WEHI Special ACRF Chemical Biology Seminar hosted by Dr Niccolay Madiedo Soler

Professor Max Cryle

Department of Biochemistry and Molecular Biology, Monash Biomedicine Institute – Monash University

Engineered cytochrome P450 enzymes as catalysts for peptide crosslinking

 

Davis Auditorium / Bundoora Large Boardroom 

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Including Q&A session

Cytochrome P450s are capable of a wide range of oxidative transformations across diverse biosynthetic processes. Given this synthetic utility and combination of oxidative power and regiochemical precision, it is little surprise that this P450s have been widely implicated as potential biocatalysts. Here, I will report our recent investigations of peptide crosslinking P450 enzymes from biarylitide biosynthesis to generate a range of cyclic tripeptide species. We demonstrate that such enzymes can generate a range of crosslinked tripeptides involving tyrosine, histidine, and tryptophan residues in minimal pentapeptide substrates, which can be easily isolated following proteolytic digestion of the parent pentapeptides. We have determined the structure of a P450 from biarylitide crosslinking both in isolation and in complex with the peptide substrate, which provides the first molecular insights into the crosslinking of linear peptide substrates by Cytochrome P450 enzymes. Most recently, we have gained insights into how such P450s can also be employed as biocatalysts to generate novel amino acids as building blocks for peptide biosynthesis. Given the utility of peptide crosslinks in important natural products and the synthetic challenge that these can represent, these P450 enzymes have the potential to play roles as important synthetic tools in the generate of high-value cyclic tripeptides. 

All welcome!