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Catalytic mechanism and substrate specificity of HIF prolyl hydroxylases

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Abstract

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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Abbreviations

β2AR:

β2-adrenergic receptor

bHLH:

basic helix-loop-helix structural motif

CBP:

CREB binding protein

DHB:

dihydroxybenzoate

DMOG:

dimethyloxalylglycine

FDA:

Food & Drug Administration

FIH:

factor inhibiting HIF

FRET:

fluorescence resonance energy transfer

HIF:

hypoxia-inducible factor

MIF:

macrophage migration inhibitory factor

NTAD:

N-terminal transactivation domain

ODD:

oxygen degradable domain

PAS:

a protein domain named after three proteins in which it occurs (Per, period circadian protein

Arnt:

aryl hydrocarbon receptor nuclear translocator protein

Sim:

single-minded protein)

PHD:

prolyl hydroxylase domain

TPEN:

N,N,N′,N′-tetra(2-pyridyl)-1,2-ethanediamine

VHL:

von Hippel-Lindau protein

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Authors and Affiliations

  1. Burke Medical Research Institute, 785 Mamaroneck Ave, White Plains, NY, 10605, USA

    N. A. Smirnova, R. E. Speer, R. R. Ratan & I. G. Gazaryan

  2. Department of Chemical Enzymology, Lomonosov Moscow State University, 119992, Moscow, Russia

    D. M. Hushpulian

  3. Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL, 60612, USA

    I. N. Gaisina

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  1. N. A. Smirnova
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  2. D. M. Hushpulian
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  6. I. G. Gazaryan
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Correspondence to I. G. Gazaryan.

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Published in Russian in Biokhimiya, 2012, Vol. 77, No. 10, pp. 1337–1349.

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Smirnova, N.A., Hushpulian, D.M., Speer, R.E. et al. Catalytic mechanism and substrate specificity of HIF prolyl hydroxylases. Biochemistry Moscow 77, 1108–1119 (2012). https://doi.org/10.1134/S0006297912100033

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