Pyruvate carboxylase

Pyruvate carboxylase is an enzyme of the ligase class that catalyzes the reversible carboxylation of pyruvate to form oxaloacetate.

It is the most important anaplerotic reaction that provides OAA precursor for the TCA during the time of exercise. The enzyme is a mitochondrial protein containing a biotin prosthetic group, requiring magnesium or manganese and acetyl CoA, and occurs in liver but not in muscle. It is an ATP-dependent enzyme. High levels of ADP inhibits the enzyme, while acetyl-CoA acts as an allosteric stimulator of the enzyme.

Pathways for Glucose Synthesis (Gluconeogenesis)
It is also the first pathway for the synthesis of phosphoenolpyruvate from pyruvate. Pyruvate is first converted by pyruvate carboxylase to oxaloacetate in the mitochondrion. During the reaction, one molecule of ATP is hydrolysed. The OAA is then decarboxylated and simultaneously phosphorylated, which is catalyzed by PEP carboxykinase to produce PEP in the cytosol. Transport of OAA from the mitochondrion to the cytosol is mediated by the malate/OAA shuttle.

Clinical significance
A deficiency of pyruvate carboxylase can cause lactic acidosis as a result of lactate build up. Normally, excess pyruvate is shunted into gluconeogenesis via conversion of pyruvate into oxaloacetate, but because of the enzyme deficiency, excess pyruvate is converted into lactate instead. As a key role of gluconeogenesis is in the maintenance of blood sugar, deficiency of pyruvate carboxylase can also lead to hypoglycemia, among other things.