The citric acid cycle is a series of chemical reactions used by all aerobic organisms to generate energy through the oxidation of acetate derived from carbohydrates, fats, and proteins into carbon dioxide. It is an eight-step cycle that occurs in the matrix of mitochondria. Each turn of the cycle produces one molecule of carbon dioxide, reduces three NAD+ molecules to NADH, reduces one FAD molecule to FADH2, and generates one ATP or GTP from ADP or GDP. The NADH and FADH2 then transfer electrons to the electron transport chain to produce additional ATP through oxidative phosphorylation.
The citric acid cycle is a series of chemical reactions used by all aerobic organisms to generate energy through the oxidation of acetate derived from carbohydrates, fats, and proteins into carbon dioxide. It is an eight-step cycle that occurs in the matrix of mitochondria. Each turn of the cycle produces one molecule of carbon dioxide, reduces three NAD+ molecules to NADH, reduces one FAD molecule to FADH2, and generates one ATP or GTP from ADP or GDP. The NADH and FADH2 then transfer electrons to the electron transport chain to produce additional ATP through oxidative phosphorylation.
The citric acid cycle is a series of chemical reactions used by all aerobic organisms to generate energy through the oxidation of acetate derived from carbohydrates, fats, and proteins into carbon dioxide. It is an eight-step cycle that occurs in the matrix of mitochondria. Each turn of the cycle produces one molecule of carbon dioxide, reduces three NAD+ molecules to NADH, reduces one FAD molecule to FADH2, and generates one ATP or GTP from ADP or GDP. The NADH and FADH2 then transfer electrons to the electron transport chain to produce additional ATP through oxidative phosphorylation.
3-, 456 1 -"22%27& 8"9:.&7;<= - rocess ln whlch cells consume C 2 and produce CC 2 - rovldes more energy (A1) from glucose Lhan glycolysls - Also capLures energy sLored ln llplds and amlno aclds - Lvoluuonary orlgln: developed abouL 2.3 bllllon years ago - used by anlmals, planLs, and many mlcroorganlsms - Cccurs ln Lhree ma[or sLages: - aceLyl CoA producuon (breakdown amlno aclds, glucose, fauy aclds) - aceLyl CoA oxldauon (clLrlc acld cycle) - elecLron Lransfer and oxldauve phosphorylauon 2 2 8"9:.&7;<=* >$7?" 4 /#"$12@-</ A&<0%#;<= CeneraLes some: A1, nAuP, lAuP 2 3 8"9:.&7;<=* >$7?" ( /#"$12@-</ <B.07;<= CeneraLes more nAuP, lAuP 2 ,
and one C1 4 3 8"9:.&7;<=* >$7?" C DB.07;E" A,<9:,<&127;<= CeneraLes a loL of A1 3 +," -.$&.# /#.0 -1#2" - under aeroblc condluons, Lhe pyruvaLe produced by glycolysls ls oxldlzed Lo P 2 C and CC 2 - 1he clLrlc acld cycle ls a hub ln meLabollsm, wlLh degradauve paLhways leadlng ln and anabollc paLhways leadlng ouL. 6 4 >$7?" F* -<=E"&9.<= <G A1&%E7$" $< /#"$12@-</ - neL 8eacuon: - Cxldauve decarboxylauon of pyruvaLe - llrsL carbons of glucose Lo be fully oxldlzed - CaLalyzed by Lhe pyruvaLe dehydrogenase complex - 8equlres 3 coenzymes - llpoyllyslne, and lAu are prosLheuc groups - 1, nAu + and CoA-SP are co-subsLraLes 7 A1&%E7$" H",10&<?"=79" -<I:2"B 3AH-6 - uC ls a large (up Lo 4) JH7) muluenzyme complex - pyruvaLe dehydrogenase (L 1 ) - Coenzyme= 1 - dlhydrollpoyl LransaceLylase (L 2 ) - Coenzymes=llpolc acld, CoASP - dlhydrollpoyl dehydrogenase (L 3 ) - Coenzymes= lAu, nAu + - Complex= 24 L 2 +24 L 1 dlmers+ 12 L 3 dlmers - AdvanLages of muluenzyme complexes: ! shorL dlsLance beLween caLalyuc slLes allows channellng of subsLraLes from one caLalyuc slLe Lo anoLher. ! channellng mlnlmlzes slde reacuons ! regulauon of acuvlLy of one subunlL aecLs Lhe enure complex 8 5 DE"&722 8"7#;<= <G AH- 9 >$&%#$%&" <G -<"=K1I" / - Coenzymes are noL a permanenL parL of Lhe enzymes' sLrucLure. - 1hey assoclaLe, fulll a funcuon, and dlssoclaLe - 1he funcuon of CoA ls Lo accepL and carry aceLyl groups 10 6 >$&%#$%&" <G !.:<12219.=" - rosLheuc groups are sLrongly bound Lo Lhe proLeln - 1he llpolc acld ls covalenLly llnked Lo Lhe enzyme vla a lyslne resldue 11 DE"&722 8"7#;<= <G AH- 12 7 >"L%"=#" <G ME"=$9 .= DB.07;E" H"#7&N<B127;<= <G A1&%E7$" Lnzyme 1 - >$": 4* uecarboxylauon of pyruvaLe Lo an aldehyde - >$": (* Cxldauon of aldehyde Lo a carboxyllc acld ! LlecLrons reduce llpoamlde and form a LhloesLer Lnzyme 2 - >$": C* lormauon of aceLyl-CoA (producL 1) Lnzyme 3 - >$": O* 8eoxldauon of Lhe llpoamlde cofacLor - >$": P* 8egenerauon of Lhe oxldlzed lAu cofacLor ! lormlng nAuP (producL 2) 13 -<=$&<2 <G $," AH- - 1hls complex ls sLrongly lnhlblLed by A1, aceLyl-CoA, and nAuP. 1hey are all lndlcaLors of adequaLe energy levels. - AllosLerlc lnhlbluon ls enhanced by Lhe presence of long- chaln fauy aclds (an alLernauve fuel source). - AM, CoA, and nAu + allosLerlcally acuvaLe Lhe complex. 1hese are all lndlcaLors of lnadequaLe energy levels. - 1he complex ls also regulaLed by proLeln modlcauon. 8everslble phosphorylauon of L 1 lnhlblLs Lhe complex. - 1he klnase responslble for Lhls reacuon ls allosLerlcally acuvaLed by A1. 14 8 +," -.$&.# /#.0 -1#2" 3-/-6 13 -.$&.# /#.0 -1#2" DE"&E."Q - ln each Lurn of Lhe cycle, one molecule of aceLaLe enLers by condenslng wlLh oxaloaceLaLe Lo form clLraLe, Lwo molecules of CC 2 leave, and oxaloaceLaLe ls regeneraLed. - Slnce oxaloaceLaLe ls regeneraLed, ln Lheory only one molecule of Lhls compound ls needed Lo keep Lhe cycle golng. - lour of Lhe elghL sLeps are oxldauons, produclng nAuP or lAuP 2 . - varlous lnLermedlaLes can be slphoned o for oLher meLabollc paLhways and Lhey can be replenlshed by a varleLy of anaplerouc reacuons. - 1he enure seL of reacuons Lakes place ln Lhe mlLochondrla. MlLochondrla also conLaln Lhe enzymes for oxldauve phosphorylauon and for oxldauon of fauy aclds and amlno aclds Lo aceLyl-CoA. 16 9 +," -.$&.# /#.0 -1#2" 3-/-6 17 >$": 4* R<&I7;<= <G -.$&7$" 18 10 >$": (* R<&I7;<= <G F9<#.$&7$" - AconlLase caLalyzes Lhe formauon of lsoclLraLe from clLraLe, Lhrough Lhe lnLermedlary formauon of cls-aconlLaLe. - AconlLase conLalns an lron-sulfur cenLer whlch acLs ln blndlng of subsLraLe and ln caLalyuc addluon of P 2 C. - Addluon of P 2 C Lo Lhe lnLermedlaLe cls-aconlLaLe could produce elLher clLraLe or lsoclLraLe. - 1he reacuon ls pulled Loward formauon of lsoclLraLe, agalnsL free energy, because lsoclLraLe ls rapldly consumed ln Lhe nexL sLep of Lhe cycle. 19 20 11 >$": C* DB.07;<= <G F9<#.$&7$" - lsoclLraLe ls oxldlzed Lo !-keLogluLaraLe and CC 2 by Lhe enzyme lsoclLraLe dehydrogenase. - 1hls reacuon ls hlghly favorable and produces nAuP (or nAuP) plus P + . - 1he nAu-dependenL enzyme serves ln Lhe clLrlc acld cycle. 1he nAu + enzyme ls found ln Lhe cyLosol and Lhe mlLochondrla and ls probably requlred for Lhe generauon of nAuP ln Lhese comparLmenLs. 21 >$": O* DB.07;<= <G !@S"$<?2%$7&7$" - 1hls reacuon produces nAuP, ls hlghly favorable (-33.3 k!/mol), and conserves Lhe energy of oxldauon ln Lhe LhloesLer bond of succlnyl-CoA. - 1he reacuon of Lhls complex ls almosL ldenucal Lo LhaL of Lhe pyruvaLe dehydrogenase complex and Lhese Lwo proLelns are undoubLedly evoluuonarlly relaLed. - L 2 and L 3 are almosL ldenucal beLween Lhe Lwo complexes, whlle L 1 dlers and provldes subsLraLe speclclLy. 22 12 >$": P* >%##.=12@-</ >1=$,"$79" - Succlnyl-CoA synLheLase converLs succlnyl-CoA Lo succlnaLe, produclng C1 (or A1) from Cu (or Au) and ! ln Lhe process. - 1he enzyme ls LranslenLly phosphorylaLed on a hlsudlne resldue durlng Lhls reacuon. - Succlnyl-CoA synLheLase has Lwo subunlLs. 1he !-subunlL conLalns Lhe phosphorylaLed Pls resldue and blnds CoA. 1he "-subunlL confers speclclLy for Au or Cu. - now LhaL we have a four carbon compound agaln, we need Lo perform a few oxldauons ln order Lo generaLe oxaloaceLaLe. 23 24 13 >$": 5* >%##.=7$" H",10&<?"=79" - SucclnaLe ls oxldlzed Lo fumaraLe by Lhe avoproLeln succlnaLe dehydrogenase, produclng lAuP 2 . - SucclnaLe dehydrogenase ls a membrane bound proLeln, Lhe only one ln Lhe CAC cycle. - LlecLrons pass from succlnaLe Lo lAu and Lhen Lhrough Lhree lron-sulfur cenLers before enLerlng Lhe oxldauve phosphorylauon paLhway. - LlecLron ow from Lhls reacuon ylelds 1.3 A1 molecules per palr of elecLrons. - MalonaLe ls a sLrong compeuuve lnhlblLor of Lhls enzyme and blocks Lhe cycle. 23 >$": T* R%I7&79" - lumarase caLalyzes Lhe reverslble hydrauon of fumaraLe Lo malaLe, uslng a carbanlon Lransluon sLaLe. - 1hls enzyme ls hlghly sLereospeclc, hydraung Lhe Lrans double bond of fumaraLe buL noL Lhe cls double bond of maleaLe. - ln Lhe reverse dlrecuon only L-malaLe ls a subsLraLe, noL Lhe u-lsomer. 26 14 >$": U* DB.07;<= <G J727$" - L-malaLe dehydrogenase oxldlzes malaLe Lo oxaloaceLaLe, regeneraung Lhe sLarung compound and produclng nAuP. - 1hls reacuon ls unfavorable under sLandard condluons (29.7 k!/mol), buL oxaloaceLaLe ls kepL aL a low concenLrauon (<10 -6 M), pulllng Lhe reacuon forward. 27 M="&?1 -<=9"&E7;<= - Lnergy released durlng oxldauon ls conserved ln Lhe reducuon of 3 nAu + and one lAu, as well as Lhe producuon of one A1 (C1). - 1he Lwo carbons LhaL exlL as CC 2 are noL Lhe same carbons LhaL enLer as aceLaLe. - ln oxldauve phosphorylauon, Lhe elecLrons from nAuP produce 2.3 A1 and Lhe elecLrons from lAuP 2 produce 1.3 A1. - As many as 32 molecules of A1 are obLalned per glucose molecule. 28 15 D$,"& 8<2"9 <G $," +-/ -1#2" - Cxldauon of aceLaLe appears Lo be a compllcaLed process. - lL probably evolved under anaeroblc condluons and Lhen conunued Lo provlde a selecuve advanLage. Some modern anaeroblc organlsms have an lncompleLe clLrlc acld cycle, whlch lacks !-keLogluLaraLe dehydrogenase, whlch Lhey use as a source of blosynLheuc precursors. - 1he role of Lhe clLrlc acld cycle ls noL conned Lo oxldauon of aceLaLe, lL serves as Lhe hub of lnLermedlary meLabollsm. - lnLermedlaLes such as oxaloaceLaLe and !-keLogluLaraLe can be drawn ouL of Lhe cycle and used as precursors ln blosynLheuc paLhways of mosL amlno aclds. - Succlnyl-CoA serves as a precursor of Lhe porphyrln rlng of heme groups. - CxaloaceLaLe ls also a precursor ln glucose synLhesls. 29 30 16 /=7:2"&<;# 8"7#;<=9 - lnLermedlaLes ln Lhe clLrlc acld cycle are replenlshed by anaplerouc reacuons. - 1he concenLrauons of all of Lhe lnLermedlaLes ln Lhe cycle remaln almosL consLanL. - 1hese anaplerouc reacuons generally produce elLher oxaloaceLaLe or malaLe. - ln Lhe kldney and llver, pyruvaLe carboxylase forms oxaloaceLaLe from pyruvaLe and CC 2 . - yruvaLe carboxylase ls sLrongly sumulaLed by aceLyl-CoA. 31 32 17 8"?%27;<= <G $," -.$&.# /#.0 -1#2" 1. 1he clLrlc acld cycle ls under ughL regulauon aL Lwo levels: - 1he converslon of pyruvaLe Lo aceLyl-CoA (Lhe pyruvaLe dehydrogenase complex). - 1he enLry of aceLyl-CoA lnLo Lhe cycle (clLraLe synLhase). 2. 1he cycle ls also regulaLed aL Lhe lsoclLraLe dehydrogenase and !-keLogluLaraLe dehydrogenase reacuons. 33 8"?%27;<= <G A1&%E7$" H",10&<?"=79" -<I:2"B - lnhlblLed by hlgh energy lndlcaLors - AcuvaLed by low energy lndlcaLors CovalenL modlcauon: -phosphaLase removes l from L1 (acuve). AcuvaLed by calclum - klnase adds l Lo L1 (lnacuve). AcuvaLed by nAuP, aceLyl-CoA 34 18 -<=$&<2 7$ MB"&?<=.# >$":9 - lnhlbluon of clLraLe synLhase by A1 ls relleved by Au. - ln verLebraLe muscle, Ca 2+
acuvaLes lsoclLraLe dehydrogenase and !- keLogluLaraLe dehydrogenase. - 1he raLes of glycolysls and Lhe clLrlc acld cycle are lnLegraLed so LhaL boLh are operaung aL Lhe same raLe. 33 >%II7&.K" $," -/- aLhway: ClLrlc Acld Cycle urpose: aLhways leadlng ln: aLhways leadlng ouL: Locauon: Molecules needed for lnpuL: CuLpuL: AcuvaLors: lnhlblLors: 36 19 >%II7&.K" $," -/- aLhway: ClLrlc Acld Cycle urpose: aLhways leadlng ln: aLhways leadlng ouL: Locauon: Molecules needed for lnpuL: CuLpuL: AcuvaLors: lnhlblLors: 37 Generate energy in the form of NADH, FADH2, and GTP by oxidizing acetate Mainly glycolysis, fatty acid oxidation, amino acid degradation NADH, FADH 2 ! Oxidative phosphorylation (where ATP is made) Other intermediates ! anabolic pathways Mitochondrial matrix Acetyl-CoA, oxaloacetate (recycled) 2CO 2 , 3 NADH, 1FADH 2
AMP, Calcium, NAD, CoA ATP, Acetyl-CoA, NADH 8"7#;<=9 <G $," AHV -<I:2"B 7=0 -/- uP complex and CAC 8eacuons 1 ! 8 LlsL ouL for each: SubsLraLe(s) ! roducL(s) CofacLors (lf any) lmporLanL feaLures of Lhe mechanlsm lnhlblLors/acuvaLors 38 20 !"7&=.=? MB"&#.9" 3( :$96 MaLch Lhe cofacLor wlLh lLs funcuon ln Lhe clLrlc acld cycle. A glven funcuon may be used more Lhan once or noL aL all. CofacLor luncuon (1) nAu + /nAuP (a) carrles C 2
(2) lAu/lAuP 2 (b) carrles small carbon-conLalnlng molecules (3) CoA (c) carrles e -