In-depth studies of actinobacterial coproheme decarboxylases

Heme is essential for the survival of most bacteria. Gram-positive organisms produce heme in a way that is fundamentally different from the biosynthetic pathway used by Gram-negative organisms or even mammals. Many mechanistic questions relating to this heme biosynthetic pathway, which was only described a few years ago, are currently still open. In this project, the enzyme called "coproheme decarboxylase" is being studied in detail to elucidate structure-function relationships. Coproheme decarboxylases catalyze the ultimate step of the heme biosynthesis pathway of Gram- positive bacteria. They convert coproheme to the final product heme b by decarboxylation of two propionate groups to form vinyl groups. Some mechanistic details are already known, but all in all the reaction is far from being completely understood. In this project we specifically aim to understand important mechanistic details, which occur during the redox reaction by performing advanced structural and mechanistic studies on the actinobacterial representative from the pathogen Corynebacterium diphteriae. From these studies essential conclusions can be drawn about the mode of action of this enzyme and can be linked to its structural properties. Knowledge of the reaction mechanism of coproheme decarboxylases is necessary to design further studies that will attempt to inhibit enzymatic activity. A substance that can specifically inhibit the heme biosynthesis pathway of pathogenic Gram-positive bacteria is a promising starting point for the development of urgently needed novel antibiotics.