13.2 Regulation of the Citric Acid Cycle

The citric acid cycle, a crucial metabolic pathway, is tightly regulated to meet cellular energy demands. ATP/ADP and NADH/NAD+ ratios, along with acetyl-CoA and calcium levels, play key roles in modulating cycle activity through feedback mechanisms.

Allosteric regulation fine-tunes enzyme activity in the citric acid cycle. Effector molecules bind to sites distinct from the active site, causing conformational changes that either enhance or inhibit enzyme function, allowing for rapid and reversible control of the cycle's flux.

Energy Charge Regulation

ATP and NADH Ratios

• ATP/ADP ratio measures cellular energy status
• High ATP/ADP ratio indicates abundant energy supply
• Low ATP/ADP ratio signals energy depletion
• NADH/NAD+ ratio reflects the cell's redox state
• Elevated NADH/NAD+ ratio suggests reduced cellular conditions
• Lower NADH/NAD+ ratio indicates more oxidized cellular environment
• Both ratios influence citric acid cycle activity through feedback mechanisms

Acetyl-CoA and Calcium Ion Regulation

• Acetyl-CoA levels serve as a key metabolic indicator
• Increased acetyl-CoA concentrations stimulate citric acid cycle activity
• Acetyl-CoA accumulation signals abundance of fuel molecules (glucose, fatty acids)
• Calcium ions act as important signaling molecules in cellular metabolism
• Elevated calcium levels enhance the activity of several citric acid cycle enzymes
• Calcium ions activate pyruvate dehydrogenase phosphatase, promoting pyruvate oxidation
• Mitochondrial calcium uptake stimulates NADH production and ATP synthesis

Allosteric Enzyme Regulation

Allosteric Regulation Mechanisms

• Allosteric regulation involves binding of effector molecules to enzyme sites distinct from the active site
• Allosteric activators enhance enzyme activity by promoting favorable conformational changes
• Allosteric inhibitors decrease enzyme activity by inducing unfavorable conformational changes
• Allosteric regulation allows for rapid and reversible control of enzyme activity
• Citric acid cycle enzymes exhibit various allosteric regulatory mechanisms

Regulation of Key Citric Acid Cycle Enzymes

• Citrate synthase inhibition occurs through negative feedback from citrate and ATP
• High citrate levels allosterically inhibit citrate synthase, preventing excessive cycle activity
• ATP binding to citrate synthase reduces its affinity for acetyl-CoA, slowing down the cycle
• Isocitrate dehydrogenase activation involves positive allosteric regulation by ADP
• ADP binding to isocitrate dehydrogenase increases its affinity for substrates, accelerating the cycle
• α-Ketoglutarate dehydrogenase inhibition results from elevated NADH and succinyl-CoA levels
• High NADH and succinyl-CoA concentrations allosterically inhibit α-ketoglutarate dehydrogenase, regulating cycle flux