REVIEW: Catalytic Mechanism and Substrate Specificity of HIF Prolyl Hydroxylases

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N. A. Smirnova¹, D. M. Hushpulian², R. E. Speer¹, I. N. Gaisina³, R. R. Ratan¹, and I. G. Gazaryan^1*

¹Burke Medical Research Institute, 785 Mamaroneck Ave, White Plains NY 10605, USA; fax: (914) 597-2225; E-mail: nsmirnova@burke.org; respeer@gmail.com; rratan@burke.org; igazarya@burke.org

²Department of Chemical Enzymology, Lomonosov Moscow State University, 119992 Moscow, Russia; fax: (495) 939-3208; E-mail: hushpulian@gmail.com

³Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago IL 60612, USA; fax: (312) 996-7107; E-mail: igaysina@uic.edu

^* To whom correspondence should be addressed.

Received April 28, 2012

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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.

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KEY WORDS: hypoxia-inducible factor, alpha-ketoglutarate-dependent iron dioxygenase, crystal structure, computer modeling, inhibitor binding mode

DOI: 10.1134/S0006297912100033

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