Citric acid cycle - cuni.cz

Citric acid cycle

Tomáš Kučeratomas.kucera@lfmotol.cuni.cz

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

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Wile

y&So

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.,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

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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

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.,20

11(4th

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Glyoxylate cycle

Ada

pted

from

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.,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

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TCA cycle – the core of metabolism

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.,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

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.: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

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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

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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

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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

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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

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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

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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