Pyruvate carboxylase structure

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Figure 16.25. Domain Structure of Pyruvate Carboxylase. The ATP-grasp domain activates HCO3 and transfers CO2 to the biotin-binding domain. From there, the CO2 is transferred to pyruvate generated in the central domain.

Figure 16.26. Biotin-Binding Domain of Pyruvate Carboxylase. This likely structure is based on the structure of the homologous domain from the enzyme acetyl CoA carboxylase (Section 22.4.1). The biotin is on a flexible tether, allowing it to move between the ATP-bicarbonate site and the pyruvate site.

Biotin is a water-soluble vitamin. It is a cofactor for four ATP-dependent carboxylases acetyl-CoA carboxylase, pyruvate carboxylase, propionyl-CoA carboxylase, and p-methylcrotonyl-CoA carboxylase. Biotin occurs covalently bound to the enzymes via the terminal amino group of a lysine residue. With the normal and continual turnover of these enzymes in the body, the biotin is released, but then utilized again as a cofactor when the enzymes are re-synthesized. The structure of biotin is shown in Figure 9.32,... 

Pyruvate Carboxylase. This enzyme has manganese firmly in its structure and acts together with phosphoenol pyruvate (PEP) carboxykinase, an enzyme that is activated by manganese ions. These enzymes are required to catalyze the formation of PEP from pyruvate, a key reaction in the hepatic synthesis of glucose. 

Pyruvate carboxylase is of special interest because of its structural, catalytic, and allosteric properties. The N-terminal 300 to 350 amino acids form an ATP-grasp domain (Figure 16.23), which is a widely used ATP-activating... 

For PEPCK to function in gluconeogenesis, oxaloacetate produced in the pyruvate carboxylase reaction in the mitochondria, must be transported to the cytoplasm. PEPCK is not under any known allosteric control. Activity of the enzyme is regulated by hormonal control of its transcription. Glucagon stimulates transcription of the structural gene for PEPCK. Insulin inhibits transcription of the enzyme. By inhibiting PEPCK gene transcription, insulin tends to depress gluconeogenesis rates. 

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