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

Abstract

AbstractCoenzyme 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.