THE CITRIC ACID CYCLE AND REGULATION

Assist. Prof.Dr. zlem Dalmzrak Near East University Faculty of Medicine Department of Medical Biochemistry

Reference: Lehninger Principles of Biochemistry,5th Edition, David L. Nelson and Michael M. Cox, Chapter:16, The Citric Acid Cycle

In aerobic conditions, glucose is oxidized to H2O and CO2. This aerobic phase of catabolism is called respiration. In biochemical aspect, consuming O2 and producing CO2 is called cellular respiration. Sir Hans Adolf Krebs 1932 urea cycle identified

1937 citric acid cycle found 1953 Nobel Physiologi Prize Laurate

Cellular respiration occurs in three major stages: 1. Organic fuel molecules (glucose, fatty acids and some amino acitds) are oxidized to yield two-carbon fragments in the form of the acetyl group of acetylcoenzyme A. 2. Acetyl groups enter the citric acid cycle, which enzymatically oxidizes them to CO2. The energy released is conserved in the reduced electron carriers (NADH, FADH2). 3. Reduced coenzymes are oxidized, giving up protons (H+) and electrons. The electrons are tranferred to O2 via chain of electron-carrying molecules known as the respiratory chain. In the course of electron transfer, the large amount of energy is conserved in the form of ATP (Oxidative phosphorylation).

Production of Acetyl-CoA
Before entering the citric acid cycle, the carbon skeletons of sugars and fatty acids are degraded to the acetyl group of acetyl-CoA. Many amino acid carbons also enter the cycle this way, although several amino acids are degraded to other cycle intermediates.

Thiamine pyrophosphate (TPP) Flavin adenin dinucleotide (FAD) Coenzyme A (CoA) Nicotinamid adenine dinucleotide (NAD) Lipoate

Cryoelectron micrograph of PDH Complex

Pyruvate Dehydrogenase Complex

E1:Pyruvate dehydrogenase E2:Dihydrolipoyl transacetylase E3: Dihydrolipoyl dehydrogenase

Reactions of the Citric Acid Cycle

1. Formation of Citrate

The flexible domain of each subunit of Citrate Synthase undergoes a large conformational change on binding of oxaloacetate :

2. Formation of Isocitrate

3. Oxidation of Isocitrate to -Ketoglutarate

4. Oxidation of -Ketoglutarate to Succinyl-CoA

5. Conversion of Succinyl-CoA to Succinate

6. Oxidation of Succinate to Fumarate

7. Hydration of Fumarate to Malate

Fumarase does not catalyze cis-double bonds

8. Oxidation of Malate to Oxaloacetate

Some anaerobic microorganisms use an incomplete citric acid cycle as a source of biosynthetic precursors, not energy. These anaerobs lack -ketoglutarate dehydrogenase,therefore cannot carry out complete cycle.

TCA Cycle Regulation

Glioksilat Dngs

2 Asetil-CoA + NAD+ + 2H2O Sksinat + 2CoA + NADH + H+