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Báo cáo khoa học: Evidence for the slow reaction of hypoxia-inducible factor prolyl hydroxylase 2 with oxygen

The response of animals to hypoxia is mediated by the hypoxia-inducible transcription factor. Human hypoxia-inducible factor is regulated by four Fe(II)- and 2-oxoglutarate-dependent oxygenases: prolyl hydroxylase domain enzymes 1–3 catalyse hydroxylation of two prolyl-residues in hypoxia-inducible factor, triggering its degradation by the proteasome. | ỊFEBS Journal Evidence for the slow reaction of hypoxia-inducible factor prolyl hydroxylase 2 with oxygen Emily Flashman1 Lee M. Hoffart2 Refaat B. Hamed1 3 J. Martin Bollinger Jr2 Carsten Krebs2 and Christopher J. Schofield1 1 Department of Chemistry and Oxford Centre for Integrative Systems Biology Oxford UK 2 Department of Chemistry and Department of Biochemistry and Molecular Biology The Pennsylvania State University University Park PA USA 3 Department of Pharmacognosy Faculty of Pharmacy Assiut University Egypt Keywords 2-oxoglutarate hypoxia-inducible factor oxygen oxygenase prolyl hydroxylase spectroscopy Correspondence C. J. Schofield Department of Chemistry and Oxford Centre for Integrative Systems Biology 12 Mansfield Road Oxford OX1 3TA UK Fax 44 1865 275674 Tel 44 1865 275625 E-mail christopher.schofield@chem. ox.ac.uk C. Krebs and J. M. Bollinger Jr. Department of Chemistry and Department of Biochemistry and Molecular Biology The Pennsylvania State University University Park PA16802 USA Fax 1 814 865 2927 Tel 1 814 865 6089 E-mail ckrebs@psu.edu and Fax 1 814 863 7024 Tel 1 814 863 5707 E-mail jmb21@psu.edu Received 10 June 2010 revised 29 July 2010 accepted 2 August 2010 doi 10.1111 j.1742-4658.2010.07804.x The response of animals to hypoxia is mediated by the hypoxia-inducible transcription factor. Human hypoxia-inducible factor is regulated by four Fe II - and 2-oxoglutarate-dependent oxygenases prolyl hydroxylase domain enzymes 1-3 catalyse hydroxylation of two prolyl-residues in hypoxia-inducible factor triggering its degradation by the proteasome. Factor inhibiting hypoxia-inducible factor catalyses the hydroxylation of an asparagine-residue in hypoxia-inducible factor inhibiting its transcriptional activity. Collectively the hypoxia-inducible factor hydroxylases negatively regulate hypoxia-inducible factor in response to increasing oxygen concentration. Prolyl hydroxylase domain 2 is the most important oxygen sensor in human cells however the .