Invited Talk 21st International Conference on Biological Inorganic Chemistry 2025

Investigating P450s from biarylitide biosynthesis pathways (120879)

Max J Cryle 1
  1. Monash University, Melbourne, Victoria, Australia

Cytochrome P450s are capable of a wide range of oxidative transformations across diverse biosynthetic processes.1 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, which can generate a range of cyclic tripeptide species from minimal pentapeptide substrates.2,3

I will detail the results of our ongoing research to characterise new and engineered members of this P450 family,4-5 which can perform crosslinking between a range of different aromatic residues. I will report our structural analysis of the binding of these substrates by the P450 enzyme and detail our investigations into alternate transformations performed by these enzymes, including the unprecedented role of nitration performed by a biarylitide-like P450 during rufomycin biosynthesis.6 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.

  1. 1. A. Greule, J. E. Stok, J. J. De Voss, M. J. Cryle, Natural Product Reports 2018, 35, 757-791.
  2. 2. Y. Zhao, E. Marschall, M. Treisman, A. McKay, L. Padva, M. Crüsemann, D. R. Nelson, D. L. Steer, R. B. Schittenhelm, J. Tailhades, M. J. Cryle, Angewandte Chemie International Edition 2022, 61, e202204957.
  3. 3. M. Hansen,A. Keto, M. Treisman, V. Mini Sasi, L. Coe, Y. Zhao, L. Padva, C. Hess, V. Leichthammer, D. L. Machell, R. B. Schittenhelm, C. J. Jackson, J. Tailhades,M. Crüsemann, J. J. De Voss, E. H. Krenske, M. J. Cryle, ACS Catalysis 2024, 14, 812 – 826.
  4. 4. M. Treisman, L. Coe, Y. Zhao, V. Mini Sasi, J. Gullick, M. H. Hansen, R. B. Schittenhelm, J. Hooper, C. J. Jackson, J. Tailhades, J. J. De Voss, M. J. Cryle, Organic Letters 2024, 26 (9), 1828 – 1833.
  5. 5. Y. Zhao, J. Gullick, M. H. Hansen, L. Coe, M. Treisman, R. B. Schittenhelm, A. McKay, L. A. M. Murray, J. Tailhades, J. J. De Voss, E. H. Krenske, M. J. Cryle, Chemical Communications 2024, 60, 13951-13954.
  6. 6. L. Padva, L. Zimmer, J. Gullick, Y. Zhao, V. Mini Sasi, R. B. Schittenhelm, C. J. Jackson, M. J. Cryle, M. Crüsemann, Chem 2025, 10.1016/j.chempr.2025.102438.