Pyruvate carboxylase modifiers

The widespread occurrence of mitochondria in eukaryotic cells indicates that segregation of some of the most important aspects of energy metabolism has been evolutionarily useful. Such segregation has been accompanied by modifications of regulatory interrelationships which depend upon the movement of metabolites into and out of mitochondria and upon the specific modification of regulatory enzymes by specific allosteric modifiers. For example, the activity of pyruvate carboxylase, an enzyme which fulfills an anaplerotic function in a wide variety of cells, depends upon allosteric activation by acetyl CoA. Since the inner mitochondrial membrane is virtually impermeable to coenzyme A and its esters, the activation of pyruvate carboxylase may be looked upon as a compartmentation phenomenon in which this acetyl CoA is separated from the cytosol acetyl CoA pool and must be formed intramitochondrially. In this case movement across the membrane is not involved, since both the activation and the formation of the activator occur within the same compartment. Although a distinct possibility. 

The regulation of covalent phosphorylation of acetyl-CoA carboxylase by the allosteric effectors is especially interesting from the point of view that the cellular metabolites could be determinants of the substrate specificity of protein kinases. At present, very little is known as to how the specificity of protein kinase is determined beyond the required primary amino acid sequence. Such metabolite-regulated covalent phosphorylation was shown to exist in the liver pyruvate kinase system 100), and it could be interesting to examine whether such regulation is a general phenomenon of covalent modifiable systems. 

Certain microorganisms synthesize acetoin by a modified pathway. The enzymes involved have been partially purified from extracts of Aerobacter aerogenes. The first step resembles the carboxylase reaction of pig heart, in that acetaldehyde is not found, but all of the two-carbon fragment is transferred to another carbonyl group, forming an acyloin. The only known acceptor is pyruvate, and the product is d-a-acetolactate. 

---