Research in the Jenner Lab focuses on the application of mass spectrometryLink opens in a new wi, in combination with other analyticalLink opens in a new window and structural techniquesLink opens in a new window, to solve complex biological problems.
Our primary interest concerns the enzymes involved in the biosynthesis of polyketideLink opens in a new window and non-ribosomal peptideLink opens in a new window natural products – this includes a fundamental understanding of their structures, mechanisms and protein-protein interactions. Our key research themes are outlined below.
Enzymology of Polyketide Synthases and Non-Ribosomal Peptide Synthetases
Many important pharmaceuticals and agrichemicals are derived from polyketide and non-ribosomal peptide natural products. These complex and diverse classes of molecules are biosynthesised by polyketide synthases (PKSs)Link opens in a new window and non-ribosomal synthetases (NRPSs)Link opens in a new window, respectively. Often referred to as ‘megasynth(et)ases’, both PKS and NRPS systems are enormous multidomain carrier protein-dependent enzymatic complexes that function in a highly programmed manner to achieve biosynthetic fidelity. Our interests focus on understanding the structures and mechanisms of enzymatic domains in PKSs and NRPSs from various microbial origins.
Mapping Carrier Protein Interactions in Biosynthetic Systems
Central to many biosynthetic systems is a small (~10 kDa) carrier proteinLink opens in a new window domain that is post-translationally modified with a 4'-phosphopantetheine (Ppant)Link opens in a new window prosthetic ‘arm’, to which intermediates and extender units are covalently tethered via a thioester bond. The carrier protein sits at the heart of multi-domain enzymes such as PKSs and NRPSs, engaging in specific protein interactions with each catalytic domain during the biosynthesis. Understanding the molecular details of these interactions is critical to improve our ability to engineer and reprogram these systems to make novel products. Our current efforts are focussed on carrier proteins from bacterial trans-AT PKSsLink opens in a new window and the highly programmed fungal hrPKSsLink opens in a new window.
Genomics-Driven Natural Product Discovery & Biosynthetic Pathway Elucidation
Bacteria and fungi are prolific producers of structurally complex, highly bioactive natural products. Advances in post-genomic techniques and the propensity for biosynthetic genes to clusters – termed biosynthetic gene clusters (BGCs)Link opens in a new window - have allowed the prediction of pathways from genetic sequences alone and have facilitated numerous targeted discovery methods. In this area, our current focus is on Gram negative bacteria (BurkholderiaLink opens in a new window & PseudomonasLink opens in a new window), fungi of the AscomycetesLink opens in a new window genus, and the development of effective genomics-driven natural product discovery platforms to exploit these organisms.