Schofield, Christopher J. - University of Oxford

个人简介

Chris Schofield studied for an undergraduate degree in chemistry at the University of Manchester Institute of Science and Technology. He moved to Oxford for DPhil studies with Jack Baldwin on the synthesis and biosynthesis of antibiotics. He subsequently became a Departmental Demonstrator in the Dyson Perrins Laboratory, and in 1990 Lecturer in Chemistry and Fellow of Hertford College. In 1998 he became Professor of Chemistry, and in 2011 was appointed Head of Organic Chemistry. He is a Fellow of the Royal Society and Head of Chemistry at the Ineos Oxford Institute for Antimicrobial Research. His research group works at the interface of chemistry, biology and medicine. His work has opened up new fields in antibiotic research, oxygen sensing and gene regulation in organisms ranging from bacteria to plants and animals. His work has identified new opportunities for medicinal intervention that are being pursued by numerous academic and commercial laboratories.

研究领域

Our group’s research focuses on contributing to a chemical understanding of systems of biological importance, and enabling the exploitation of the results for societal benefit. The two major research fields of the laboratory concern antibacterial resistance and the role of oxygenases in the regulation of expression / protein biosynthesis. These fields synergise because of the group’s expertise in enzymes, in particular iron and zinc dependent metallo-enzymes. Our work has opened up new fields in antibiotic research, oxygen sensing and gene regulation. After ground-breaking work on plant and microbial oxygenases (including in β-lactam biosynthesis), the group pioneered structurally informed functional assignments for uncharacterized human and microbiological metallo-enzymes. This research identified unanticipated roles for oxygenases in regulating gene expression, antibiotic resistance, has revealed new post-translational modifications (to chromatin, ribosomes, RNA splicing proteins), and importantly in animal hypoxic responses. Our work has identified new opportunities for medicinal intervention (basic science from the group has helped enable approved drugs), and new ways of inhibiting antibiotic targets that are being pursued by numerous academic and commercial laboratories. Current Major Research Interests of the group are (i) Antibiotics and antibiotic resistance, especially via metallo-enzymes, including β-lactamases and oxygenases; (ii) The role of oxygenases in regulating gene expression, including in response to limiting oxygen availability - we are interested in the mechanisms of these enzymes, which often catalyse reactions not presently possible for synthesis; (iii)The roles and inhibition of Zn(II) dependent nucleases in DNA repair; (iv) Methodology for the identification of highly selective inhibitors of metallo-enzymes, and nucleophilic enzymes, including via novel screening methods; (v) Histone modifying enzymes, especially demethylases and hydroxylases; the chemistry of cancer metabolism. Although focused on basic science, our group is keen to translate its basic science to societally useful outcomes. The group has extensive collaborations with clinicians and industry, principally concerning the basic science of antibiotic resistance/biosynthesis, rare diseases, and the regulation of gene expression by oxygen (notably with Peter Ratcliffe). Important outcomes of this work have been contributions to the industrial application of oxygenases, to a new class of beta-lactamase inhibitors and to the identification of new targets for the pharmaceutical industry - including the hypoxia inducible factor prolyl hydroxylases and human metallo beta lactamase fold enzymes involved in resistance to anti-cancer agents.

近期论文

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Inhibition of the Oxygen-Sensing Asparaginyl Hydroxylase Factor Inhibiting Hypoxia-Inducible Factor: A Potential Hypoxia Response Modulating Strategy. May 2021 | Journal article | J Med Chem Structural Basis of Metallo-β-lactamase Inhibition by N-Sulfamoylpyrrole-2-carboxylates. May 2021 | Journal article | ACS Infect Dis Human oxygenase variants employing a single protein Fe(II) ligand are catalytically active. April 2021 | Journal article | Angewandte Chemie (International ed. in English) Faropenem reacts with serine and metallo-β-lactamases to give multiple products. April 2021 | Journal article | European journal of medicinal chemistry Structural Basis of Prolyl Hydroxylase Domain Inhibition by Molidustat. April 2021 | Journal article | ChemMedChem Discovery of neuroprotective agents that inhibit human prolyl hydroxylase PHD2. March 2021 | Journal article | Bioorganic & medicinal chemistry The methyltransferase METTL9 mediates pervasive 1-methylhistidine modification in mammalian proteomes. February 2021 | Journal article | Nat Commun Synthesis of 2-oxoglutarate derivatives and their evaluation as cosubstrates and inhibitors of human aspartate/asparagine-beta-hydroxylase January 2021 | Journal article | CHEMICAL SCIENCE Structural Investigations of the Inhibition of Escherichia coli AmpC β-Lactamase by Diazabicyclooctanes. January 2021 | Journal article | Antimicrobial agents and chemotherapy Mass spectrometry reveals potential of β-lactams as SARS-CoV-2 Mpro inhibitors. January 2021 | Journal article | Chemical communications (Cambridge, England) Improved Synthesis of Phosphoramidite-Protected N6-Methyladenosine via BOP-Mediated SNAr Reaction. December 2020 | Journal article | Molecules Author Correction: Aspartate/asparagine-β-hydroxylase: a high-throughput mass spectrometric assay for discovery of small molecule inhibitors. December 2020 | Journal article | Sci Rep Use of cyclic peptides to induce crystallization: case study with prolyl hydroxylase domain 2. December 2020 | Journal article | Scientific reports Analysis of β-lactone formation by clinically observed carbapenemases informs on a novel antibiotic resistance mechanism. December 2020 | Journal article | J Biol Chem Biochemical and biophysical analyses of hypoxia sensing prolyl hydroxylases from Dictyostelium discoideum and Toxoplasma gondii. December 2020 | Journal article | J Biol Chem Natural variants modify Klebsiella pneumoniae carbapenemase (KPC) acyl-enzyme conformational dynamics to extend antibiotic resistance. December 2020 | Journal article | The Journal of biological chemistry Allosteric Inhibition of the SARS-CoV-2 Main Protease: Insights from Mass Spectrometry Based Assays*. December 2020 | Journal article | Angewandte Chemie (International ed. in English) Analysis of β-lactone formation by clinically observed carbapenemases informs on a novel antibiotic resistance mechanism. December 2020 | Journal article | The Journal of biological chemistry Biochemical and biophysical analyses of hypoxia sensing prolyl hydroxylases from Dictyostelium discoideum and Toxoplasma gondii. December 2020 | Journal article | The Journal of biological chemistry Natural variants modify Klebsiella pneumoniae carbapenemase (KPC) acyl-enzyme conformational dynamics to extend antibiotic resistance. November 2020 | Journal article | J Biol Chem