Cytochrome P450s are a superfamily of oxidative hemoproteins capable of performing a wide range of oxidative transformations across diverse biosynthetic processes. Whilst the archetypal P450-mediated transformation is hydroxylation of non-activated C-H bonds, these enzymes are capable of a wide range of transformations including epoxidation, heteroatom oxidation, C-C bond cleavage, carbon skeleton rearrangements and the crosslinking of aromatic groups. Given this synthetic utility and combination of oxidative power and regiochemical precision, it is little surprise that this family of enzymes have been widely implicated as potential biocatalysts. The application of P450s as tools for generation of specific, high-value synthetic precursors has been anticipated, but few systems have been found that display the combination of substrate promiscuity with the importance of the potential synthon of the P450-catalysed transformation.

Here, I will present the results of our investigations into the utility of peptide crosslinking P450 enzymes from biarylitide biosynthesis to generate a range of cyclic tripeptide species. Our results show that these enzymes can generate a range of crosslinked tripeptides in minimal pentapeptide substrates, which can be isolated following proteolytic digestion of the parent peptides in a facile manner. We have determined the structure of a biarylitide P450 both in isolation and in complex with its peptide substrate, which provides the first molecular insights into the crosslinking of linear peptide substrates by Cytochrome P450 enzymes. This has also allowed us to explore the engineering of these P450s to accept yet further diversity in their peptide substrates.

Given the utility of peptide crosslinking in important natural products and the synthetic challenge often present in such systems, these P450 enzymes have the potential to play roles as important synthetic tools in the generate of high-value cyclic tripeptides for incorporation in synthesis pathways, which can be further diversified using selective chemical techniques targeting specific handles contained within these tripeptides.


About School research seminars

Seminars cover all aspects of chemistry and molecular biosciences and are delivered by visiting national and international academics. PhD completion seminars are also incorporated into the program.

Seminars are usually held in person and via zoom. All are welcome to attend.  



50-N201 Hawken Engineering Building, Learning Theatre