Pyruvatcarboxylase

Pyruvate carboxylase is a mitochondrial enzyme that catalyzes the ATP-dependent carboxylation of pyruvate to oxaloacetate using bicarbonate as the carbon source. It is biotin-dependent and plays a central role in gluconeogenesis and anaplerosis, providing oxaloacetate to replenish the citric acid cycle in tissues such as liver and kidney, and under conditions of metabolic stress in other tissues.

The enzyme is a large biotin-dependent carboxylase composed of domains dedicated to biotin carboxylation, biotin carrier, and carboxyl transfer. In mammals it forms a homotetramer, and the biotin prosthetic group is covalently attached to a lysine residue on the biotin carboxyl carrier protein domain. Acetyl-CoA acts as an allosteric activator, increasing catalytic efficiency in response to energy demand. The catalytic cycle transfers a carboxyl group from ATP-activated CO2 to pyruvate to yield oxaloacetate, with ADP and inorganic phosphate produced.

Biological significance and clinical aspects: Pyruvate carboxylase is essential for maintaining TCA cycle intermediates and supplying oxaloacetate for gluconeogenesis, particularly in liver and kidney. Mutations in the PC gene can cause pyruvate carboxylase deficiency, a rare autosomal recessive disorder characterized by metabolic acidosis, lactic acidosis, hypotonia, and encephalopathy in infancy. Diagnosis relies on metabolic profiling and genetic testing; management is supportive and aims to optimize energy metabolism.