Chemical Biology

Available research areas within this group:

• Terpene Biosynthesis: Terpenes are the most abundant and structurally diverse class of natural products yet they are constructed from only a small pool of biosynthetic precursors. We use a combination of synthetic organic chemistry, molecular biology and enzymology to understand how terpene synthases achieve this masterclass in natural combinatorial chemistry. Through use of chemical and synthetic biology we also use these enzymes to expand the ‘terpenome’ in order to generate unnatural products with novel biological activity.
• The physical basis of enzyme catalysis: Enzymes often catalyse reactions at rates that approach catalytic perfection but how they achieve these vast rate accelerations is still not fully understood.  Dihydrofolate reductase is used as a model system to study how protein structure, dynamics, and quantum mechanical tunnelling all coordinate to achieve the rate accelerations observed in the chemical steps taking place.
• Biophotonic Nanoswitches: Protein-protein and protein-DNA interactions lie at the heart of many processes that control cellular events including those underlying many disease conditions.  By combining small peptides with molecules that switch shape when irradiated with visible light it is possible to design systems that allow photo-control of such cellular events.  This has many potential benefits for better understanding of cell cycles and in the treatment of disease.
• Medicinal Biochemistry: In collaboration with Cardiff University School of Medicine we are targeting enzymes involved in the process of white blood cell migration.  Inhibiting this process has the potential to treat inflammatory diseases such as rheumatoid arthritis as well as to improve our understanding of the roles these enzymes have in cell biology. Organic synthesis, enzymology and structural biology are combined in order to generate new generations of compounds that target these enzymes in a new way.
• Mechanisms of light-sensitive flavoprotiens: Flavoproteins are well known to catalyse biochemical redox reactions but  have been found relatively recently to play a crucial role in blue light  sensing in bacteria, fungi and especially plants. Research comprises work on  the detailed reaction mechanism and the photochemistry. We are currently  exploring the potential to use them as optogenetic photoswitches for the  control of the cell cycle of mammalian cells.
• Peptide and protein interactions with nucleic acids: Controlling the interactions between proteins and nucleic acids has the potential for artificial means of regulating genes and nucleic acid processing involved in cell replication. Organic synthesis and peptide chemistry are used to create new molecules that target specific secondary structures of DNA and RNA.
• Mass spectrometry of  cyclic peptides: Peptides in which the termini are joined to make a macrocycle are less flexible and more  protease resistant than their linear counterparts which makes them more  attractive from a drug discovery perspective. Large numbers of peptides can be  synthesised in parallel but structural characterisation is more challenging.  Software is being developed to assist in rapid assignment of structures of  cyclic peptides using collision induced dissociation mass spectra.

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