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Citric acid cycle
Tomáš Kuč[email protected]
Department of Medical Chemistry and Clinical Biochemistry2nd Faculty of Medicine, Charles University in Prague andMotol University
Hospital
MMXVIII
Energy metabolism scheme
Ac~S–CoA
CO2
O2
H2O
NADH NAD+
ATP
ADP
NADPH NADP+
hν
NADH
NAD+
NADH NAD+
ATP
ADP
pyruvate
sugars
glycolysis
fatty acids
β-oxidation
amino acids
citric acidcycle
respiratorychain
oxidativephosphorylation
lactateethanolpropionatebutyratebutanolformateH2CO2acetate2,3-butandiolsuccinate
Calvin cycle
photosyntheticelectron transportchain
alternativepathways
fermentativeNAD+
regeneration
photophosphorylation
oxidativedecarboxylation
The cycle overview
Berg,J. M
.,Tymoc
zko,
Gatto,G
. J. Jr.,
J. L.,Strye
r,L.:B
ioch
emistry,W.H
.Freem
anan
dCom
pany
,2012
(8th
edition) location
mitochondrial matrixthe innermitochondrialmembrane (SDH)
stoichiometry3NAD+ + FAD + GDP + P + acetyl-SCoA
3 NADH + 3 H+ + FADH2 + GTP + H-SCoA + 2 CO2
The cycle overview
Importancecenter of metabolism
the smallest building units – the lowest levelanabolism and catabolism crossing point
degradation and synthesis
metabolism of sugars, fats, amino acids, porphyrinssource of energy in respiratory metabolism
Input – Ac-CoA
Voet,D
.,Vo
et,J.G
.:Bioc
hemistry,John
Wile
y&So
ns,Inc
.,20
11(4th
edition)
origin of the acetylfrom fatsfrom amino acidsfrom glycolysis
Pyruvate – the glycolysis end-product
CH3 C
O
COOH
important node point of metabolismgluconeogenesis, lipid and aminoacid synthesis...
fermentative (non-respiratory, “anaerobic”) processingpyruvate + NADH + H+ lactate + NAD+
pyruvate CH3 CHO + CO2CH3 CHO + NADH + H+ CH3 CH2 OH + NAD+
respiratory (“aerobic”) processingoxidative decarboxylation⇒ acetylcoenzyme A
Oxidative decarboxylation of pyruvate
multienzyme complexpyruvate dehydrogenasedihydrolipoyl acetyltransferase (transacetylase)dihydrolipoyl dehydrogenase
cofactorsthiamin diphosphatelipoamideFADNADCoA
advantages of a multienzyme complexlittle diffusion limitationminimal side reaction extentcoordinated regulation
Oxidative decarboxylation of pyruvate
Voet,D
.,Vo
et,J.G
.:Bioc
hemistry,John
Wile
y&
Sons,Inc
.,20
11(4th
edition)
Voet,D
.,Vo
et,J.G
.:Bioc
hemistry,John
Wile
y&So
ns,Inc
.,20
11(4th
edition)
Lipoic acid
Voet,D
.,Vo
et,J.G
.:Bioc
hemistry,John
Wile
y&So
ns,Inc
.,20
11(4th
edition)
Pyr ox. decarboxylation – regulation
Voet,D
.,Vo
et,J.G
.:Bioc
hemistry,John
Wile
y&So
ns,Inc
.,20
11(4th
edition)
The cycle
acetyl-CoA
CoASH + NAD+
CO2 + NADH
H2O
CoASH
CH3 C
O
COO-
CH3 C
O
CoAS
‡
‡
H2O
H2O
H2O
NAD+
NADH+H+
NAD+
NAD+
NADH+H+
NADH+H+
FAD
FADH2
GDP + Pi
GTP
CO2
*CO2
COO-
COO-
*COO-
COO-
COO-
*COO-
*COO-
COO-
COO-
*COO-
COO-
COO-
*COO-
COO-
COO-
COO-
COO-
COO-
COO-
COO-
COO-
*COO-
COO-
‡
‡
‡
‡
‡
‡
¹⁄2‡
¹⁄2‡
¹⁄2‡
¹⁄2‡
¹⁄2‡
¹⁄2‡CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CHCH
HC
C
C
C
C
C
C
C
C
C
C O
O
O
O
HO
HO
HO
H
H
H
H
S
CoASH
CoASH
CoA
pyruvate
oxaloacetate
citrate
cis-aconitate
isocitrate
oxalosuccinate
α-ketoglutarate
succinyl-CoA
succinate
fumarate
L-malate
pyruvate dehydrogenase
1. citrate synthase
2. aconitase
2. aconitase
3. isocitrate dehydrogenase
3. isocitrate dehydrogenase
4. α-ketoglutarate dehydrogenase
5. succinyl-CoA synthetase
6. succinate dehydrogenase
5. fumarase
6. malate dehydrogenase
Citric acid cycle
Redraw
nafterV
oet,D.,Vo
et,J.G
.:Bioc
hemistry,John
Wile
y&So
ns,Inc
.,20
11(4th
edition)
Glyoxylate cycle
Ada
pted
from
Voet,D
.,Vo
et,J.G
.:Bioc
hemistry,John
Wile
y&So
ns,Inc
.,20
11(4th
edition)
TCA cycle – regulation
NADH
acetyl-CoA
Ca2+
Ca2+, ADP
Ca2+
ATP
GTP
pyruvate
citrate
isocitrate
α-ketoglutaratesuccinyl-CoA
succinate
fumarate
malate
oxalacetate
Redraw
nafterV
oet,D.,Vo
et,J.G
.:Bioc
hemistry,John
Wile
y&So
ns,Inc
.,20
11(4th
edition)
TCA cycle – the core of metabolism
Redraw
nfrom
Voet,D
.,Vo
et,J.G
.:Bioc
hemistry,John
Wile
y&So
ns,Inc
.,20
11(4th
edition)
Reverse TCA cycle
Voet,D
.,Vo
et,J.G
.:Bioc
hemistry,John
Wile
y&So
ns,Inc
.,20
11(4th
edition)
Anaplerotic reactions
pyruvate carboxylasepyruvate + HCO–
3 + ATPoxaloacetate + ADP + P + H+
glutamate dehydrogenasel-glutamate + H2O + NAD(P)+
2-oxoglutarate + NH3 + NAD(P)H + H+
aspartate transaminasel-aspartate + 2-oxoglutarate
oxaloacetate + l-glutamate
purine nucleotide cycle
The End
konec – the end
Thank you for your attention!
acetyl-CoA
CoASH + NAD+
CO2 + NADH
H2O
CoASH
CH3 C
O
COO-
CH3 C
O
CoAS
‡
‡
H2O
H2O
H2O
NAD+
NADH+H+
NAD+
NAD+
NADH+H+
NADH+H+
FAD
FADH2
GDP + Pi
GTP
CO2
*CO2
COO-
COO-
*COO-
COO-
COO-
*COO-
*COO-
COO-
COO-
*COO-
COO-
COO-
*COO-
COO-
COO-
COO-
COO-
COO-
COO-
COO-
COO-
*COO-
COO-
‡
‡
‡
‡
‡
‡
¹⁄2‡
¹⁄2‡
¹⁄2‡
¹⁄2‡
¹⁄2‡
¹⁄2‡CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CHCH
HC
C
C
C
C
C
C
C
C
C
C O
O
O
O
HO
HO
HO
H
H
H
H
S
CoASH
CoASH
CoA
pyruvate
oxaloacetate
citrate
cis-aconitate
isocitrate
oxalosuccinate
α-ketoglutarate
succinyl-CoA
succinate
fumarate
L-malate
pyruvate dehydrogenase
1. citrate synthase
2. aconitase
2. aconitase
3. isocitrate dehydrogenase
3. isocitrate dehydrogenase
4. α-ketoglutarate dehydrogenase
5. succinyl-CoA synthetase
6. succinate dehydrogenase
5. fumarase
6. malate dehydrogenase
Citric acid cycle
Redraw
nafterV
oet,D.,Vo
et,J.G
.:Bioc
hemistry,John
Wile
y&So
ns,Inc
.,20
11(4th
edition)
acetyl-CoA
CoASH + NAD+
CO2 + NADH
H2O
CoASH
CH3 C
O
COO-
CH3 C
O
CoAS
‡
‡
H2O
H2O
H2O
NAD+
NADH+H+
NAD+
NAD+
NADH+H+
NADH+H+
FAD
FADH2
GDP + Pi
GTP
CO2
*CO2
COO-
COO-
*COO-
COO-
COO-
*COO-
*COO-
COO-
COO-
*COO-
COO-
COO-
*COO-
COO-
COO-
COO-
COO-
COO-
COO-
COO-
COO-
*COO-
COO-
‡
‡
‡
‡
‡
‡
¹⁄2‡
¹⁄2‡
¹⁄2‡
¹⁄2‡
¹⁄2‡
¹⁄2‡CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CHCH
HC
C
C
C
C
C
C
C
C
C
C O
O
O
O
HO
HO
HO
H
H
H
H
S
CoASH
CoASH
CoA
pyruvate
oxaloacetate
citrate
cis-aconitate
isocitrate
oxalosuccinate
α-ketoglutarate
succinyl-CoA
succinate
fumarate
L-malate
pyruvate dehydrogenase
1. citrate synthase
2. aconitase
2. aconitase
3. isocitrate dehydrogenase
3. isocitrate dehydrogenase
4. α-ketoglutarate dehydrogenase
5. succinyl-CoA synthetase
6. succinate dehydrogenase
5. fumarase
6. malate dehydrogenase
Citric acid cycle
Redraw
nafterV
oet,D.,Vo
et,J.G
.:Bioc
hemistry,John
Wile
y&So
ns,Inc
.,20
11(4th
edition)
acetyl-CoA
CoASH + NAD+
CO2 + NADH
H2O
CoASH
CH3 C
O
COO-
CH3 C
O
CoAS
‡
‡
H2O
H2O
H2O
NAD+
NADH+H+
NAD+
NAD+
NADH+H+
NADH+H+
FAD
FADH2
GDP + Pi
GTP
CO2
*CO2
COO-
COO-
*COO-
COO-
COO-
*COO-
*COO-
COO-
COO-
*COO-
COO-
COO-
*COO-
COO-
COO-
COO-
COO-
COO-
COO-
COO-
COO-
*COO-
COO-
‡
‡
‡
‡
‡
‡
¹⁄2‡
¹⁄2‡
¹⁄2‡
¹⁄2‡
¹⁄2‡
¹⁄2‡CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CHCH
HC
C
C
C
C
C
C
C
C
C
C O
O
O
O
HO
HO
HO
H
H
H
H
S
CoASH
CoASH
CoA
pyruvate
oxaloacetate
citrate
cis-aconitate
isocitrate
oxalosuccinate
α-ketoglutarate
succinyl-CoA
succinate
fumarate
L-malate
pyruvate dehydrogenase
1. citrate synthase
2. aconitase
2. aconitase
3. isocitrate dehydrogenase
3. isocitrate dehydrogenase
4. α-ketoglutarate dehydrogenase
5. succinyl-CoA synthetase
6. succinate dehydrogenase
5. fumarase
6. malate dehydrogenase
Citric acid cycle
Redraw
nafterV
oet,D.,Vo
et,J.G
.:Bioc
hemistry,John
Wile
y&So
ns,Inc
.,20
11(4th
edition)
acetyl-CoA
CoASH + NAD+
CO2 + NADH
H2O
CoASH
CH3 C
O
COO-
CH3 C
O
CoAS
‡
‡
H2O
H2O
H2O
NAD+
NADH+H+
NAD+
NAD+
NADH+H+
NADH+H+
FAD
FADH2
GDP + Pi
GTP
CO2
*CO2
COO-
COO-
*COO-
COO-
COO-
*COO-
*COO-
COO-
COO-
*COO-
COO-
COO-
*COO-
COO-
COO-
COO-
COO-
COO-
COO-
COO-
COO-
*COO-
COO-
‡
‡
‡
‡
‡
‡
¹⁄2‡
¹⁄2‡
¹⁄2‡
¹⁄2‡
¹⁄2‡
¹⁄2‡CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CHCH
HC
C
C
C
C
C
C
C
C
C
C O
O
O
O
HO
HO
HO
H
H
H
H
S
CoASH
CoASH
CoA
pyruvate
oxaloacetate
citrate
cis-aconitate
isocitrate
oxalosuccinate
α-ketoglutarate
succinyl-CoA
succinate
fumarate
L-malate
pyruvate dehydrogenase
1. citrate synthase
2. aconitase
2. aconitase
3. isocitrate dehydrogenase
3. isocitrate dehydrogenase
4. α-ketoglutarate dehydrogenase
5. succinyl-CoA synthetase
6. succinate dehydrogenase
5. fumarase
6. malate dehydrogenase
Citric acid cycle
Redraw
nafterV
oet,D.,Vo
et,J.G
.:Bioc
hemistry,John
Wile
y&So
ns,Inc
.,20
11(4th
edition)
acetyl-CoA
CoASH + NAD+
CO2 + NADH
H2O
CoASH
CH3 C
O
COO-
CH3 C
O
CoAS
‡
‡
H2O
H2O
H2O
NAD+
NADH+H+
NAD+
NAD+
NADH+H+
NADH+H+
FAD
FADH2
GDP + Pi
GTP
CO2
*CO2
COO-
COO-
*COO-
COO-
COO-
*COO-
*COO-
COO-
COO-
*COO-
COO-
COO-
*COO-
COO-
COO-
COO-
COO-
COO-
COO-
COO-
COO-
*COO-
COO-
‡
‡
‡
‡
‡
‡
¹⁄2‡
¹⁄2‡
¹⁄2‡
¹⁄2‡
¹⁄2‡
¹⁄2‡CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CHCH
HC
C
C
C
C
C
C
C
C
C
C O
O
O
O
HO
HO
HO
H
H
H
H
S
CoASH
CoASH
CoA
pyruvate
oxaloacetate
citrate
cis-aconitate
isocitrate
oxalosuccinate
α-ketoglutarate
succinyl-CoA
succinate
fumarate
L-malate
pyruvate dehydrogenase
1. citrate synthase
2. aconitase
2. aconitase
3. isocitrate dehydrogenase
3. isocitrate dehydrogenase
4. α-ketoglutarate dehydrogenase
5. succinyl-CoA synthetase
6. succinate dehydrogenase
5. fumarase
6. malate dehydrogenase
Citric acid cycle
Redraw
nafterV
oet,D.,Vo
et,J.G
.:Bioc
hemistry,John
Wile
y&So
ns,Inc
.,20
11(4th
edition)
acetyl-CoA
CoASH + NAD+
CO2 + NADH
H2O
CoASH
CH3 C
O
COO-
CH3 C
O
CoAS
‡
‡
H2O
H2O
H2O
NAD+
NADH+H+
NAD+
NAD+
NADH+H+
NADH+H+
FAD
FADH2
GDP + Pi
GTP
CO2
*CO2
COO-
COO-
*COO-
COO-
COO-
*COO-
*COO-
COO-
COO-
*COO-
COO-
COO-
*COO-
COO-
COO-
COO-
COO-
COO-
COO-
COO-
COO-
*COO-
COO-
‡
‡
‡
‡
‡
‡
¹⁄2‡
¹⁄2‡
¹⁄2‡
¹⁄2‡
¹⁄2‡
¹⁄2‡CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CHCH
HC
C
C
C
C
C
C
C
C
C
C O
O
O
O
HO
HO
HO
H
H
H
H
S
CoASH
CoASH
CoA
pyruvate
oxaloacetate
citrate
cis-aconitate
isocitrate
oxalosuccinate
α-ketoglutarate
succinyl-CoA
succinate
fumarate
L-malate
pyruvate dehydrogenase
1. citrate synthase
2. aconitase
2. aconitase
3. isocitrate dehydrogenase
3. isocitrate dehydrogenase
4. α-ketoglutarate dehydrogenase
5. succinyl-CoA synthetase
6. succinate dehydrogenase
5. fumarase
6. malate dehydrogenase
Citric acid cycle
Redraw
nafterV
oet,D.,Vo
et,J.G
.:Bioc
hemistry,John
Wile
y&So
ns,Inc
.,20
11(4th
edition)
acetyl-CoA
CoASH + NAD+
CO2 + NADH
H2O
CoASH
CH3 C
O
COO-
CH3 C
O
CoAS
‡
‡
H2O
H2O
H2O
NAD+
NADH+H+
NAD+
NAD+
NADH+H+
NADH+H+
FAD
FADH2
GDP + Pi
GTP
CO2
*CO2
COO-
COO-
*COO-
COO-
COO-
*COO-
*COO-
COO-
COO-
*COO-
COO-
COO-
*COO-
COO-
COO-
COO-
COO-
COO-
COO-
COO-
COO-
*COO-
COO-
‡
‡
‡
‡
‡
‡
¹⁄2‡
¹⁄2‡
¹⁄2‡
¹⁄2‡
¹⁄2‡
¹⁄2‡CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CHCH
HC
C
C
C
C
C
C
C
C
C
C O
O
O
O
HO
HO
HO
H
H
H
H
S
CoASH
CoASH
CoA
pyruvate
oxaloacetate
citrate
cis-aconitate
isocitrate
oxalosuccinate
α-ketoglutarate
succinyl-CoA
succinate
fumarate
L-malate
pyruvate dehydrogenase
1. citrate synthase
2. aconitase
2. aconitase
3. isocitrate dehydrogenase
3. isocitrate dehydrogenase
4. α-ketoglutarate dehydrogenase
5. succinyl-CoA synthetase
6. succinate dehydrogenase
5. fumarase
6. malate dehydrogenase
Citric acid cycle
Redraw
nafterV
oet,D.,Vo
et,J.G
.:Bioc
hemistry,John
Wile
y&So
ns,Inc
.,20
11(4th
edition)
NADH
acetyl-CoA
Ca2+
Ca2+, ADP
Ca2+
ATP
GTP
pyruvate
citrate
isocitrate
α-ketoglutaratesuccinyl-CoA
succinate
fumarate
malate
oxalacetate