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Title
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Selective inhibition of factor inhibiting hypoxia-inducible factor.
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Authors
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M.A.McDonough,
L.A.McNeill,
M.Tilliet,
C.A.Papamicaël,
Q.Y.Chen,
B.Banerji,
K.S.Hewitson,
C.J.Schofield.
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Ref.
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J Am Chem Soc, 2005,
127,
7680-7681.
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PubMed id
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Abstract
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A set of four non-heme iron(II) and 2-oxoglutarate-dependent enzymes catalyze
the post-translational modification of a transcription factor, hypoxia inducible
factor (HIF), that mediates the hypoxic response in animals. Hydroxylation of
HIF both causes its degradation and limits its activity. We describe how the use
of structural data coupled to solid-phase synthesis led to the discovery of a
selective inhibitor of one of the HIF hydroxylases. The inhibitor
N-oxalyl-d-phenylalanine was shown to inhibit the HIF asparaginyl hydroxylase
(FIH) but not a HIF prolyl hydroxylase. A crystal structure of the inhibitor
complexed to FIH reveals that it binds in the 2OG and, likely, in the dioxygen
binding site. The results will help to enable the modulation of the hypoxic
response for the up-regulation of specific genes of biomedical importance, such
as erythropoietin and vascular endothelial growth factor.
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