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.
2009 – 2014: PI of ERC Advanced Investigator Grant SPA GA 2008 233240 (with Sir Peter Ratcliffe); Molecular Mechanism of Oxygen Sensing by Enzymes (MOOSE)
^
abHamed, Refaat B.; Gomez-Castellanos, J. Ruben; Henry, Luc; Ducho, Christian; McDonough, Michael A.; Schofield, Christopher J. (10 December 2012). "The enzymes of β-lactam biosynthesis". Natural Product Reports. 30 (1): 21–107.
doi:
10.1039/C2NP20065A.
ISSN1460-4752.
PMID23135477.
^
abHon, Wai-Ching; Wilson, Michael I.; Harlos, Karl; Claridge, Timothy D. W.; Schofield, Christopher J.; Pugh, Christopher W.; Maxwell, Patrick H.; Ratcliffe, Peter J.; Stuart, David I. (27 June 2002). "Structural basis for the recognition of hydroxyproline in HIF-1α by pVHL". Nature. 417 (6892): 975–978.
Bibcode:
2002Natur.417..975H.
doi:
10.1038/nature00767.
ISSN0028-0836.
PMID12050673.
S2CID4388644.
^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.
ISSN1552-4450.
PMID18277970.
^Aik, WeiShen; Demetriades, Marina; Hamdan, Muhammad K. K.; Bagg, Eleanor. A. L.; Yeoh, Kar Kheng; Lejeune, Clarisse; Zhang, Zhihong; McDonough, Michael A.; Schofield, Christopher J. (23 April 2013). "Structural Basis for Inhibition of the Fat Mass and Obesity Associated Protein (FTO)". Journal of Medicinal Chemistry. 56 (9): 3680–3688.
doi:
10.1021/jm400193d.
PMID23547775.
^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.
PMID20685276.
^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.
PMID16513174.
^Rose, Nathan R.; McDonough, Michael A.; King, Oliver N. F.; Kawamura, Akane; Schofield, Christopher J. (14 July 2011). "Inhibition of 2-oxoglutarate dependent oxygenases". Chemical Society Reviews. 40 (8): 4364–97.
doi:
10.1039/C0CS00203H.
ISSN1460-4744.
PMID21390379.
^Mecinović, Jasmin; Chowdhury, Rasheduzzaman; Flashman, Emily; Schofield, Christopher J. (15 October 2009). "Use of mass spectrometry to probe the nucleophilicity of cysteinyl residues of prolyl hydroxylase domain 2". Analytical Biochemistry. 393 (2): 215–221.
doi:
10.1016/j.ab.2009.06.029.
PMID19563769.
^Rydzik AM, Leung IK, Kochan GT, Thalhammer A, Oppermann U, Claridge TD, Schofield CJ (July 2012). "Development and application of a fluoride-detection-based fluorescence assay for γ-butyrobetaine hydroxylase". ChemBioChem. 13 (11): 1559–1563.
doi:
10.1002/cbic.201200256.
PMID22730246.
S2CID13956474.
^Thinnes, C. C.; Tumber, A.; Yapp, C.; Scozzafava, G.; Yeh, T.; Chan, M. C.; Tran, T. A.; Hsu, K.; Tarhonskaya, H. (8 October 2015). "Betti reaction enables efficient synthesis of 8-hydroxyquinoline inhibitors of 2-oxoglutarate oxygenases". Chemical Communications. 51 (84): 15458–15461.
doi:
10.1039/C5CC06095H.
ISSN1364-548X.
PMID26345662.
^van Berkel, Sander S.; Nettleship, Joanne E.; Leung, Ivanhoe K. H.; Brem, Jürgen; Choi, Hwanho; Stuart, David I.; Claridge, Timothy D. W.; McDonough, Michael A.; Owens, Raymond J. (15 August 2013). "Binding of (5 S )-Penicilloic Acid to Penicillin Binding Protein 3". ACS Chemical Biology. 8 (10): 2112–2116.
doi:
10.1021/cb400200h.
PMID23899657.
^MacKenzie, Alasdair K.; Kershaw, Nadia J.; Hernandez, Helena; Robinson, Carol V.; Schofield, Christopher J.; Andersson, Inger (19 January 2007). "Clavulanic Acid Dehydrogenase: Structural and Biochemical Analysis of the Final Step in the Biosynthesis of the β-Lactamase Inhibitor Clavulanic Acid † , ‡". Biochemistry. 46 (6): 1523–1533.
doi:
10.1021/bi061978x.
PMID17279617.
^Mackenzie, Alasdair K.; Valegård, Karin; Iqbal, Aman; Caines, Matthew E. C.; Kershaw, Nadia J.; Jensen, Susan E.; Schofield, Christopher J.; Andersson, Inger (19 February 2010). "Crystal Structures of an Oligopeptide-Binding Protein from the Biosynthetic Pathway of the β-Lactamase Inhibitor Clavulanic Acid". Journal of Molecular Biology. 396 (2): 332–344.
doi:
10.1016/j.jmb.2009.11.045.
PMID19941870.
^Liénard, Benoît M. R.; Horsfall, Louise E.; Galleni, Moreno; Frère, Jean-Marie; Schofield, Christopher J. (15 February 2007). "Inhibitors of the FEZ-1 metallo-β-lactamase". Bioorganic & Medicinal Chemistry Letters. 17 (4): 964–968.
doi:
10.1016/j.bmcl.2006.11.053.
PMID17157014.
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.
2009 – 2014: PI of ERC Advanced Investigator Grant SPA GA 2008 233240 (with Sir Peter Ratcliffe); Molecular Mechanism of Oxygen Sensing by Enzymes (MOOSE)
^
abHamed, Refaat B.; Gomez-Castellanos, J. Ruben; Henry, Luc; Ducho, Christian; McDonough, Michael A.; Schofield, Christopher J. (10 December 2012). "The enzymes of β-lactam biosynthesis". Natural Product Reports. 30 (1): 21–107.
doi:
10.1039/C2NP20065A.
ISSN1460-4752.
PMID23135477.
^
abHon, Wai-Ching; Wilson, Michael I.; Harlos, Karl; Claridge, Timothy D. W.; Schofield, Christopher J.; Pugh, Christopher W.; Maxwell, Patrick H.; Ratcliffe, Peter J.; Stuart, David I. (27 June 2002). "Structural basis for the recognition of hydroxyproline in HIF-1α by pVHL". Nature. 417 (6892): 975–978.
Bibcode:
2002Natur.417..975H.
doi:
10.1038/nature00767.
ISSN0028-0836.
PMID12050673.
S2CID4388644.
^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.
ISSN1552-4450.
PMID18277970.
^Aik, WeiShen; Demetriades, Marina; Hamdan, Muhammad K. K.; Bagg, Eleanor. A. L.; Yeoh, Kar Kheng; Lejeune, Clarisse; Zhang, Zhihong; McDonough, Michael A.; Schofield, Christopher J. (23 April 2013). "Structural Basis for Inhibition of the Fat Mass and Obesity Associated Protein (FTO)". Journal of Medicinal Chemistry. 56 (9): 3680–3688.
doi:
10.1021/jm400193d.
PMID23547775.
^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.
PMID20685276.
^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.
PMID16513174.
^Rose, Nathan R.; McDonough, Michael A.; King, Oliver N. F.; Kawamura, Akane; Schofield, Christopher J. (14 July 2011). "Inhibition of 2-oxoglutarate dependent oxygenases". Chemical Society Reviews. 40 (8): 4364–97.
doi:
10.1039/C0CS00203H.
ISSN1460-4744.
PMID21390379.
^Mecinović, Jasmin; Chowdhury, Rasheduzzaman; Flashman, Emily; Schofield, Christopher J. (15 October 2009). "Use of mass spectrometry to probe the nucleophilicity of cysteinyl residues of prolyl hydroxylase domain 2". Analytical Biochemistry. 393 (2): 215–221.
doi:
10.1016/j.ab.2009.06.029.
PMID19563769.
^Rydzik AM, Leung IK, Kochan GT, Thalhammer A, Oppermann U, Claridge TD, Schofield CJ (July 2012). "Development and application of a fluoride-detection-based fluorescence assay for γ-butyrobetaine hydroxylase". ChemBioChem. 13 (11): 1559–1563.
doi:
10.1002/cbic.201200256.
PMID22730246.
S2CID13956474.
^Thinnes, C. C.; Tumber, A.; Yapp, C.; Scozzafava, G.; Yeh, T.; Chan, M. C.; Tran, T. A.; Hsu, K.; Tarhonskaya, H. (8 October 2015). "Betti reaction enables efficient synthesis of 8-hydroxyquinoline inhibitors of 2-oxoglutarate oxygenases". Chemical Communications. 51 (84): 15458–15461.
doi:
10.1039/C5CC06095H.
ISSN1364-548X.
PMID26345662.
^van Berkel, Sander S.; Nettleship, Joanne E.; Leung, Ivanhoe K. H.; Brem, Jürgen; Choi, Hwanho; Stuart, David I.; Claridge, Timothy D. W.; McDonough, Michael A.; Owens, Raymond J. (15 August 2013). "Binding of (5 S )-Penicilloic Acid to Penicillin Binding Protein 3". ACS Chemical Biology. 8 (10): 2112–2116.
doi:
10.1021/cb400200h.
PMID23899657.
^MacKenzie, Alasdair K.; Kershaw, Nadia J.; Hernandez, Helena; Robinson, Carol V.; Schofield, Christopher J.; Andersson, Inger (19 January 2007). "Clavulanic Acid Dehydrogenase: Structural and Biochemical Analysis of the Final Step in the Biosynthesis of the β-Lactamase Inhibitor Clavulanic Acid † , ‡". Biochemistry. 46 (6): 1523–1533.
doi:
10.1021/bi061978x.
PMID17279617.
^Mackenzie, Alasdair K.; Valegård, Karin; Iqbal, Aman; Caines, Matthew E. C.; Kershaw, Nadia J.; Jensen, Susan E.; Schofield, Christopher J.; Andersson, Inger (19 February 2010). "Crystal Structures of an Oligopeptide-Binding Protein from the Biosynthetic Pathway of the β-Lactamase Inhibitor Clavulanic Acid". Journal of Molecular Biology. 396 (2): 332–344.
doi:
10.1016/j.jmb.2009.11.045.
PMID19941870.
^Liénard, Benoît M. R.; Horsfall, Louise E.; Galleni, Moreno; Frère, Jean-Marie; Schofield, Christopher J. (15 February 2007). "Inhibitors of the FEZ-1 metallo-β-lactamase". Bioorganic & Medicinal Chemistry Letters. 17 (4): 964–968.
doi:
10.1016/j.bmcl.2006.11.053.
PMID17157014.