Pyruvate carboxylase catalyzes the first committed reaction of hepatic gluconeogenesis. During prolonged fasting, rising fatty acid oxidation increases flux through this enzyme even though pyruvate concentration changes little. What explains this increased activity?

• A Long-chain acyl-CoA binds the biotin carrier domain and stabilizes the enzyme
• B NADH produced by beta-oxidation competes with pyruvate for the active site
• C Citrate released from mitochondria activates pyruvate carboxylase directly
• D Acetyl-CoA generated by beta-oxidation allosterically activates pyruvate carboxylase ✓

Explanation

Pyruvate carboxylase is absolutely dependent on acetyl-CoA as an obligatory allosteric activator; without it the enzyme is essentially inactive. During fasting, hepatic beta-oxidation raises mitochondrial acetyl-CoA, signalling abundant fuel and driving pyruvate toward oxaloacetate and glucose rather than acetyl-CoA via PDH. Citrate activates acetyl-CoA carboxylase, not pyruvate carboxylase, and NADH has no such regulatory role here.

Reference: Lehninger Principles of Biochemistry, 8th ed.

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