Exploring Oxygenase Chemistry: Enzymatic Pathways to Novel Antibiotics

About the Project

Nature uses a remarkable range of oxygenase enzymes to perform highly selective oxidation reactions—transformations that are often challenging or wasteful to achieve chemically. Among these, Fe(II)/2-oxoglutarate (2OG)-dependent oxygenases are particularly versatile, catalysing hydroxylation, halogenation, and desaturation reactions that underpin natural product biosynthesis and modern biocatalysis. Despite their importance, the mechanistic principles that govern their selectivity and reactivity remain poorly understood.

This project will uncover how oxygenases control substrate binding and oxygen activation to achieve precise chemical outcomes relevant to antibiotic biosynthesis and sustainable chemistry. The student will recombinantly express and purify a newly discovered non-heme iron/2OG-dependent oxygenase from a Streptomyces, which catalyses the selective hydroxylation of amino acid substrates. Using a combination of biochemical assays, spectroscopy, and structural biology, the project will characterise substrate scope, reaction kinetics, and catalytic intermediates.

The project will explore time-resolved crystallography and spectroscopy to visualise short-lived intermediates in real time, linking electronic and atomic structures during catalysis. These data will feed into a mechanistic model describing how substrate positioning and active-site architecture dictate reaction outcome.

The broader goal is to leverage this understanding to expand the enzyme’s biocatalytic potential for synthesis of β-hydroxylated amino acids and related building blocks. Such molecules are key intermediates in pharmaceuticals and natural products but are expensive and time consuming to obtain chemically. Mechanistic insight into oxygenase control could therefore enable enzyme engineering for improved selectivity, turnover, and substrate versatility—contributing to antibiotic diversification and sustainable manufacturing.

This interdisciplinary project sits at the interface of enzymology, structural biology, and biocatalysis, offering the opportunity to make fundamental and applied contributions to the understanding and exploitation of oxygenase chemistry.

The student will receive training in molecular cloning, protein expression and purification, and anaerobic enzymology, as well as advanced skills in UV–vis spectroscopy, mass spectrometry, X-ray crystallography, and time-resolved structural methods. They will also gain experience with bioinformatics, kinetic data analysis, and enzyme engineering. Collaborative visits to national facilities (e.g., Diamond Light Source) will provide exposure to cutting-edge synchrotron and XFEL experiments. The project will equip the student with an interdisciplinary skill set spanning mechanistic biochemistry, structural biology, and biocatalyst development—highly transferable across both academic and industrial research environments.

This PhD is expected to deliver:

• The mechanistic and structural characterisation of a newly identified oxygenase from an antibiotic pathway.
• Insights into how Fe(II)/2OG enzymes control regio- and stereoselectivity.
• Demonstration of enzyme-driven synthesis of hydroxylated amino acids as sustainable chemical intermediates.
• Publications in high-impact enzymology and biocatalysis journals, and presentations at international conferences.
• Overall, the project will establish a mechanistic framework for exploiting oxygenases in antibiotic discovery and green chemistry.