2016-03-08
The TCA cycle: terminal oxidization to CO2
Course 2851 Principles of Metabolism
Metabolism and endocrinology programme, Karolinska Institutet
Stepwise oxidation
A flexible enzyme system, accepting a variety of substrates
Acetyl-CoA
sugars
CoA
fat
amino acids
Citrate
Synthase
Lecture 7
The tricarboxylic acid (TCA) cycle
NH4
NADH
Carboxylic
acids
NAD+
Oxaloacetate
Cytosol
NAD+
Dehydrogenase
Dehydrogenase
NADH + CO2
Mitochondria
L-malate
Roland Nilsson, Ph.D
Department of Medicine, Solna
Center for Molecular Medicine
Karolinska Institutet
TCA
cycle
NADH
CO2
a-ketoglutarate
Hydratase
NAD+
Respiratory
chain
Dehydrogenase
H2O
ATP + CO2
Dehydrogenase
fumarate
QH2
Q
ADP + H+
succinate
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2016-03-08
A carbon perspective
Three ”turns” of the cycle
Molecular symmetry complicates things further ...
Carbon perspective
Oxaloacetate
Acetyl-CoA
Acetyl-CoA
Acetyl-CoA
E
E
F
F
Citrate
A
C
A
B
D
B
D
1st
E
turn
CO2
B
A
CO2
B
D
E
B
B
D
C
L-malate
E
F
C
Oxaloacetate
A
CO2
Acetyl-CoA
2nd turn
F
C
D
Succinate
Oxaloacetate
Citrate
A
C
A
a-ketoglutarate
CO2
F
C
Oxaloacetate
Citrate
Citrate
E
F
CO2
a-ketoglutarate
CO2
a-ketoglutarate
F/B
C/E
B
D
E/C
B/F
C
L-malate
E
F
a-ketoglutarate
Succinate
Oxaloacetate
D
CO2
F
C
B
fumarate
F
C
E
B
succinate
D
Acetyl-CoA
3rd turn
Citrate
CO2
E
a-ketoglutarate
CO2
Succinate
CO2
F/B
C/E
B/F
fumarate
F
C
E/C
B
E
Symmetric!
succinate
...
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2016-03-08
Molecular symmetry complicates things further ...
The TCA cycle in biosynthesis
Anaplerosis
As a source of precursor metabolites
Lost carbon must be “refilled”
Fatty acid
synthesis
sugars
Glucose oxidation in brain tumors (NMR)
fat
amino acids
Acetyl-CoA
CoA
Citrate
NH4
Carboxylic
acids
Cytosol
Oxaloacetate
CO2
anaplerosis
Mitochondria
Glutamate
L-malate
A-ketoglutarate
TCA
cycle
CO2
Marin-Valencia et al, Cell Metabolism 15:827-37, 2012.
fumarate
succinate
...
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2016-03-08
Cataplerosis
Accessory enzymes
Surplus carbon must be “drained”
•
CoA + NAD+
Acetyl-CoA
CoA
cataplerosis
The TCA cycle as a ”hub” of metabolism
The pyruvate dehydrogenase complex controls pyruvate entry
88-subunit complex
7.8 MDa
*
NADH + CO2
*
Citrate
Fatty acids
PDH
pyruvate
acetyl-CoA
Oxaloacetate
CO2
L-malate
Zhou et al, PNAS 98:14802–14807, 2001
•
Regeneration of pyruvate from oxaloacetate
A-ketoglutarate
pyruvate
phosphoenolpyruvate
ADP
GDP + CO2
CO2
fumarate
succinate
pyruvate
ATP + H+
NADH + CO2
PCK
oxidation
Valine
Isoleucine
Methionine
GTP
oxaloacetate
ME
NAD+
oxaloacetate
Owen et al, JBC 277, 30409-30412, 2002.
Yang et al, JBC 284:27025-27029, 2009.
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