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.

The project investigated the mechanistic details of the redox reaction catalyzed by coproheme decarboxylase. This is important because this enzyme is responsible for the final step of heme biosynthesis in Gram-positive bacteria. Many Gram-positive pathogens depend on a functional coproheme decarboxylase, which is why this enzyme is a possible starting point for the development of new antibiotic substances. With precise knowledge of the reaction mechanism, it is possible to develop specific inhibitors based on redox biochemistry and not just on steric considerations.