Kreb’s Cycle (Tricarboxylic acidcycle(TCA),

citric acid cycle)

IKRAM ULLAH14

Citric Acid cycleOBJECTIVES

• Brief Overview

• Pyruvate Dehydrogenase Complex (PDC)

• Reactions of TCA cycle or CAC

• Amphibolic nature of TCA cycle

• Regulation of TCA cycle

OVERVIEW

Cyclic process.

Enzymes are located in Mitochondrial Matrix.

Whole process is aerobic.

pyruvate dehydrogenase and TCA cycle reactions take place in mitochondria where oxygen

is utilized to generate ATP by oxydative phosphorylation.

Overall goal

• Makes ATP

• Makes NADH

• Makes FADH2

• Requires some Acetyl CoA to run

In Mitochondria

In Cytosol

Reaction of pyruvate dehydrogenase complex (PDC)

Reaction of TCA cycle: Enzymes Acetyl CoA 2CO 12ATP

Mg

2

REACTIONS OF TCA CYCLECitrate Synthase Reaction (First)

acetyl CoAoxaloacetate

CoASH

citrate synthase

citrate

OH2

CH3 C

O

SCoA

C O

CH2C

O

COO

O

COO

CH2CCH2

C

OH C O

O

O O

+

• Irreversable• A molecule of H O is required• No ATP is required• No Oxidation or decarboxylation.

2

Aconitase Reaction

citrate

aconitase

isocitrate

COO

CH2CCH2

C

OH C O

O

O O

COO

CHCHCH2C

C O

O

OO

OH

• Forms isocitrate• Hydroxyl moved and changed from tertiary to secondary

– (can be oxidized)• 1st dehydretion to form cis Aconitate• The rehydration to form isocitrate

Isocitrate Dehydrogenase

isocitrate

NAD NADH CO2

isocitrate dehydrogenase

alpha ketoglutarate

COO

CHCHCH2C

C O

O

OO

OH

COO

CCH2CH2

COO

O

• All dehydrogenase reactions make NADH or FADH2

• Oxidative decarboxylation

α-ketoglutarate dehydrogenase

alpha ketoglutarate

NAD NADHCoASH

CO2

succinyl CoA

alpha ketoglutaratedehydrogenase

COO

CCH2CH2

COO

OCCH2

CH2C

OO

OSCoA

• Same as pyruvate dehydrogenase reaction• Formation of thioester

Succinyl CoA synthetase

succinyl CoA

GDP GTP CoASH

succinate

succinyl CoAsynthetase

CCH2

CH2C

OO

OSCoA

CCH2

CH2

COO

OO

Succinate dehydrogenase

succinate

FAD FADH2

succinyl CoAdehydrogenase

fumarate

CCH2

CH2

COO

OO

CC

CC

OO

O O

H

H

• Dehydrogenation• Uses FAD

Fumarase

fumarate

OH2

malate

fumarase

CC

CC

OO

O O

H

H

CCH

CH2

COO

O

OH

O

• Addition of water to a double bond

Malate Dehydrogenase

oxaloacetatemalate

NAD NADH

malatedehydrogenase

CCH

CH2

COO

O

OH

O

C O

CH2C

O

COO

O

• Makes NADH• Regenerates oxaloacetate for another round

Net From Kreb’s

• Oxidative process– 3 NADH– FADH2

– GTP

• X 2 per glucose– 6 NADH– 2 FADH2

– 2 GTP

• All ultimately turned into ATP (ETC)

Total Energy per glucose

• Cytosol– Glycolysis

• 2 NADH• 2 ATP

• Mitochondrion– Pyruvate dehydrogenase

• 2 NADH

• Krebs– 6 NADH– 2 FADH2

– 2 GTP

The amphibolic nature of Citric acid cycle:

• Cycle Has dual role.

Catabolic Role

• The Acetyl CoA produced from metabolism of carbohydrates , Proteins and lipids oxidized in this cycle to produce CO , H O and energy as ATP .2 2

Enzymes Acetyl CoA 2CO 12ATP

2

Anabolic Role

• Intermediate of TCA cycle are utilized for Synthesis of Various compounds :

• Synthesis of non essential amino acids

• Haem Synthesis

• Fatty acids and cholestrol synthesis

Regulation of CAC:

• Rate controlling enzymes:

• Citrate synthatase

• Isocitrate dehydrogenase-keoglutaratedehydrogenase

These enzymes are inhibited by ATP , NADH+H ,FADH+H and succinyl CoA.

While activated by ADP , Ca , NAD and FAD.

NOTE: Hormones doesn’t regulate the TCA Cycle

directly.