Catalytic mechanism and substrate specificity of HIF prolyl hydroxylases

This review describes the catalytic mechanism, substrate specificity, and structural peculiarities of alpha-ketoglutarate dependent nonheme iron dioxygenases catalyzing prolyl hydroxylation of hypoxia-inducible factor (HIF). Distinct localization and regulation of three isoforms of HIF prolyl hydrox...

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Bibliographic Details
Published in:Biochemistry (Moscow) 2012-10, Vol.77 (10), p.1108-1119
Main Authors: Smirnova, N. A., Hushpulian, D. M., Speer, R. E., Gaisina, I. N., Ratan, R. R., Gazaryan, I. G.
Format: Article
Language:English
Subjects:
Analysis
Biochemistry
Biomedical and Life Sciences
Biomedicine
Bioorganic Chemistry
Catalysis
Cellular biology
Crystal structure
Drug Design
Enzymes
Hydroxylases
Hydroxylation
Hypoxia
Hypoxia-Inducible Factor 1 - chemistry
Hypoxia-Inducible Factor 1 - metabolism
Ketoglutaric Acids - chemistry
Ketoglutaric Acids - metabolism
Life Sciences
Microbiology
Procollagen-Proline Dioxygenase - chemistry
Procollagen-Proline Dioxygenase - metabolism
Protein Isoforms
Review
RNA
Substrate Specificity
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Summary:This review describes the catalytic mechanism, substrate specificity, and structural peculiarities of alpha-ketoglutarate dependent nonheme iron dioxygenases catalyzing prolyl hydroxylation of hypoxia-inducible factor (HIF). Distinct localization and regulation of three isoforms of HIF prolyl hydroxylases suggest their different roles in cells. The recent identification of novel substrates other than HIF, namely β2-adrenergic receptor and the large subunit of RNA polymerase II, places these enzymes in the focus of drug development efforts aimed at development of isoform-specific inhibitors. The challenges and prospects of designing isoform-specific inhibitors are discussed.
ISSN:0006-2979
1608-3040
DOI:10.1134/S0006297912100033