8.1 Citric acid cycle: steps and regulation

The citric acid cycle is a crucial metabolic pathway that breaks down nutrients for energy. It involves a series of enzyme-catalyzed reactions, producing high-energy molecules like NADH and FADH2 that fuel ATP production.

Regulation of the cycle is key to maintaining energy balance. Allosteric enzymes respond to cellular energy levels, adjusting cycle activity based on ATP, NADH, and substrate availability. This fine-tuning ensures efficient energy production.

Citric Acid Cycle Enzymes

Catalytic Roles and Reactions

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• Citrate synthase catalyzes the condensation of oxaloacetate and acetyl-CoA to form citrate, marking the first step of the citric acid cycle
• Aconitase isomerizes citrate to isocitrate via the intermediate cis-aconitate, allowing for the continuation of the cycle
• Isocitrate dehydrogenase oxidatively decarboxylates isocitrate to form α-ketoglutarate, generating NADH in the process and contributing to the cycle's energy production
• α-Ketoglutarate dehydrogenase catalyzes the oxidative decarboxylation of α-ketoglutarate to form succinyl-CoA, generating NADH and serving as a key regulatory point in the cycle
• Succinyl-CoA synthetase catalyzes the substrate-level phosphorylation of GDP or ADP to form GTP or ATP, respectively, while converting succinyl-CoA to succinate

Oxidation-Reduction Reactions and Electron Transport

• Succinate dehydrogenase oxidizes succinate to fumarate, reducing FAD to FADH2 and serving as a direct link between the citric acid cycle and the electron transport chain
• Fumarase catalyzes the hydration of fumarate to form malate, preparing the substrate for the final step of the cycle
• Malate dehydrogenase oxidizes malate to oxaloacetate, regenerating the starting compound of the citric acid cycle and reducing NAD+ to NADH, which can feed into the electron transport chain

Energy Molecules and Regulation

High-Energy Compounds and Electron Carriers

• Acetyl-CoA, a high-energy compound derived from the oxidation of carbohydrates, fats, and proteins, serves as the primary input for the citric acid cycle
• NADH, produced by several enzymes in the citric acid cycle (isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, and malate dehydrogenase), transfers electrons to the electron transport chain for ATP production
• FADH2, generated by succinate dehydrogenase, also transfers electrons to the electron transport chain, contributing to the proton gradient and subsequent ATP synthesis
• ATP, the primary energy currency of the cell, is directly produced by succinyl-CoA synthetase through substrate-level phosphorylation and indirectly via the electron transport chain and oxidative phosphorylation

Allosteric Regulation and Metabolic Control

• Allosteric regulation of citric acid cycle enzymes allows for precise control of the cycle's activity in response to the cell's energy demands and substrate availability
• Citrate synthase is inhibited by high levels of ATP, acetyl-CoA, and NADH, ensuring that the cycle does not proceed when energy is abundant or when there is a build-up of intermediates
• Isocitrate dehydrogenase is allosterically stimulated by ADP and inhibited by ATP and NADH, fine-tuning the cycle's activity based on the cell's energy status
• α-Ketoglutarate dehydrogenase is inhibited by high levels of NADH and succinyl-CoA, preventing the excessive accumulation of these compounds and maintaining the cycle's balance
• The citric acid cycle's regulation is closely linked to that of glycolysis and the electron transport chain, allowing for the coordinated control of cellular energy production in response to varying conditions (glucose availability, oxygen levels)