CATALYTIC MECHANISM AND SUBSTRATE SPECIFICITY OF HIF PROLYL HYDROXYLASES
This review describes the catalytic mechanism, substrate specificity, and structural features of alpha-ketoglutarate- dependent non-heme 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 the cell. The recent identification of novel substrates other than HIF, namely beta-adrenergic receptor and the large subunit of RNA polymerase II, places these enzymes in focus of drug development efforts aimed at development of isoform-spe- cific inhibitors. The challenges and prospects of designing isoform-specific inhibitors are discussed.