION OF ACETYL-COA (ACTIVATED ACETATE)

Py ruv a te , d er ived f ro m g lucose an d o th er sug a rs b y g lyco lysis, iso x id i ze d t o a ce t y l - Co A a n d C O 2 b y t h e p y r u v a t e d e h y d r o g en a se(PD H ) com p lex , a c luster o f enzym es, t h ree enzym es loca t ed in t h e

m i t ochondr ia o f euk a ryo t i c ce l ls an d in t he cy t oso l o f p rok a ryo t es. The PDH com p lex i s a c lassi c, o f a m u l t i enzyme com p lex , F i v e

co f ac t o r s, f o u r d e ri v ed f ro m v i t a m i ns, pa r t i ci pa t e i n t he rea ct i onm echa nism .

T h ia m i n e- d e f ici en t a n i m a l s a r e u n a b l e t o o x i d i ze p y r u v a t en o r m a l l y ( B ra i n ) Ber iber i is chara cter ized b y loss neu ra l fun ct ion

.


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Co e nzy m e A ( Co - A )

Piruvat dehidrogenase

Co m p l ex en zy m e : p y r u v a t ed ehyd rogen a se (E1) ,d ihyd ro l ipo y l t r a nsace t y lase(E2) , an d d ihyd ro l ipo y ldehyd rogena se (E3 ) ; 5coenzyme (p rost he t i c g roup s) :t h i a m i n e p y r o p h o sp h a t e ( T P P ) ,f la v i n a d e n in e d i n u cl eo t i d e(FA D) , coenzym e A (CoAsom et im es deno t ed CoA- SH )a n d lip o a t e

4 d i f fe re n t v it a m i ns requ i red i nh u m a n n u t r it io n a r e v it a lcom po nen t s o f t h i s syst em :t h i a m i n e ( i n T P P ) , r ib o f l a v i n (i nFAD ) , n iac in ( i n NA D) , andp a n t o t h e n a t e ( in Co A )


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Oxidativedecarboxylationof

pyruvateto acetyl-CoAby the PDH complex

P y r u v a t e r ea c t s w i t h t h e b o u n d t h i a m i n e p y r o p h o sp h a t e ( TP P ) o fp y ruv a t e dehy drogena se (E1) , un dergo ing decarb oxy la t ion to th e

h y d r o xy e t h y l d e r iv a t i v eThe t ransfe r o f 2 e lect rons and the ace ty l g roup f rom TPP to t he ox id i zedfo rm o f th e li poy l l ysy l g roup o f the core enzym e, d ihyd ro l ip oy l t ra nsace ty lase( E 2 ) , t o f o r m t h e a c e t y l t h i oe st e r o f t h e r e d u c e d l ip o y l g r o u pTranseste r i f ica t ion in w h ich the OSH grou p o f CoA rep laces the O SH grou po f E 2 t o y i el d a c e t y l- C o A a n d t h e f u l l y r ed u c e d ( d i t h i o l ) f or m o f t h e l ip o y lg r o u p


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Dihydrolipoyl dehydrogenase(E3) promotestransfer of two hydrogen atoms from the reducedlipoyl groups of E2 to the FAD prosthetic group ofE3, restoring the oxidized form of the lipoyllysylgroup of E2

the reduced FADH2 of E3 transfers a hydride ionto NAD, forming NADH. The enzyme complex isnow ready for another catalytic cycle.

Citric acid cycle, also called the tricarboxylic acid(TCA) cycle or the Krebs cycle (after its discoverer1937)

In eukaryotes, the entire set of reactions of thecitric acid cycle takes place in mitochondria(Eugene Kennedy & Albert Lehninger, 1948)

In each turn of the cycle, one acetyl group (two

carbons) enters as acetyl-CoA and two moleculesof CO2

The reaction is a circular not a linear

Reactions of the Citric Acid Cycle


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The Citric AcidThe Citric AcidCycle Has EightCycle Has Eight

StepsSteps

1 Format ion of Citrate

The condensation of acetyl-CoA (methyl carbon) with oxaloacetate(carbonyl groups) to form citrate, catalyzed bycitrate synthase

It rapidly undergoes hydrolysis to free citrate and CoA (liberated inthis reaction is recycledto participate in the oxidative decarboxylationof another molecule of pyruvateby the PDH complex)


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II .II. Format ion of Isocit rate via cisFormat ion of Isocit rate via cis--AconitateAconitate

A n a conitase (more formally,aconitate hydratase) catalyzes thereversible transformation of citrate to isocitrate, through theintermediary formation of thetricarboxylic acidcis-aconitate

Aconitase contains anironsulfur center , which acts both in the bindingof the substrate at the active site and in the catalytic addition orremoval of H2O.


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I soc it ra te d ehyd rogena se cata lyzes ox ida t ive decarboxy la t iono f i so ci t r a t e t o f o rm k et o g lu t a ra t e

M n 2+ i n t he a ct i v e si t e i n t e r ac t s w i t h t he ca r b ony l g r oup o f t hei n t er m e d i a t e o x a l o su c ci n a t e

- k e t o g lu t a r a t e i s co n v e rt e d t o su c ci n y l- C o A a n d C O 2 b y t h eac t i on o f t he - k e t o g lu t a r a t e d e h y d r og e na se co m p l exN A D se r v es as e lect r on a ccep to r an d C oA as t he c a r r i er o f t hesuccinyl


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The enzym e tha t ca ta lyzes th is rev ersib le react ion iscal led succiny l -CoAsyn t he ta se or succ in i c th iok inase , t h e e n z y m e i t se lf b e c o m e s p h o sp h o r y la t e dat a H is residu e in th e act iv e si te

Th is ph osp hory l g roup , i s t ra nsfe r red to A DP ( o r GDP ) g roup t ra nsfe rp o t e n t i a l , t o f o r m A T P ( o r G T P )


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V I .V I . Oxidation ofOxidat ion of SuccinateSuccinate toto FumarateFumarate

The su ccina t e fo rm ed f rom su cc iny l -Co A is o xid i ze d t o f u m a r a t e b y t h ef l av op r o te in su cc ina te d ehyd rogena se

M a lona te i s a st r ong c om pe t i t i v einh ib i t o r o f suc cina te dehy d r ogenase

V I I .V I I . H i d r a H i d r a t t ii on o f on of f um ar a t f um ar at e t o e t o ma l at ma l a t e e

T h e r e v e r si b le h y d r a t i o n o ff u m a r a t e t o m a l a t e isc a t a l y z ed b y F u m a r a s e( f u m a r a t h id r a t a se)

The enzym e is h igh lystereospecif ic; i t cat a lyzedh y d r a t i o n of t h e t r a n s d o u b l eb o n d o f f u m a r a t e , b u t n o tt h e cis d o u b l e b o n d m a l ea t e( cis iso m e r o f f u m a r a t e )


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V I I I . O V I I I . Oxx i d a i da tt ii on o f on o f m al at ma l a t ee t ot o oox axaaloaaloaccet ate t a t ee

L - m a l a t e d e h y d ro g en a se ca t a l yze d o x id a t io n o f L -m a l a t e t o o xa l o a se t a t e

Th is k eeps th e concent ra t ion o f oxa loase ta te in t he cel lex t rem ely low (10 - 6 M )

ProduPr oduct of t he one t ur n of t he ci t r icct of t he one t ur n of t he ci t r ic

acid cycl eacid cycl e


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Role of the citric acid cycle in anabolism

Regul at ion of ci t r i c acid cycRegul at ion of ci t r i c acid cycll ee


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Pent hose Phosphat e

pat hw ays

Pent hose Phosphat e O x ida t i on o f g lucose 6 - p hosph a t e t o pen t ose p hosph a t es by t he

p e n t o se p h o sp h a t e p a t h w a y (a lso ca l led t he phos phog luc ona tep a t h w a y o r t h e h e xo se m o n o p h o sp h a t e p a t h w a y

Glu cose 6- P p e n t h o se p h o sp h a t e

Bo ne m a r row , sk in , in test ina l m u cosa : pen th ose RN A , D N A ,co e n zy m e - A , A T P , N A D H , F A D H 2

The essent ia l p rod uc t o f the p ento se pho sph a te pa th w a y is no tt h e p e n t o se s b u t t h e e le ct r o n d o n o r N A D P H , n e ed e d f o rreduct ive b iosynthes is

O x id a t i v e a n d d e k a r b o x y la t i o n a t C - 1 o f g l u co se 6 - p h o sp h a t e ,r ed u ci n g N A D P t o N A D P H a n d p r o d u ci n g p e n t o se p h o sp h a t e s.

N A D P H p r ov ides r educ ing po w er f o r b iosy n th e t i c r eact i ons,an d r ib ose 5-ph osph a te is a p recursor fo r nu cleo t ide a nd nu c le ica cid syn t hesis


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Citric Acid Cycles