Substrate Selectivity Analyses of Factor Inhibiting Hypoxia-Inducible Factor

Authors

  • Dr. Ming Yang,

    1. Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA (UK)
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    • These authors contributed equally to this work.

  • Dr. Adam P. Hardy,

    1. Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA (UK)
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    • These authors contributed equally to this work.

  • Dr. Rasheduzzaman Chowdhury,

    1. Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA (UK)
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    • These authors contributed equally to this work.

  • Nikita D. Loik,

    1. Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA (UK)
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  • John S. Scotti,

    1. Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA (UK)
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  • Dr. James S. O. McCullagh,

    1. Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA (UK)
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  • Dr. Timothy D. W. Claridge,

    1. Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA (UK)
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  • Dr. Michael A. McDonough,

    1. Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA (UK)
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  • Dr. Wei Ge,

    Corresponding author
    1. Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA (UK)
    • Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA (UK)
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    • These authors contributed equally to this work.

  • Prof. Dr. Christopher J. Schofield

    Corresponding author
    1. Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA (UK)
    • Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA (UK)
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    • These authors contributed equally to this work.


  • We thank M. Jiang for amino acid standards; H. Tarhonskaya for the FIH specific activity measurement; the Wellcome Trust, the Biotechnology and Biological Sciences Research Council, and the European Research Council for funding and Diamond Light Source for access to beamline IO3.

Abstract

original image

Substrate specificity: Biochemical and crystallographic analyses reveal the hypoxia-inducible factor hydroxylase (FIH) as being promiscuous with respect to the residues that it can hydroxylate in β-position, which in addition to Asn, Asp, and His include Leu and Ser residues. The Ser substrate is oxidized to an epimeric β-geminal diol product (see picture).

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