Harmer Group Enzyme cascades and their applications Enzymes are nature’s catalysts. They are molecules that make reactions in biology work faster. All the chemical changes needed in living systems rely on enzymes speeding up reactions at the right time. Our work seeks to understand sets of enzymes working together – a “cascade” – to drive desirable reactions. We engineer some enzymes using evolutionary methods. We then apply this understanding to practical problems. Our key examples are: the production of sugars for use in vaccines against bacteria; and chemical transformations for drug manufacture. Our work will help to deliver vaccines or drugs at scale using fewer resources and producing less waste. It will help both with overcoming antimicrobial resistance, and achieving a green future. Time-resolved structural studies of enzymes The key steps in enzyme catalysis occur quickly in rare events on a molecular timescale. To gain deeper understanding of how enzymes work, we want to determine the structure of enzymes as they move through the catalytic cycle. Achieving this requires the latest structural biology innovations. We aim to use our well-characterised systems from the enzyme cascade projects to work with synchrotron experts to catch enzymes in the act of catalysis and better understand how enzymes achieve their amazing speeding up of reactions. Research Team Anil Jamithireddy (Postdoc) Courtney Tremlett (PhD) William Stuart (PhD) Freddie Moore (PhD) Zhaorui Gu (PhD) Andrew Cadzow (PhD) Opportunities Funded PhD opportunities Living Systems Institute PhD programme for 2024 entry: Designer proteins to rewire living systems Supervisors: Nicholas Harmer, JJ Phillips, Benjamin Housden, Austin Smith In this project, you will learn the latest protein design tools and apply them to re-wire specific cell signalling interactions to understand spatial and temporal rules of cell decision making. De novo design of proteins is an emerging technique that offers us the opportunity to study entirely new questions in living systems. In this project, you will learn the latest generative AI protein design tools and apply them to important challenges in understanding how cells signal. The core supervisors have experience in GenAI protein design and will teach this, whilst co-supervisors will guide the research challenges. We will ask important questions about how cellular signalling pathways cross-talk; how poorly understood signalling pathways are triggered and deliver their signals; and how spatial and temporal effects of signalling affect the overall output. We will use the results from this project in our research on drug discovery against rare diseases and the latest stem cell research. As such, you will gain expertise in both protein design and in advanced eukaryotic cell biology. This project will particularly appeal to students with broad interests who are happy to use both GenAI and laboratory-based methods in their research, and who value the opportunity to work with other groups to influence diverse research areas. LSI has a strong structural and cell biology groups using the latest techniques to gain a molecular understanding of life. You will join an integrated PhD community who organise their own programme of scientific and social events. LSI provides an ideal environment for a successful PhD in this area. Click here to apply GW4 BioMed MRC DTP Developing new therapies against the most dangerous antibiotic resistant bacteria Supervisors: Professor Nic Harmer and Professor James Wakefield Antimicrobial resistance is an increasing societal issue, contributing to ~5,000,000 deaths in 2019. The highest priority bacteria are the ESKAPE pathogens that account for over half this mortality and morbidity. This project will contribute to fighting antimicrobial resistance by developing new high-throughput in vivo ESKAPE pathogen infection models in the wax moth Galleria mellonella. These will be used to test resistant clinical isolates with our novel compounds that make bacteria more susceptible to conventional antibiotics and facilitate further development of the compounds. The project will accelerate the development of our compounds and provide new in vivo models for antimicrobial discovery. Click here to apply