Christopher J. Schofield

Last updated

Christopher J. Schofield
Born
Christopher Joseph Schofield

(1960-06-17) 17 June 1960 (age 64)
United Kingdom
NationalityBritish
Other namesChris Schofield, CJS
Alma materUniversity of Manchester (BSc) University of Oxford (DPhil)
AwardsFellow of the Royal Society
Scientific career
FieldsHypoxic Response, Epigenetic, Oxygenases, Antibiotic Resistance
InstitutionsChemistry Research Laboratory, University of Oxford
Website http://schofield.chem.ox.ac.uk/home http://research.chem.ox.ac.uk/christopher-schofield.aspx

Christopher Joseph Schofield (also known as Chris Schofield) is a Professor of Chemistry at the University of Oxford [1] and a Fellow of the Royal Society. Chris Schofield is a professor of organic chemistry at the University of Oxford, Department of Chemistry [2] and a Fellow of Hertford College. [3] Schofield studied functional, structural and mechanistic understanding of enzymes that employ oxygen and 2-oxoglutarate as a co-substrate. [4] His work has opened up new possibilities in antibiotic research, [5] oxygen sensing, [6] and gene regulation. [7]

Contents

After work on plant and microbial oxygenases, [4] he studied uncharacterised human oxygenases. [8] His research has identified unanticipated roles for oxygenases [9] in regulating gene expression, importantly in the cellular hypoxic response, [10] and has revealed new post-translational modifications to chromatin and RNA splicing proteins. [11] The work has identified new opportunities for medicinal intervention. [12]

Education

Chris Schofield attended St Anselm's College catholic grammar school in Merseyside, then studied for a Bachelor of Science in chemistry at the University of Manchester and graduated with a first class honour (1979–1982). In 1982, he moved to Oxford to study for a DPhil with Professor Jack E. Baldwin. In 1985, he became a Departmental Demonstrator in the Dyson Perrins Laboratory, Oxford University followed by his appointment as a Lecturer in Chemistry [2] and a Fellow of Hertford College [3] in 1990. In 1998, he became professor of Chemistry, [1] and in 2011 he was appointed the Head of Organic Chemistry [13] at the Department of Chemistry, University of Oxford. In 2013, he was elected a Fellow of the Royal Society, FRS. [14]

Research

The work in laboratory of Chris Schofield focuses on different areas of research, including:

Molecular Mechanisms of the Hypoxic Response

Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric α,β-transcriptional complex [15] that mediates the cellular response to oxygen availability in multi-cellular organisms, [6] [16] ranging from the simplest known animal Trichoplax adhaerens to humans. [4] [6] [17] [18] [19] Investigating the structures and mechanisms of the HIF prolyl hydroxylases is a current focus of the work. [10] [20] The group solved crystal structures of PHD2 [9] [21] - one of the human prolyl hydroxylases - and discovered that the HIF asparaginyl hydroxylase also catalyses hydroxylation of conserved motifs, [22] the ankyrin repeat domain.

Chemical Basis of Epigenetics

A current focus of the group is modification of histones, in particular oxygenase catalysed N-demethylation of histone methylated-lysine residues [7] [23] – in collaboration with the Structural Genomics Consortium. The histone demethylases [24] [25] are of interest both with respect to their links to diseases, including cancer [26] [27] and inflammatory diseases, [28] as well as the role of methylation in transcriptional regulation. [29] Recent areas of interest include the fat mass and obesity protein [30] [31] which was shown to be a nucleic acid demethylase [32] and JMJD6 [33] [34] which is a lysyl hydroxylase modifying RNA splicing protein. [11]

Structural and Functional Studies on 2OG Oxygenases

The 2-oxoglutarate (2OG)-dependent oxygenases are a superfamily of non-haem iron dependent oxygenases, [35] most of which use the Krebs cycle intermediate, 2OG, as a co-substrate. [36] The group are interested in understanding these enzymes [37] for their ability to catalyse synthetically difficult or 'impossible' reactions (e.g. the stereoselective hydroxylation of unactivated carbon-hydrogen bonds), for their diverse physiological roles, [8] and for their links to disease. [38] The research focuses on members of the family that are linked to disease, or can be targeted for the treatment of disease. [39] [40] Techniques involved in this interdisciplinary research include proteomics, [41] X-ray crystallography, [42] nuclear magnetic resonance (NMR) spectroscopy, [43] [44] [45] [46] [47] biological mass spectrometry, [48] molecular biology, [49] enzyme kinetics, [50] [51] protein-directed dynamic combinatorial chemistry [52] [53] and organic synthesis/medicinal chemistry. [54] [55]

Antibiotics: Biosynthesis and Resistance Mechanisms

Most clinically used antibiotics are based upon natural products. [5] The most important family of antibiotics contains a β-lactam ring, and includes the penicillin, [56] cephalosporin, clavam, [57] and carbapenem [58] antibiotics. The group's biosynthetic work has focused on the clavams [59] and carbapenems, [58] with a particular focus being on the mechanism and structures of enzymes that catalyse chemically 'interesting' steps. [60] [61] The biggest threat to the continued use of β-lactam antibiotics is that of bacterial resistance. Schofield is currently working on the design and synthesis of enzyme inhibitors [62] [63] [64] [65] for the metallo β-lactamases [66] – there are no clinically used inhibitor [67] of these enzymes but they pose a significant threat as they catalyse the hydrolysis of almost all clinically used β-lactam antibiotics. [68] A particular interest involves human metallo β-lactamases which share the same fold. [69]

Awards and honours

2015-2020: Wellcome Trust Advanced Investigator Award (with Sir Peter Ratcliffe)

2013: Fellow of the Royal Society (London); [14] Member of EMBO; Fellow of the Royal Society of Biology, UK; Member of the Biochemical Society; Member of the Society for Experimental Biology, UK

2012: Finalist – Biotechnology and Biological Sciences Research Council 'Innovator of the Year' [70]

2011: Royal Society of Chemistry, Jeremy Knowles Award, UK; [71] Highly cited paper awards (e.g. Biochemical Journal, Bioorganic & Medicinal Chemistry Letters)

2009 – 2014: PI of ERC Advanced Investigator Grant SPA GA 2008 233240 (with Sir Peter Ratcliffe); Molecular Mechanism of Oxygen Sensing by Enzymes (MOOSE)

2000: Fellow of the Royal Society of Chemistry (London)

Related Research Articles

<span class="mw-page-title-main">Succinic acid</span> Dicarboxylic acid

Succinic acid is a dicarboxylic acid with the chemical formula (CH2)2(CO2H)2. In living organisms, succinic acid takes the form of an anion, succinate, which has multiple biological roles as a metabolic intermediate being converted into fumarate by the enzyme succinate dehydrogenase in complex 2 of the electron transport chain which is involved in making ATP, and as a signaling molecule reflecting the cellular metabolic state.

Hypoxia-inducible factors (HIFs) are transcription factors that respond to decreases in available oxygen in the cellular environment, or hypoxia. They also respond to instances of pseudohypoxia, such as thiamine deficiency. Both hypoxia and pseudohypoxia leads to impairment of adenosine triphosphate (ATP) production by the mitochondria.

<span class="mw-page-title-main">Beta helix</span>

A beta helix is a tandem protein repeat structure formed by the association of parallel beta sheet in a helical pattern with either two or three faces. The beta helix is a type of solenoid protein domain. The structure is stabilized by inter-strand hydrogen bonds, protein-protein interactions, and sometimes bound metal ions. Both left- and right-handed beta helices have been identified. These structures are distinct from jelly-roll folds, a different protein structure sometimes known as a "double-stranded beta helix".

<span class="mw-page-title-main">HIF1A</span> Protein-coding gene in the species Homo sapiens

Hypoxia-inducible factor 1-alpha, also known as HIF-1-alpha, is a subunit of a heterodimeric transcription factor hypoxia-inducible factor 1 (HIF-1) that is encoded by the HIF1A gene. The Nobel Prize in Physiology or Medicine 2019 was awarded for the discovery of HIF.

<span class="mw-page-title-main">Gamma-butyrobetaine dioxygenase</span> Protein-coding gene in the species Homo sapiens

Gamma-butyrobetaine dioxygenase is an enzyme that in humans is encoded by the BBOX1 gene. Gamma-butyrobetaine dioxygenase catalyses the formation of L-carnitine from gamma-butyrobetaine, the last step in the L-carnitine biosynthesis pathway. Carnitine is essential for the transport of activated fatty acids across the mitochondrial membrane during mitochondrial beta oxidation. In humans, gamma-butyrobetaine dioxygenase can be found in the kidney (high), liver (moderate), and brain. BBOX1 has recently been identified as a potential cancer gene based on a large-scale microarray data analysis.

<span class="mw-page-title-main">Phytanoyl-CoA dioxygenase</span> Class of enzymes

In enzymology, a phytanoyl-CoA dioxygenase (EC 1.14.11.18) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Procollagen-proline dioxygenase</span> Enzyme

Procollagen-proline dioxygenase, commonly known as prolyl hydroxylase, is a member of the class of enzymes known as alpha-ketoglutarate-dependent hydroxylases. These enzymes catalyze the incorporation of oxygen into organic substrates through a mechanism that requires alpha-Ketoglutaric acid, Fe2+, and ascorbate. This particular enzyme catalyzes the formation of (2S, 4R)-4-hydroxyproline, a compound that represents the most prevalent post-translational modification in the human proteome.

<span class="mw-page-title-main">EGLN1</span> Protein-coding gene in the species Homo sapiens

Hypoxia-inducible factor prolyl hydroxylase 2 (HIF-PH2), or prolyl hydroxylase domain-containing protein 2 (PHD2), is an enzyme encoded by the EGLN1 gene. It is also known as Egl nine homolog 1. PHD2 is a α-ketoglutarate/2-oxoglutarate-dependent hydroxylase, a superfamily non-haem iron-containing proteins. In humans, PHD2 is one of the three isoforms of hypoxia-inducible factor-proline dioxygenase, which is also known as HIF prolyl-hydroxylase.

<span class="mw-page-title-main">EGLN3</span> Protein-coding gene in the species Homo sapiens

Egl nine homolog 3 is a protein that in humans is encoded by the EGLN3 gene. ELGN3 is a member of the superfamily of alpha-ketoglutarate-dependent hydroxylases, which are non-haem iron-containing proteins.

<span class="mw-page-title-main">HIF1AN</span> Protein-coding gene in the species Homo sapiens

Hypoxia-inducible factor 1-alpha inhibitor (FIH) is a protein that in humans is encoded by the HIF1AN gene.

α-Hydroxyglutaric acid Chemical compound

α-Hydroxyglutaric acid is an alpha hydroxy acid form of glutaric acid.

<span class="mw-page-title-main">Dynamic combinatorial chemistry</span>

Dynamic combinatorial chemistry (DCC); also known as constitutional dynamic chemistry (CDC) is a method to the generation of new molecules formed by reversible reaction of simple building blocks under thermodynamic control. The library of these reversibly interconverting building blocks is called a dynamic combinatorial library (DCL). All constituents in a DCL are in equilibrium, and their distribution is determined by their thermodynamic stability within the DCL. The interconversion of these building blocks may involve covalent or non-covalent interactions. When a DCL is exposed to an external influence, the equilibrium shifts and those components that interact with the external influence are stabilised and amplified, allowing more of the active compound to be formed.

Hypoxia-inducible factor-proline dioxygenase (EC 1.14.11.29, HIF hydroxylase) is an enzyme with systematic name hypoxia-inducible factor-L-proline, 2-oxoglutarate:oxygen oxidoreductase (4-hydroxylating). This enzyme catalyses the following chemical reaction

Hypoxia-inducible factor-asparagine dioxygenase (EC 1.14.11.30, HIF hydroxylase) is an enzyme with systematic name hypoxia-inducible factor-L-asparagine, 2-oxoglutarate:oxygen oxidoreductase (4-hydroxylating). This enzyme catalyses the following chemical reaction:

hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2 hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2

<span class="mw-page-title-main">Avibactam</span> Chemical compound

Avibactam is a non-β-lactam β-lactamase inhibitor developed by Actavis jointly with AstraZeneca. A new drug application for avibactam in combination with ceftazidime was approved by the FDA in 2015 for treating complicated urinary tract (cUTI) and complicated intra-abdominal infections (cIAI) caused by antibiotic-resistant pathogens, including those caused by multidrug resistant Gram-negative bacterial pathogens.

Alpha-ketoglutarate-dependent hydroxylases are a major class of non-heme iron proteins that catalyse a wide range of reactions. These reactions include hydroxylation reactions, demethylations, ring expansions, ring closures, and desaturations. Functionally, the αKG-dependent hydroxylases are comparable to cytochrome P450 enzymes. Both use O2 and reducing equivalents as cosubstrates and both generate water.

<span class="mw-page-title-main">AlkB homolog 5, RNA demethylase</span> Protein-coding gene in the species Homo sapiens

RNA demethylase ALKBH5 is a protein that in humans is encoded by the ALKBH5 gene.

Factor Inhibiting HIF (FIH) Asparaginyl Hydroxylase Inhibitors inhibit the FIH pathway also catalyzed by Asparaginyl Hydroxylase inhibition. Before 2010s thought to be identical to HIF prolyl-hydroxylase pathway, studies have shown FIH to be the master regulator that controls HIF transcriptional activity in an oxygen-dependent manner. and that HIF prolyl-hydroxylase inhibitors may only minimally inhibit FIH. Skeletal muscle expresses 50-fold higher levels of FIH than other tissues.

Akane Kawamura is a Japanese chemist who is Professor of Chemical Biology at Newcastle University in the UK. Her research considers the chemistry of epigenetics. She was awarded the Royal Society of Chemistry Jeremy Knowles Award for her development of chemical probes to study biological processes.

Carmen Domene is a Spanish academic who is a professor of chemistry at the University of Bath. Her research makes use of computational simulations to understand biological systems and processes. She was awarded the 2020 International Society of Quantum Biology and Pharmacology Loew Award and the 2023 Royal Society of Chemistry Corday-Morgan Prize.

References

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  20. ↑ Loenarz, Christoph; Schofield, Christopher J. (1 March 2008). "Expanding chemical biology of 2-oxoglutarate oxygenases". Nature Chemical Biology. 4 (3): 152–156. doi:10.1038/nchembio0308-152. ISSN   1552-4450. PMID   18277970.
  21. ↑ McDonough, Michael A.; Li, Vivian; Flashman, Emily; Chowdhury, Rasheduzzaman; Mohr, Christopher; Liénard, Benoît M. R.; Zondlo, James; Oldham, Neil J.; Clifton, Ian J. (27 June 2006). "Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2)". Proceedings of the National Academy of Sciences. 103 (26): 9814–9819. Bibcode:2006PNAS..103.9814M. doi: 10.1073/pnas.0601283103 . ISSN   0027-8424. PMC   1502536 . PMID   16782814.
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  33. ↑ Church, Chris; Lee, Sheena; Bagg, Eleanor A. L.; McTaggart, James S.; Deacon, Robert; Gerken, Thomas; Lee, Angela; Moir, Lee; Mecinović, Jasmin (14 August 2009). "A Mouse Model for the Metabolic Effects of the Human Fat Mass and Obesity Associated FTO Gene". PLOS Genet. 5 (8): e1000599. doi: 10.1371/journal.pgen.1000599 . ISSN   1553-7404. PMC   2719869 . PMID   19680540.
  34. ↑ Mantri, Monica; Krojer, Tobias; Bagg, Eleanor A.; Webby, Celia J.; Butler, Danica S.; Kochan, Grazyna; Kavanagh, Kathryn L.; Oppermann, Udo; McDonough, Michael A. (13 August 2010). "Crystal Structure of the 2-Oxoglutarate- and Fe(II)-Dependent Lysyl Hydroxylase JMJD6". Journal of Molecular Biology. 401 (2): 211–222. doi:10.1016/j.jmb.2010.05.054. PMID   20685276.
  35. ↑ Clifton, Ian J.; McDonough, Michael A.; Ehrismann, Dominic; Kershaw, Nadia J.; Granatino, Nicolas; Schofield, Christopher J. (1 April 2006). "Structural studies on 2-oxoglutarate oxygenases and related double-stranded β-helix fold proteins". Journal of Inorganic Biochemistry. High-valent iron intermediates in biologyHigh-valent iron intermediates in biology. 100 (4): 644–669. doi:10.1016/j.jinorgbio.2006.01.024. PMID   16513174.
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