Re-engineering the building blocks of bacterial natural product assembly lines
Lead Research Organisation:
University of Bristol
Department Name: Chemistry
Abstract
Type I polyketide synthases (PKS) are highly complex biosynthetic machines that produce valuable bioactive natural products. Rational engineering and manipulation of PKS building blocks could provide a route to the production of novel high value chemical entities and this project aims to advance our understanding of these fundamental pathways. Kalimantacin is a polyketide assembled by a hybrid type I trans-acyltransferase (AT) PKS/non-ribosomal peptide synthase (NRPS) and displays potent antibacterial properties, including high selectivity for staphylococcal species. Its -branches are critical for its antibiotic activity and incorporated by a multi-protein 3-hydroxy-3-methylglutaryl synthase (HMGS) cassette. Further understanding of how these enzymes tightly control the incorporation of -branches is essential for the generation of novel chemicals with potent biological activities. Studying the kalimantacin assembly line therefore provides an excellent opportunity to achieve this. Key components of the HMGS cassette (enoyl-CoA hydratase domains, both modular and trans-acting) that form either an endo--methyl or exo--methylene will be studied to understand their structure and function and determine if the order of -branch incorporation can be reversed by logical protein engineering. X-ray crystallography, site-directed mutagenesis, Cryo-EM and NMR assays are just some of the techniques that will be employed to explore this exciting avenue.
Organisations
People |
ORCID iD |
Matthew Crump (Primary Supervisor) | |
Annabel Phillips (Student) |
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
BB/T008741/1 | 01/10/2020 | 30/09/2028 | |||
2439555 | Studentship | BB/T008741/1 | 01/10/2020 | 30/09/2024 | Annabel Phillips |
Description | Flash talk and Poster Presentation at Directing Biosynthesis VI |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Over 100 attendees in-person at the Directing Biosynthesis VI conference, where I presented a flash talk and poster on my research. Questions and discussions took place during the poster session which led to ideas for developing my research further. |
Year(s) Of Engagement Activity | 2022 |
Description | Poster Presentation at the Chemistry and Biology of Natural Products Symposium XV |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Around 100 people attended the Chemistry and Biology of Natural Products Symposium XV where I presented a poster on my research. Questions and discussions took place during the poster presentation session, and my poster was voted by the audience for the best poster prize. |
Year(s) Of Engagement Activity | 2022 |