ClbP

ClbP is a periplasmic, membrane-associated peptidase encoded within the pks island in certain strains of Escherichia coli and related bacteria. It plays a crucial role in the biosynthesis of colibactin, a hybrid nonribosomal peptide–polyketide genotoxin. ClbP cleaves a protective prodrug motif from precolibactin, specifically an N-acyl-D-asparagine side chain, thereby releasing the mature colibactin molecule that can damage DNA in mammalian cells. This maturation step is essential for the genotoxic activity attributed to colibactin.

Localization and structure: ClbP is anchored to the inner membrane with its catalytic domain oriented toward the periplasm, where colibactin precursors are processed. It belongs to a family of serine protease–like peptidases, and the catalytic mechanism is associated with conserved residues forming a serine protease–type active site. Structural studies have provided insight into the catalytic pocket and substrate recognition.

Genetic and functional context: ClbP is part of the pks island gene cluster, which includes other enzymes such as ClbN, ClbB, ClbC, ClbD, ClbE, ClbF, and ClbQ. Disruption of clbP abolishes the activation of precolibactin, significantly diminishing colibactin production and its genotoxic effects in cellular and animal models.

Research and relevance: ClbP has been studied through genetic, biochemical, and structural approaches to understand colibactin maturation. It is a focal point for research aimed at mitigating colibactin-associated genotoxic risk and exploring inhibitors as potential therapeutic or preventive tools.