Citric Acid Cycle and Glyoxylate Cycle

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What is the Citric Acid Cycle?

• The citric acid cycle is the common mode of oxidative degradation in eukaryotes and prokaryotes.

• It is the aerobic oxidation of pyruvate that takes place in the mitochondria.

• Also known as tricarboxylic acid cycle and Krebs cycle.

• The cycle is amphibolic: it operates catabolically (destructive) and anabolically (constructive).

• The citric acid cycle begins with a compound called acetyl-coenzyme A (acetyl-CoA).

• The cycle oxidizes the acetyl group of acetyl-CoA to two molecules of CO2 in a manner that conserves the liberated free energy for utilization in ATP generation.

• Acetyl groups enter the Citric Acid Cycle as acetyl-coenzyme A, the common product of carbohydrate, fatty acid, and amino acid breakdown.

• Acetyl-CoA is an energy rich compound.

Reactions and Enzymes of Citric Acid Cycle:

1. Citrate synthase:

• This enzyme catalyzes the condensation of acetyl-CoA and oxaloacetate.

• Basically, carbon atoms are "fed into the furnace" as acetyl-CoA.

2. Aconitase

• This enzyme catalyzes the reversible isomerization of citrate and isocitrate with cis-aconitate as an intermediate.

• Aconitase can distinguish between citrate's pro-R and pro-S carboxymethyl groups.

3. Isocitrate dehydrogenase

• This enzyme catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate to produce the citric acid cycle's first CO2 and NADH.

• Mammalian tissues contain two isoforms of this enzyme.

• One exists entirely in mitochondria, and the other exists in mitochondria and also in cytosol.

• Both the forms catalyze the same reaction.

4. Alpha-Ketoglutarate dehydrogenase

• This enzyme catalyzes the oxidative decarboxylation of an alpha-keto acid, releasing the Citric Acid Cycle's second CO2 and NADH.

5. Succinyl CoA synthetase

• Succinyl-CoA synthetase hydrolyzes the high-energy compound succinyl-CoA with the coupled synthesis of a high-energy nucleoside triphosphate.

6. Succinate dehydrogenase

• This enzyme catalyzes stereospecific dehydrogenation of succinate to fumarate.

• The enzyme is h2ly inhibited by malonate, a structural analog of succinate and an example of competitive inhibitor.

• The enzyme contains an FAD, the enzyme's electron acceptor.

7. Fumarase

• This enzyme (also known as Fumarate Hydratase) catalyzes the hydration of fumarate's double bond to form (S)-malate (L-malate).

8. Malate dehydrogenase

• This enzyme catalyzes the last reaction of Citric Acid Cycle: the regeneration of oxaloacetate.

• This occurs through the oxidation of (S)-malate's hydroxyl group to a ketone in an NAD+ -dependent reaction.

Regulation of the Citric Acid Cycle

• Citric Acid Cycle's rate controlling enzymes are citrate synthase, isocitrate dehydrogenase, and alpha-ketoglutarate dehydrogenase.

• Controlling Citric Acid Cycle is more difficult than glycolysis because most of the cycle's metabolites are present in both mitochondria and cytosol, and we don't know the distribution between these two compartments.

• The Citric Acid Cycle is largely regulated by substrate availability, product inhibition, and inhibition by other cycle intermediates.

• ADP, ATP, and Ca2+ are allosteric regulators of Citric Acid Cycle enzymes.

Amphibolic Nature of the Citric Acid Cycle

• The Citric Acid Cycle is catabolic because it involves degradation and is a major free energy conservation system in most organisms.

• However, several biosynthetic pathways utilize Citric Acid Cycle's intermediates as starting materials.

The Glyoxylate Cycle

• Plants, but not animals, possess enzymes that mediate the net conversion of acetyl-CoA to succinate, which is then converted, via malate, to oxaloacetate.

• This is done via the glyoxylate cycle.

• This cycle involves the enzymes of glyoxysome (a plant organelle).

• Name - the glyoxylate cycle is an anaerobic variant of the citric acid cycle.

• The cycle involves 5 enzymes, three of which also participate in Citric Acid Cycle.

• Plants, certain invertebrates, and some microorganisms such as E. coli and yeast have the glyoxylate cycle.

• Other cells cannot convert acetate to PEP.

• Allows net conversion of acetate into oxaloacetate.

• The glyoxylate cycle results in the net conversion of two acetyl-CoA to succinate instead of to four molecules of CO2, as would occur in Citric Acid Cycle.

• Overall rxn: conversion of two molecules of acetyl-CoA to one molecule of oxaloacetate.

Additional Readings:

Basic Biochemistry

1. Nucleic Acid Structure and Organization
2. DNA Replication and Repair
3. Transcription and RNA Processing
4. Genetic Code, Mutations, and Translation
5. Genetic Regulation
6. Recombinant DNA
7. Amino Acids, Proteins, Enzymes
8. Hormones
9. Vitamins
10. Energy Metabolism
11. Glycolysis and Pyruvate Dehydrogenase
12. Citric Acid Cycle and Oxidative Phosphorylation
13. Glycogen, Gluconeogenesis, and Hexose Monophosphate Shunt
14. Lipid Synthesis and Storage
15. Lipid Mobilization and Catabolism
16. Amino Acid Metabolism Disorders
17. Purine and Pyrimidine Metabolism
18. Electron Transport
19. Citric Acid Cycle and Glyoxylate Cycle
20. Glycolysis
21. Pyruvate Metabolism
22. Mitochondrial ATP formation
23. Gluconeogenesis
24. Glycogen Metabolism
25. Nitrogen Fixation (Metabolism) reactions, and Heme Metabolism
26. Amino Acid Metabolism
27. What is Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCADD)?

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