2013 citric acid cycle
Post on 20-Jul-2016
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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
CH3
O
SC CoA
C
CH2
COO
COO
O-
-
CoA SH+ + + + H+
C
CH2
COO
COO
CH2
CO
O
-
-
-
HO
O
H2
5
Aconitase
G°´ = +6,3 kJ/mol G 0
citrate cis-aconitate (2R,3S)-isocitrate
C
CH
COO
COO
CH2
COO-
-
-
C
C
COO
COO
CH2
COO
OH
H
H
-
-
-
H O2
H O2
H O2
H O2
C
C
COO
COO
CH2
COO
H
H
OH
-
-
-
6
Isocitrate dehydrogenase
G°´ = -20,9 kJ/mol G = negative
(2R,3S)-isocitrate oxalosuccinate a-ketoglutarate
COO
CH2
C
C
CO O
HOH
CHO
O
-
-
-COO
CH2
C
C
CO O
O
CHO
O
-
-
-
Mn2+
COO
CH2
C
C
CO O
O
H
-
-
Mn2+
-
NAD+ + +
H+
H NADH CO2
COO
CH2
C
C
CO O
O
H H
-
-
G°´ = -33,5 kJ/mol G = negative
a-ketoglutarate succinyl-CoA
NAD+ CO
2+ + CoA-SH + + NADH
COO
CH2
C
C
CO O
O
H H
-
-COO
CH2
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
CH2
C
C
S
O
H H
CoA
-
+ O P O
OH
O-
- + CoASH
COO
CH2
C
C O
H H
O PO3
-
2-
H+
COO
CH2
C
C O
H H
O PO3
-
2-
+ +
COO
CH2
C
C O
H H
O
-
-
enzyme His. enzyme 3-phosphohistidine
+GDP
+ GTPenzyme His.succinylphosphate succinate
Succinate dehydrogenase
G°´ = 0 kJ/mol G 0
succinate fumarate
COO
C
C
COO
H H
H H
-
-
+ E FADC
COOC H
H COO
+ E FADH2
-
-
8
Fumarase
G°´ = -3,8 kJ/mol G 0
(S)-malate fumarate
+ H O2
C
COOC H
H COO
-
-
C
COOC
H COOH
OH
H
-
-
Malate dehydrogenase
G°´ = +29,7 kJ/mol G 0
(S)-malate oxaloacetate
C
COOC
H COOH
O
H
-
-
H+ + + H
+NADHNAD
+ C
COOC
H COOH
O-
-
9
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
10
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
11
Anaplerotic sequences of CAC
• Oxidative carboxylation - pyruvate carboxylase
• Reductive carboxylation - malate dehydrogenase
+ + +H+
NADP+ + H2OC O
CH3
COO-
CO3H-
NADPH +C O
COO
CH2
COO
H H
-
-
+ + ATP + ADP + Pi +C O
CH3
COO-
CO3 -
HC O
COO
CH2
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
12
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
CH2
COO
H
H
OH
-
-
-
CH2
CH2
COO
COO-
-
+O C COO
H
-
– isocitrate lyase
succinate glyoxylate
O C COO
H
-+ CH
3C
O
S CoA + H O2
COO
C
CH2
COO
HOH
-
-
+ CoA SH + H+
– malate synthase
malate
13
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