HIF prolyl hydroxylases

McNeill LA, Hewitson KS, Gleadle J, Horsfall LE, Oldham NJ, Maxwell P, Pugh CW, Ratcliffe PJ, Schofield CJ. The use of dioxygen by HIF prolyl hydroxylase (PHDl). Bioorg. Med. 

Flashman E, Bagg EAL, Chowdhury R, Mecinovic J, Loenarz C, McDonough MA, Hewitson KS, Schofield CJ. Kinetic rationale for selectivity towards the N- and C-terminal oxygen dependent degradation domain substrates mediated by a loop region of HIF prolyl hydroxylases. J. Biol. Chem. 2008 582 434-438. 

Appelhoff RJ, Tian YM, Raval RR, Turley H, Hands AL, Pugh CW, Ratcliffe PJ, Gleadle JM. Differential function of the prolyl hydroxylases, PHDl, 2 and 3 in the regulation of hypoxia inducible factor (HIF). J. Biol. Chem. 2004 279 38458-38465. Berra E, Benizri E, Ginouves A, Vofinat V, Roux D, Pouysse-gur J. HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-la in normoxia. EMBO J. 2003 22 4082-4090. 

Landazuri MO, Vara-Vega A, Viton M, Cuevas Y, del Peso L. Analysis of HIF-prolyl hydroxylases binding to substrates. Biochem. Biophys. Res. Commun. 2006 351 313-320. 

Ratcliffe PJ, Mole DR. Determination and comparison of specific activity of the HIF-prolyl hydroxylases. FEBS Lett. 2004 576 145-150. 108. 

Maxwell P, Salnikow K. HIF-1 an oxygen and metal responsive transcription factor. Cancer Biol. Ther. 2004 3 29-35. Schlemminger I, Mole DR, McNeill LA, Dhanda A, Hewitson KS, Tian YM, Ratcliffe PJ, Pugh CW, Schofield CJ. Analogues of dealanylalahopcin are inhibitors of human HIF prolyl hydroxylases. Bioorg. Med. Chem. Lett. 2003 13 1451. 

Three different, but closely related, genes encoding mammalian HIF prolyl hydroxylase enzymes have been identified in the human genome, which are also present in Mus musculus, referred to as PHDl, PHD2, and PHDS (Table 1) (10,56). In vitro experiments have established that each fimctions as a prolyl hydroxylase for HIF-1 alpha and have demonstrated some selectivity for the two different hydroxylation sites within HIF-1 alpha (10). As yet, mammalian cells with defects in these enzymes have not been identified, and it is not clear how much redundancy there may be in the system. What is clear is that the rate of the enzymatic reaction in cell extracts is sensitive to the amount of oxygen (10). 

Importantly, HIF prolyl hydroxylase inhibitors might antagonize other enzymes in the overall class of 2-oxoglutarate-dependent dioxygenases. Conversely, it is possible that compounds developed as inhibitors of other enzymes in the class, such as collagen prolyl 4-hydroxylase, may have significant activity as inhibitors of PHD enzymes. To target the HIF system with precision it will clearly be important to develop inhibitors that are specific for HIF prolyl hydroxylase. 

Wang, Q.,Gou,G.,Guenzler,V., eta/. (2004) Stimulation of erythropoiesis and treatment of anemia in rodents by oral administration of FG-2216, a novel HIF-prolyl hydroxylase inhibitor./owma/ of the American Society of Nephrology JASN, 15,773A. 

Hsieh, M.M., Linde, N.S.,Wynter,A., eta/. (2007) HIF prolyl hydroxylase inhibition results in endogenous erythropoietin induction, erythrocytosis, and modest fetal hemoglobin expression in rhesus macaques. Blood, 110, 2140-2147. 

Molidustat (BAY 85-3934) is a novel inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase (PH), which stimulates erythropoietin (EPO) production and the formation of red blood cells. Phase I data have shown that inhibition of HIF-PH by Molidustat results in an increase in endogenous production of EPO [136]. Molidustat is currently under clinical trials at Bayer for the treatment of patients suffering from renal anemia due to chronic kidney disease. 

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