The Origin of Coproporphyrin III in Acne
Abstract
Theoretical framework: Coproporphyrin III is an important virulence factor associated with the skin disease acne vulgaris, which is caused by an infection with the monoderm actinobacterium Cutibacterium acnes. Monoderm bacteria utilize the so-called “coproporphyrin-dependent” heme biosynthesis pathway. In this pathway several enzymes catalyse the formation of the final product heme b, two of those (coproporphyrin ferrochelatase, CpfC; coproheme decarboxylase, ChdC) are uniquely found to be fused in one open reading frame in pathogenic C. acnes strains. Objectives: Employing high-end biochemical and biophysical methods to study different constructs of pathogenic C. acnes CpfC-ChdC fusion protein (full length; N-terminal CpfC domain only; C-terminal ChdC domain only), but also of CpfC and ChdC (not fused) of non-pathogenic C. acnes strains will provide in-depth knowledge of protein folding, interaction and enzymatic capabilities. Further, state-of-the art structural studies will be used to describe the enzyme in the most complete way, in order to understand steric constraints of the overall structure and active site architecture, which may lead to the secretion of coproporphyrin III. Methods: Biochemical and biophysical characterization of the selected CpfC-ChdC constructs and variants will be performed using multiple high-end spectroscopic methods, steady-state and pre-steady state kinetic characterizations. Further we will employ state-of the art structural biology methods (X-ray crystallography, Cryo-EM, SAXS) to gain profound knowledge of the enzyme’s structure to the very detail. Innovation: Combining our long-standing expertise on CpfCs and ChdCs is the perfect starting point to investigate the molecular mechanisms and enzymatic shortcomings that lead to the production and secretion of the very important virulence factor coproporphyrin III. Knowledge of this underlying biochemical features is a precondition for further studies, including future drug development.
Publikationen
Structural aspects of enzymes involved in prokaryotic Gram-positive heme biosynthesis.
Autoren: Falb, N; Patil, G; Furtmüller, PG; Gabler, T; Hofbauer, S; Jahr: 2023
Journal articles
Project staff
Stefan Hofbauer
Priv.-Doz. Dipl.-Ing. Stefan Hofbauer Ph.D.
stefan.hofbauer@boku.ac.at
Tel: +43 1 47654-77258
Project Leader
01.09.2023 - 31.08.2026
Thomas Gabler
Dipl.-Ing. Dr. Thomas Gabler B.Sc.
thomas.gabler@boku.ac.at
Tel: +43 1 47654-77278
Project Staff
01.09.2023 - 31.08.2026