How an overlooked gene in coenzyme a synthesis solved an enzyme mechanism predicament.

Coenzyme A (CoA) is an essential cofactor throughout biology. The first committed step in the CoA synthetic pathway is synthesis of β-alanine from aspartate. In Escherichia coli and Salmonella enterica panD encodes the responsible enzyme, aspartate-1-decarboxylase, as a proenzyme. To become active, the E. coli and S. enterica PanD proenzymes must undergo an autocatalytic cleavage to form the pyruvyl cofactor that catalyzes decarboxylation. A problem was that the autocatalytic cleavage was too slow to support growth. A long-neglected gene (now called panZ) was belatedly found to encode the protein that increases autocatalytic cleavage of the PanD proenzyme to a physiologically relevant rate. PanZ must bind CoA or acetyl-CoA to interact with the PanD proenzyme and accelerate cleavage. The CoA/acetyl-CoA dependence has led to proposals that the PanD-PanZ CoA/acetyl-CoA interaction regulates CoA synthesis. Unfortunately, regulation of β-alanine synthesis is very weak or absent. However, the PanD-PanZ interaction provides an explanation for the toxicity of the CoA anti-metabolite, N5-pentyl pantothenamide.