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The Citric Acid Cycle (Tricarboxylic Acid Cyle)

1. The link between gycolysis and

citric acid cycle

2. TCA cycle oxidizes 2 –C units

3. Entry and metabolism

controlled

4. Source of precursors

5. Glyoxylate cycle enables plants

and bacteria to grow on acetate

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Glucose Metabolism Under Aerobic and Anaerobic Conditions

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Citric Acid Cycle takes place in the Matrix of the Mitochondria

(Eukaryotic cells, under aerobic conditions)

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Citric Acid Cycle is the first step in Cellular Respiration

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The link between Glycolysis and Citric Acid Cycle

Pyruvate dehydrogenase complex (E. coli)

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The conversion from Pyruvate -> Acetyl-CoA

-> goes in 3 steps:

And requires:

1. The 3 enzymes of the complex

2. 5 co-enzymes (thiamine pyrophosphate TPP, lipoic acid, FAD, CoA, and NAD+

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Reaction mechanism of the conversion Pyruvate -> Acetyl-CoA

Carbanion of TPP

Oxidized form Reduced form

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Reaction mechanism of the conversion Pyruvate -> Acetyl-CoA

Reduced form

Oxidized formReduced form

Oxidation

+ 2e-

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Pyruvate dehydrogenase complex

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The Citric Acid Cycle

Isomerization

Oxidative Decarboxylation

Oxidation (Regeneration of Oxaloacetate)

Oxidation + Decaroboxylation

Generation of electrons

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1. Citric Synthase forms citrate from oxaloacetate and acetyl-CoA

Aldol Condensation

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2. Citrate is isomerized into Isocitrate

Aconitase

Hydroxy group is not located correct for decarboxylation reaction -> Isomerization

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3. Isocitrate is Oxidized and Decarboxylated to α-Ketoglutarate

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4. Oxidative Decarboxylation of α-Ketoglutarate gives Succinyl-CoA

Mechanism analog to decarboxylation of pyruvate

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5. GTP is generated from Succinyl-CoA

Energy-rich thioester

Synthetase

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6. Oxaloacetate is regenerated by Oxidation of Succinate

This metabolic motif -> also found in fatty acid Synthesis + degradation, degradation of some AA

Methylene group (CH2) -> carbonyl group (C=O)

1. Oxidation2. Hydration3. Oxidation

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3 NADH -> 6e-

1 FADH2 -> 2e-

-----------------------> 8e-

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Regulation of the Pyruvate dehydrogenase complex

Regulation by Allosterie +

Phosphorylation

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Regulation of the Pyruvate dehydrogenase complex

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Control of the Citric Acid Cycle

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The Citric Acid Cycle is a Source of Precursors

”Fast refill” of oxaloacate by carboxylation of pyruvate (in mammals)

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Pathway Integration

Pathways active during exercise after a night’s rest

Rate of citric acid cycle increases during exercise -> requiring the “refill” of oxaloacetate + acetyl CoAOxaloacetate -> from pyruvate

Acetyl CoA -> from pyruvate + fatty acids

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Blocking of Pyruvate -> Acetyl-CoA Reaction

By Poisoning with Hg and As

By Vitamin B1 (thiamine) deficiency – Beriberi

TPP (thiamine) is co-factor in reaction

Relieves the inhibition -> forms complex -> excreted

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The Glyoxylate Cycle

Enables Plant and Bacteria to grow on Acetate

It bypasses the decarboxylation steps of citric acid cycle

Enzymes that allow conversion from acetate into succinate are in blue boxes

- Intake of 2 acetyl groups/cycle

- production of succinate -> glucose

- regeneration of oxaloacetate from glyoxylate

Plant cell

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Regulation of the glyoxylate cycle