citric acid cycle. figure 17-2 citric acid cycle
TRANSCRIPT
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Citric Acid Cycle
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Figure 17-2
Citric Acid Cycle
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Summary of Citric Acid Cycle
Acetyl-CoA + 3 NAD+ + FAD + GDP + Pi
2 CO2 + 3 NADH + 3H+ + FADH2 + GTP + CoA-SH
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Reactions of the Citric Acid Cycle
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Citrate Synthase(citrate condensing enzyme)
Acetyl- SCoA Oxaloacetate
H3C C
O
S CoA
C
H2C
COOH
COOH
O+
H2C
C
H2C
HO
COOH
COOH
COOH
Citrate
CoA–SH
∆Go’ = –31.5 kJ/mol
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Figure 17-10 part 1
Mechanism of Citrate Synthase
(Formation of Acetyl-SCoA Enolate)
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Figure 17-10 part 2
Mechanism of Citrate Synthase
(Acetyl-CoA Attack on Oxaloacetate)
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Figure 17-10 part 2
Mechanism of Citrate Synthase
(Hydrolysis of Citryl-SCoA)
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Regulation of Citrate Synthase
• Pacemaker Enzyme (rate-limiting step)
• Rate depends on availability of substrates
– Acetyl-SCoA
– Oxaloacetate
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Aconitase
Stereospecific
Addition
Cis- aconitate(~3%)
I socitrate(~6%)
H2C
C
H2C
HO
COOH
COOH
COOH
Citrate(~91%)
H2C
C
HC
COOH
COOH
COOH
H2C
HC
CH
COOH
COOH
COOH
HO
H2OH2O
∆Go’ = ~0
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Iron-Sulfur Complex(4Fe-4S]
Thought to coordinate citrate –OH to facilitate elimination
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Stereospecificity of Aconitase Reaction
Prochiral Substrate Chiral Product
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Figure 11-2
Stereospecificity in Substrate Binding
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NAD+–DependentIsocitrate Dehydrogenase
I socitrate
H2C
HC
CH
COOH
COOH
COOH
HO
NAD+ NADH + H+
- ketoglutarate
H2C
CH2
C
COOH
COOHO
+ CO2
Mn2+ or Mg2+
Oxidative Decarboxylation
NOTE: CO2 from oxaloacetate
∆Go’ = -20.9 kJ/mol
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Figure 17-11 part 1
Mechanism of Isocitrate Dehydrogenase
(Oxidation of Isocitrate)
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Figure 17-11 part 2
Mechanism of Isocitrate Dehydrogenase
(Decarboxylation of Oxalosuccinate)
Mn2+ polarizes C=O
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Figure 17-11 part 2
Mechanism of Isocitrate Dehydrogenase(Formation of -Ketoglutarate)
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Regulation of Isocitrate Dehydrogenase
• Pulls aconitase reaction
• Regulation (allosteric enzyme)
– Positive Effector: ADP (energy charge)
– Negative Effector: ATP (energy charge)
• Accumulation of Citrate: inhibits Phosphofructokinase
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Accumulation of Citrate
CO2
Isocitrate dehydrogenase
CO2
Isocitrate dehydrogenase
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-Ketoglutarate Dehydrogenase
NAD+ NADH + H+
- ketoglutarate
H2C
CH2
C
COOH
COOHO
+ CO2+ CoASH
Succinyl- CoA
H2C
CH2
C
COOH
SCoAO
Oxidative Decarboxylation
Mechanism similar to PDH
CO2 from oxaloacetate
High energy thioester
∆Go’ = -33.5 kJ/mol
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-Ketoglutarate Dehydrogenase
(Multienzyme Complex)
• E1: -Ketoglutarate Dehydrogenase or -Ketoglutarate Decarboxylase
• E2: Dihydrolipoyl Transsuccinylase
• E3: Dihydrolipoyl Dehydrogenase (same as E3 in PDH)
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Regulation of -Ketoglutarate Dehydrogenase
• Inhibitors
– NADH
– Succinyl-SCoA
• Activator: Ca2+
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Origin of C-atoms in CO2
H2C
C
H2C
HO
COOH
COOH
COOH
Citrate I socitrate
H2C
HC
CH
COOH
COOH
COOH
HO
- ketoglutarate
H2C
CH2
C
COOH
COOHO
Succinyl- CoA
H2C
CH2
C
COOH
SCoAO
Both CO2 carbon atoms derived from oxaloacetate
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Succinyl-CoA Synthetase(Succinyl Thiokinase)
GDP + Pi GTP
+ CoASH
Succinyl- CoA
H2C
CH2
C
COOH
SCoAO
H2C
H2C
COOH
COOH
Succinate
High Energy Thioester —> Phosphoanhydride Bond
Plants and Bacteria: ADP + Pi —> ATP
Randomizationn of labeled C atoms
∆Go’ = ~0
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Thermodynamics(Succinyl-SCoA Synthetase)
Succinyl-SCoA+ H2O Succinate + CoA
GDP + Pi GTP + H2O
Succinyl-SCoA + GDP + Pi
² Go' = –32.6 kJ / mol
² Go' = +30.5 kJ / mol
² Go' = –2.1 kJ /molSuccinate + GTP + CoA
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Evidence for Phosphoryl-enzyme Intermediate
(Isotope Exchange)
Absence of Succinyl-SCoA
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Figure 17-12 part 1
Mechanism of Succinyl-CoA Synthetase
(Formation of High Energy Succinyl-P)
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Figure 17-12 part 2
Mechanism of Succinyl-CoA Synthetase
(Formation of Phosphoryl-Histidine)
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Figure 17-12 part 3
Mechanism of Succinyl-CoA Synthetase(Phosphoryl Group Transfer)
Substrate-level phosphorylation
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Nucleoside Diphosphate Kinase
(Phosphoryl Group Transfer)
GTP + ADP ——> GDP + ATP
∆Go’ = ~0
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Succinate Dehydrogenase
Randomization of C-atom Labeling
Membrane-Bound Enzyme
H2C
H2C
COOH
COOH
Succinate
CH
HC COOH
HOOC
Fumarate
FAD FADH2
∆Go’ = ~0
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Figure 17-13
Covalent Attachment of FAD
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FAD used for Alkane Alkene
• Reduction Potential– Affinity for electrons; Higher E, Higher Affinity
– Electrons transferred from lower to higher EEh
o’ = Go’/nF = -(RT/nF)ln (Keq)
FAD/FADH2
Succinate/Fumarate
NAD+/NADH
Isocitrate/α-Ketoglutarate
Reduction Potential
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Fumarase
H2O
CH
HC COOH
HOOC
Fumarate
HC
H2C COOH
HO COOH
Malate
∆Go’ = ~0
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Mechanism of Fumarase
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Malate Dehydrogenase
NAD+ NADH + H+
HC
H2C COOH
HO COOH
Malate
C
H2C COOH
O COOH
Oxaloacetate
∆Go’ = +29.7 kJ/mol
Low [Oxaloacetate]
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Thermodynamics
Malate + NAD+ Oxaloacetate + NADH + H+
Acetyl-SCoA + Oxaloacetate Citrate + CoA
Malate + NAD+
+ Acetyl-SCoA
² Go' = +29.7 kJ / mol
² Go' = –31.5 kJ / mol
² Go' = –1.8 kJ /molNADH + H+ +
Citrate + CoA
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Figure 17-14
Products of the Citric Acid Cycle
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ATP Production from Products
of the Central metabolic Pathway
= 32 ATP
NADH 2.5 ATPFADH2 1.5 ATP
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Amphibolic Nature of Citric
Acid Cycle
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Carbons of Glucose:1st cycle
1 2 36 5 4
3, 4
2,51,6
2,51,61,62,5
2,51,61,62,5
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Carbons of Glucose:2nd cycle:
Carbons 2,5:After 1½ turns:all radioactivity is CO2
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Carbons of Glucose:2nd cycle:
Carbons 1,6:After 2 turns:¼ radioactivity in each carbon of OAA
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Carbons of Glucose:3rd cycle:
Carbons 1,6:After 3 turns:½ radioactivity is CO2
Each turn after willlose ½ remainingradioactivity
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Carbon Tracing from Glucose
• Glucose radiolabeled at specific Carbons– Can determine fate of individual carbons
• Carbons 1,6– 1st cycle: 1, 4 of oxaloacetate– Starting at 3rd cycle ½ radioactivity CO2/cycle
• Carbons 2,5– 1st cycle: 2, 3 of oxaloacetate
– 2nd cycle: all eliminated as CO2
• Carbons 3,4– All eliminated at CO2 during Pyruvate Acetyl-CoA
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You are following the metabolism of pyruvate in which the methyl-carbon is radioactive: *CH3COCOOH.
-assuming all the pyruvate enters the TCA cycle as Acetyl-CoA, indicate the labeling pattern and its distribution in oxaloacetate first formed by operation of the TCA cycle.
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Generation of Citric Acid Cycle Intermediates
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Pyruvate Carboxylase
Mitochondrial Matrix
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Pyruvate Carboxylase
Animals and Some Bacteria
ATP
HCO3–
(CO2)H3C C COOH
O
COOH
CH2
CO COOH
Oxaloacetate
ADP + Pi
+
PyruvatePyruvate
Carboxylase
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Biotin Cofactor(CO2 Carrier)
NHC
HN
H2CS
CH
O
(CH2)4 C NH
O
(CH2)4 CH
C
NH
O
Biotin
Lysine
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Reaction Mechanism I(Dehydration/Activation of HCO3
–)
NHC
HN
H2CS
CH
O
(CH2)4 C NH
O
(CH2)4 Enzyme
O P O
O
O–
P
O
O–
O–AMP –O COH
O
HCO3–
ATP
CO
–ONH
CN
H2CS
CH
O
(CH2)4 C NH
O
(CH2)4 Enzmye
Biotinyl-Enzyme
ADP + Pi
Carboxybiotinyl- Enzyme
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Reaction Mechanism II(Transfer of CO2 to Pyruvate)
C C CH2–
OO
–O CO
–ONH
CN
H2CS
CH
O
(CH2)4 C NH
O
(CH2)4 EnzymeC C CH2
O–
O
–O
CO
O–C C CH2
OO
–O
Pyruvate EnolateCarboxybiotinyl-Enzyme
Oxaloacetate
Biotinyl- Enzyme
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Fates of Oxaloacetate
Regulation!
COO–
C
CH3
O
ATP COO–
C
CH2
O
COO–
ADP + Pi
Pyruvate
+ HCO3–
Oxaloacetate
PyruvateCarboxylase
Gluconeogenesis
Citric AcidCycle
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Regulation of Pyruvate Carboxylase
Allosteric ActivatorAcetyl-SCoA
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Glyoxylate Cycle
Glyoxysome
Plants and Some Microorganisms
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Citrate Synthase(citrate condensing enzyme)
Acetyl- SCoA Oxaloacetate
H3C C
O
S CoA
C
H2C
COOH
COOH
O+
H2C
C
H2C
HO
COOH
COOH
COOH
Citrate
CoA–SH
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Aconitase
Cis- aconitate(~3%)
I socitrate(~6%)
H2C
C
H2C
HO
COOH
COOH
COOH
Citrate(~91%)
H2C
C
HC
COOH
COOH
COOH
H2C
HC
CH
COOH
COOH
COOH
HO
H2OH2O
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Glyoxylate Cycle Enzymes
CHO
COOH
Glyoxylate
H2C
HC
CH
COOH
COOH
COOHHO
H3C C S–CoA
O
H2C
H2C
COOH
COOH
CoA-SH
CH
H2C
COOH
COOH
HO
CHO
COOH
Glyoxylate
+
SuccinateI socitrate
I socitrateLyase
Acetyl–SCoA Malate
+
MalateSynthase
Plants and Some Microorganisms
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Malate Dehydrogenase
NAD+ NADH + H+
HC
H2C COOH
HO COOH
Malate
C
H2C COOH
O COOH
Oxaloacetate
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Net Reaction of Glyoxylate Cycle
Net increase of one 4-carbon unit!
2 Acetyl-CoA 1 Oxaloacetate
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Figure 17-18
Glyoxylate Cycle and the Glyoxysome
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Regulation of the Citric Acid Cycle
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Regulatory Mechanisms
• Availability of substrates– Acetyl-CoA– Oxaloacetate
– Oxygen (O2)
• Need for citric acid cycle intermediates as biosynthetic precursors
• Demand for ATP
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Table 17-2
Free Energy Changes of Citric Acid Cycle Enzymes
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Regulation of Pyruvate Dehydrogenase
• Product Inhibition (competitive)
– NADH
– Acetyl-SCoA
• Phosphorylation/Dephosphorylation
– PDH Kinase: inactivation
– PDH Phosphatase: reactivation
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Figure 17-15
Covalent Modification and Regulation of PDH
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Regulation of PDH Kinase(Inactivation)
• Activators– NADH– Acetyl-SCoA
• Inhibitors– Pyruvate– ADP– Ca2+ (high Mg2+)
– K+
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Regulation of PDH Phosphatase(Reactivation)
• Activators– Mg2+
– Ca2+
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Regulation of Citrate Synthase
• Pacemaker Enzyme (rate-limiting step)
• Rate depends on availability of substrates
– Acetyl-SCoA
– Oxaloacetate
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Regulation of Isocitrate Dehydrogenase
• Pulls aconitase reaction
• Regulation (allosteric enzyme)
– Positive Effector: ADP (energy charge)
– Negative Effector: ATP (energy charge)
• Accumulation of Citrate: inhibits Phosphofructokinase
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Regulation of -Ketoglutarate Dehydrogenase
• Inhibitors
– NADH
– Succinyl-SCoA
• Activator: Ca2+
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Figure 17-16
Regulation of the Citric Acid Cycle