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The molecular and structural enzymology (MSE) team is interested in understanding the molecular enzymology and structure/function relationships within enzymes and multienzymatic complexes, addressing issues of catalytic and chemical mechanisms, as well as the structural basis for substrate specificity and interactions with partner proteins or domains.

The MSE team has had a long-standing interest in the study of enzymes which depend on the complex chemistry of sulfur, and participate in a number of critical cellular processes including metabolism, repair, detoxification, redox regulation via reactive oxygen species (ROS) and sulfur mobilization. The current projects focus on diverse families of enzymes, whose unifying feature is the involvement in their catalytic mechanism of cysteine/methionine chemistry, including the following species: thiolate, disulfide, sulfenic and sulfinic acids, and thiosulfinate for Cys, and sulfoxide for Met. These enzyme families include the aldehyde dehydrogenases (ALDHs), which catalyze the oxidation of aldehydes to activated or non-activated acids and are known to be essential in cellular metabolism and detoxification processes; the methionine sulfoxide reductases (Msrs), which are antioxidant repair enzymes which reduce methionine sulfoxide (Met-O) back to Met using thioredoxin (Trx) or Trx-like proteins as the physiological reductants; and the sulfiredoxins (Srx), which catalyze the reduction of overoxidized typical 2-Cys peroxiredoxins (PrxSO2), and thus regulate the various functions of Prx which translate, the dual action of H2O2 as a toxin/carcinogen and as a signalling molecule.

The team has recently expanded its interests to encompass the multi-modular polyketide synthase (PKS). These gigantic protein catalysts are responsible for the assembly-line biosynthesis of numerous polyketides, small molecules which are used clinically to treat a wide range of both chronic and acute conditions. Our aim is to decipher how these complex enzymes function, with particular emphasis on structure, protein-protein interactions and catalytic mechanism, in order to facilitate on-going efforts to genetically reengineer PKS to produce novel analogues of therapeutic value (an emerging field termed ‘synthetic biology’).

Research in the MSE team relies on the full range of expertise in molecular enzymology and biophysical techniques, including protein and genetic engineering, classical and rapid (stopped-flow, quenched-flow) enzyme kinetics, fluorescence and CD spectroscopy, mass spectrometry, X-ray crystallography, SAXS, NMR and techniques for monitoring biomolecular interactions (e.g. ITC and SPR).