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Biochemistry. 2008 Oct 28;47(43):11165-7. doi: 10.1021/bi801624f. Epub 2008 Oct 4.

Biochemical characterization of human prolyl hydroxylase domain protein 2 variants associated with erythrocytosis.

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Department of Enzymology and Mechanistic Pharmacology, Oncology CEDD, GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA.


Prolyl hydroxylase domain proteins (PHD isozymes 1-3) regulate levels of the alpha-subunit of the hypoxia inducible factor (HIF) through proline hydroxylation, earmarking HIFalpha for proteosome-mediated degradation. Under hypoxic conditions, HIF stabilization leads to enhanced transcription and regulation of a multitude of processes, including erythropoiesis. Herein, we examine the biochemical characterization of PHD2 variants, Arg371His and Pro317Arg, identified from patients with familial erythrocytosis. The variants display differential effects on catalytic rate and substrate binding, implying that partial inhibition or selective inhibition with regard to HIFalpha isoforms of PHD2 could result in the phenotype displayed by patients with familial erythrocytosis.

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