The citric acid cycle is a crucial metabolic pathway that breaks down acetyl-CoA, producing energy and important molecules. It involves a series of reactions that release carbon dioxide, generate ATP, and create reduced electron carriers like NADH and FADH2.

This cycle is a key part of cellular respiration, connecting glycolysis to the electron transport chain. It occurs in the mitochondrial matrix of eukaryotes and the cytoplasm of prokaryotes, playing a vital role in energy production for cells.

Citric Acid Cycle Overview

Acetyl-CoA and Initial Reactions

• Acetyl-CoA enters the citric acid cycle as a two-carbon molecule
• Acetyl-CoA combines with oxaloacetate (four-carbon molecule) to form citrate (six-carbon molecule)
• Citrate synthase catalyzes the condensation reaction between acetyl-CoA and oxaloacetate
• This reaction marks the first step of the citric acid cycle
• Citrate synthase releases coenzyme A and produces citrate

Carbon Dioxide Release and Energy Production

• The citric acid cycle releases two molecules of CO2 per acetyl-CoA
• CO2 release occurs during oxidative decarboxylation steps
• The cycle produces energy in the form of GTP (guanosine triphosphate)
• GTP can be converted to ATP through substrate-level phosphorylation
• The cycle also generates reduced electron carriers (NADH and FADH2)

Cycle Completion and Regeneration

• Oxaloacetate regenerates at the end of each cycle
• Regenerated oxaloacetate can combine with another acetyl-CoA molecule
• This regeneration allows the cycle to continue indefinitely
• The cycle occurs in the mitochondrial matrix of eukaryotic cells
• Prokaryotes perform the citric acid cycle in their cytoplasm

Oxidative Decarboxylation Steps

Isocitrate Dehydrogenase Reaction

• Isocitrate dehydrogenase catalyzes the oxidative decarboxylation of isocitrate
• This reaction converts isocitrate to α-ketoglutarate
• The process releases one molecule of CO2
• Simultaneously produces one molecule of NADH
• Isocitrate dehydrogenase requires NAD+ as a cofactor

α-Ketoglutarate Dehydrogenase Complex

• α-Ketoglutarate dehydrogenase complex catalyzes the next oxidative decarboxylation
• Converts α-ketoglutarate to succinyl-CoA
• Releases the second molecule of CO2 in the cycle
• Generates another molecule of NADH
• Requires thiamine pyrophosphate, lipoic acid, and NAD+ as cofactors

NADH Production and Electron Transport Chain

• The citric acid cycle produces a total of three NADH molecules per acetyl-CoA
• NADH serves as a high-energy electron carrier
• Transfers electrons to the electron transport chain
• Electron transport chain uses these electrons for ATP production via oxidative phosphorylation
• Each NADH can lead to the production of approximately 2.5 ATP molecules

Regeneration of Oxaloacetate

Succinyl-CoA to Succinate Conversion

• Succinyl-CoA synthetase catalyzes the conversion of succinyl-CoA to succinate
• This reaction produces GTP through substrate-level phosphorylation
• GTP can be converted to ATP by nucleoside diphosphate kinase
• Succinyl-CoA synthetase requires ADP or GDP as a phosphate acceptor
• This step marks the only substrate-level phosphorylation in the citric acid cycle

Succinate Oxidation and FADH2 Production

• Succinate dehydrogenase oxidizes succinate to fumarate
• This reaction reduces FAD to FADH2
• Succinate dehydrogenase anchored in the inner mitochondrial membrane
• FADH2 transfers electrons directly to the electron transport chain
• Each FADH2 leads to the production of approximately 1.5 ATP molecules

Final Steps and Oxaloacetate Formation

• Fumarase catalyzes the hydration of fumarate to malate
• Malate dehydrogenase oxidizes malate to oxaloacetate
• This final step produces another molecule of NADH
• Regenerated oxaloacetate can combine with a new acetyl-CoA to restart the cycle
• Malate dehydrogenase requires NAD+ as a cofactor