1

The Citric Acid Cycle

Syllabus
Pyruvate Dehydrogenase Complex
Overview of the Citric Acid Cycle
The Reactions of the Citric Acid Cycle
Regulation of the Citric Acid Cycle
Amphibolic character of the CAC
Anaplerotic Sequences of the CAC
Glyoxylate Cycle
2
Pyruvate Dehydrogenase
Complex
Pyruvate oxidation: a major entry route for carbon into the
citric acid cycle
the three enzymes involved are assembled into a highly
organized multienzyme assembly
pyruvate decarboxylase (dehydrogenase) (E1)
dihydrolipoamide transacetylase (E2)
dihydrolipoamide dehydrogenase (E3)
1
2
3
4
5
6
3
4
Citrate synthase
G = -32,2 kJ/mol G = negative
acetyl-CoA oxaloacetate citrate
C H
3
O
S C CoA
C
C H
2
COO
COO
O
-
-
CoA SH
+ + + +
H
+
C
C H
2
COO
COO
C H
2
CO
O
-
-
-
H
O
O
H
2
5
Aconitase
G = +6,3 kJ/mol G 0
citrate cis-aconitate (2R,3S)-isocitrate
C
C H
COO
COO
C H
2
COO
-
-
-
C
C
COO
COO
C H
2
COO
O H
H
H
-
-
-
H O
2
H O
2
H O
2
H O
2
C
C
COO
COO
C H
2
COO
H
H
OH
-
-
-
6
Isocitrate dehydrogenase
G = -20,9 kJ/mol G = negative
(2R,3S)-isocitrate oxalosuccinate a-ketoglutarate
COO
CH
2
C
C
C
O O
H O H
C H
O
O
-
-
-
COO
CH
2
C
C
C
O O
O
C H
O
O
-
-
-
Mn
2+
COO
CH
2
C
C
C
O O
O
H
-
-
Mn
2+
-
NAD
+
+
+
H
+
H NADH CO
2
COO
CH
2
C
C
C
O O
O
H H
-
-
G = -33,5 kJ/mol G = negative
a-ketoglutarate succinyl-CoA
NAD
+
CO
2 + +
CoA-SH + +
NADH
COO
CH
2
C
C
C
O O
O
H H
-
-
COO
CH
2
C
C
S
O
H H
CoA
-
a-ketoglutarate dehydrogenase
a-ketoglutarate decarboxylase
dihydrolipoamide succinyltransferase
dihydrolipoamide dehydrogenase
7
Succinyl-CoA-synthetase
G = -33,5 kJ/mol G = negative
succinyl-CoA succinylphosphate
COO
CH
2
C
C
S
O
H H
CoA
-
+ O P O
OH
O
-
-
+
CoASH
COO
CH
2
C
C O
H H
O PO
3
-
2-
H
+
COO
CH
2
C
C O
H H
O PO
3
-
2-
+
+
COO
CH
2
C
C O
H H
O
-
-
enzyme His
. enzyme 3-phosphohistidine
+
GDP
+ GTP enzyme His
.
succinylphosphate succinate
Succinate dehydrogenase
G = 0 kJ/mol G 0
succinate fumarate
COO
C
C
COO
H H
H H
-
-
+ E FAD
C
C
OOC H
H COO
+ E FADH
2
-
-
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Fumarase
G = -3,8 kJ/mol G 0
(S)-malate fumarate
+ H O
2
C
C
OOC H
H COO
-
-
C
C
OOC
H
COO
H
OH
H
-
-
Malate dehydrogenase
G = +29,7 kJ/mol G 0
(S)-malate oxaloacetate
C
C
OOC
H
COO
H
O
H
-
-
H
+
+ + H
+
NADH NAD
+
C
C
OOC
H
COO
H
O
-
-
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Regulation of the Citric Acid Cycle
Three key enzymes of the Citric Acid Cycle
operate under physiologic conditions far
from equilibrium ( G is negative)
citrate synthase
isocitrate dehydrogenase
a-ketoglutarate dehydrogenase

Control of the citric acid cycle by three simple ways

availability of substrates (Ac-CoA, oxaloacetate)
inhibition by product (NADH)
competitive inhibition by other intermediates of
the cycle
Regulation of the Citric Acid Cycle
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Regulation of the CAC
Amphibolic character of CAC
biosynthesis of glucose (gluconeogenesis)
in cytosol - uses malate from mitochondria
biosynthesis of lipids
in cytosol - Ac-CoA by spliting of citrate (ATP-citrate lyase)
biosynthesis of amino acids
a-ketoglutarate for glutamate synthesis
a-ketoglutarate and oxaloacetate - transamination
with Ala
synthesis of porphyrin
Cy+Mit - uses succinyl-CoA as a building material
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Anaplerotic sequences of CAC
Oxidative carboxylation - pyruvate carboxylase
Reductive carboxylation - malate dehydrogenase
+ +
+
H
+
NADP
+
+
H
2
O
C O
CH
3
COO
-
CO
3
H
-
NADPH +
C O
COO
CH
2
COO
H H
-
-
+ +
ATP
+
ADP
+
P
i + C O
CH
3
COO
-
CO
3

-
H
C O
COO
CH
2
COO
-
-
H
+
Oxidation of FA with odd C - production of succinyl-CoA
Degradation of isoleucine, valine, methionine - succinyl-CoA
Degradation of phenylalanine, tyrosine, aspartate - fumarate
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Glyoxylate cycle
in plants different fate of Ac-CoA - oxaloacetate
reactions are localised into two cell organels
mitochondrion
glyoxysome
conversion of Ac-CoA into glyoxylate
glyoxylate and Ac-CoA form malate in
glyoxysome - the formation of glucose
Glyoxylate cycle
2 enzymes differ from citrate acid cycle
C
C
COO
COO
C H
2
COO
H
H
OH
-
-
-
C H
2
C H
2
COO
COO
-
-
+
O C COO
H
-
isocitrate lyase
succinate glyoxylate
O C COO
H
-
+
C H
3
C
O
S CoA
+
H O
2
COO
C
CH
2
COO
H O H
-
-
+ CoA SH
+ H
+
malate synthase
malate
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