Nature on resin – understanding non-ribosomal peptide biosynthesis

Abstract

Non-ribosomal peptide synthesis is a vital source of important natural products, which include compounds with anticancer, antibiotic, antifungal and immunosuppressive activity. Non-ribosomal peptide synthesis exploits a range of building blocks far greater than the proteinogenic amino acids (>500 vs 20), which themselves can be further modified (for example by chlorination or oxidation) by additional enzymes during NRPS-biosynthesis. This combination of diversity in the building blocks available to construct non-ribosomal peptides combined with the additional modifications performed by external enzymes leads to the immense structural and biological diversity of these compounds that we find in nature.

The enzymatic machinery that produces these peptides is a group of fascinating mega-enzyme synthetases known as non-ribosomal peptide synthetases (NRPSs). Using a modular architecture of repeating catalytic domains that is capable of interfacing with polyketide and fatty acid synthesis and combined with multiple interaction partners (such as Cytochrome P450s) in trans, NRPSs have long been recognised as potential targets for enzymatic engineering to produce new, bioactive compounds. To date, however, this research has largely been hindered by a lack of understanding of how NRPSs function at the molecular level. 

In this presentation, Associate Professor Cryle will report the recent discoveries of his group that provide fundamental insights into NRPS biosynthesis. This includes understanding the mechanism and selectivity of key peptide synthesis and amino acid selection domains, which are common to all NRPS assembly lines and central to their function. He will also detail our efforts to reconstitute enzymatic crosslinking during glycopeptide antibiotic maturation, which is a highly challenging chemical transformation that limits our ability to produce new members of this important class of clinical antibiotics through chemical synthesis. Throughout this presentation, he will further discuss the importance of integrating chemical synthesis into engineering strategies for these complex biosynthetic pathways.

Biography

Associate Professor Max Cryle is an EMBL Australia Group leader based in the Biomedicine Discovery Institute at Monash University. Since 2020, he has also been a chief investigator in the ARC Centre of Excellence for Innovations in Peptide and Protein Science.

After obtaining his PhD in Chemistry from UQ in 2006, he moved to the Max Planck Institute for Medical Research in Heidelberg as a HFSP Cross Disciplinary Fellow. He was subsequently awarded funding from the German Research Foundation to establish his own group to investigate glycopeptide antibiotic biosynthesis as part of the Emmy Noether program. It is for this work, he was awarded the 2016 Otto Schmeil prize by the Heidelberg Academy of Arts and Sciences.

In 2016, he joined EMBL Australia where his group investigates the biosynthesis of important peptide antibiotics together with novel strategies and targets for antimicrobial development, for which he was recently awarded the Tregear Award from the Australian Peptide Society.