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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
11
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pubmed:dateCreated |
2004-3-8
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pubmed:databankReference |
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pubmed:abstractText |
The activity of hypoxia-inducible transcription factor HIF, an alphabeta heterodimer that has an essential role in adaptation to low oxygen availability, is regulated by two oxygen-dependent hydroxylation events. Hydroxylation of specific proline residues by HIF prolyl 4-hydroxylases targets the HIF-alpha subunit for proteasomal destruction, whereas hydroxylation of an asparagine in the C-terminal transactivation domain prevents its interaction with the transcriptional coactivator p300. The HIF asparaginyl hydroxylase is identical to a previously known factor inhibiting HIF (FIH). We report here that recombinant FIH has unique catalytic and inhibitory properties when compared with those of the HIF prolyl 4-hydroxylases. FIH was found to require particularly long peptide substrates so that omission of only a few residues from the N or C terminus of a 35-residue HIF-1alpha sequence markedly reduced its substrate activity. Hydroxylation of two HIF-2alpha peptides was far less efficient than that of the corresponding HIF-1alpha peptides. The K(m) of FIH for O(2) was about 40% of its atmospheric concentration, being about one-third of those of the HIF prolyl 4-hydroxylases but 2.5 times that of the type I collagen prolyl 4-hydroxylase. Several 2-oxoglutarate analogs were found to inhibit FIH but with distinctly different potencies from the HIF prolyl 4-hydroxylases. For example, the two most potent HIF prolyl 4-hydroxylase inhibitors among the compounds studied were the least effective ones for FIH. It should therefore be possible to develop specific small molecule inhibitors for the two enzyme classes involved in the hypoxia response.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/HIF1A protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/HIF1AN protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Hypoxia-Inducible Factor 1, alpha...,
http://linkedlifedata.com/resource/pubmed/chemical/Ketoglutaric Acids,
http://linkedlifedata.com/resource/pubmed/chemical/Mixed Function Oxygenases,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Oxygen,
http://linkedlifedata.com/resource/pubmed/chemical/Peptides,
http://linkedlifedata.com/resource/pubmed/chemical/Procollagen-Proline Dioxygenase,
http://linkedlifedata.com/resource/pubmed/chemical/Proline,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Repressor Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Trans-Activators,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/alpha-ketoglutaric acid
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
12
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pubmed:volume |
279
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
9899-904
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pubmed:dateRevised |
2011-8-29
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pubmed:meshHeading |
pubmed-meshheading:14701857-Animals,
pubmed-meshheading:14701857-Anoxia,
pubmed-meshheading:14701857-Binding Sites,
pubmed-meshheading:14701857-Catalysis,
pubmed-meshheading:14701857-Cell Line,
pubmed-meshheading:14701857-Dimerization,
pubmed-meshheading:14701857-Dose-Response Relationship, Drug,
pubmed-meshheading:14701857-Electrophoresis, Polyacrylamide Gel,
pubmed-meshheading:14701857-Humans,
pubmed-meshheading:14701857-Hypoxia-Inducible Factor 1, alpha Subunit,
pubmed-meshheading:14701857-Inhibitory Concentration 50,
pubmed-meshheading:14701857-Insects,
pubmed-meshheading:14701857-Ketoglutaric Acids,
pubmed-meshheading:14701857-Kinetics,
pubmed-meshheading:14701857-Mixed Function Oxygenases,
pubmed-meshheading:14701857-Molecular Sequence Data,
pubmed-meshheading:14701857-Nuclear Proteins,
pubmed-meshheading:14701857-Oxygen,
pubmed-meshheading:14701857-Peptides,
pubmed-meshheading:14701857-Procollagen-Proline Dioxygenase,
pubmed-meshheading:14701857-Proline,
pubmed-meshheading:14701857-Protein Binding,
pubmed-meshheading:14701857-Protein Structure, Tertiary,
pubmed-meshheading:14701857-Recombinant Proteins,
pubmed-meshheading:14701857-Repressor Proteins,
pubmed-meshheading:14701857-Time Factors,
pubmed-meshheading:14701857-Trans-Activators,
pubmed-meshheading:14701857-Transcription Factors
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pubmed:year |
2004
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pubmed:articleTitle |
Catalytic properties of the asparaginyl hydroxylase (FIH) in the oxygen sensing pathway are distinct from those of its prolyl 4-hydroxylases.
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pubmed:affiliation |
Collagen Research Unit, Biocenter Oulu and Department of Medical Biochemistry and Molecular Biology, University of Oulu, Finland.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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