The Origin of Coproporphyrin III in Acne

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 of Gram-negative organisms or that of mammals. Gram-positive organisms use the so-called coproporphyrin-dependent heme biosynthetic pathway. The heme biosynthesis in the Gram-positive pathogenic bacterium Cutibacterium acnes shows peculiarities. Only in the genome of these bacteria are the two enzymes responsible for the penultimate and final steps of heme biosynthesis fused. These are a ferrochelatase, which has the task of incorporating iron into the porphyrin ring, and a coproheme decarboxylase, which in the last step converts two propionate groups into vinyl groups in order to produce the final product, heme b. In addition, it has been observed that, in the case of heme b, the enzymes are fused. Furthermore, it has been observed that in the skin disease acne vulgaris caused by Cutibacterium acnes, coproporphyrin III is accumulated, which is the substrate for ferrochelatase and at the same time a significant virulence factor. In this research project, the structure-function relationships of the above fusion protein will be studied in detail using kinetic, biochemical and biophysical methods. The underlying properties leading to pathogenicity will be clarified mechanistically. This in turn will form the basis for future research approaches aimed at finding therapeutic substances that have a mitigating effect on the disease pattern. To this end, several variants of the fusion protein will be generated and studied in order to systematically elucidate structural and mechanistic issues.