[HTML][HTML] Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF
P Koivunen, M Hirsil�, AM Remes, IE Hassinen…�- Journal of Biological�…, 2007 - ASBMB
The stability and transcriptional activity of the hypoxia-inducible factors (HIFs) are regulated
by two oxygen-dependent events that are catalyzed by three HIF prolyl 4-hydroxylases (HIF-
P4Hs) and one HIF asparaginyl hydroxylase (FIH). We have studied possible links between
metabolic pathways and HIF hydroxylases by analyzing the abilities of citric acid cycle
intermediates to inhibit purified human HIF-P4Hs and FIH. Fumarate and succinate were
identified as in vitro inhibitors of all three HIF-P4Hs, fumarate having K i values of 50–80 μm�…
by two oxygen-dependent events that are catalyzed by three HIF prolyl 4-hydroxylases (HIF-
P4Hs) and one HIF asparaginyl hydroxylase (FIH). We have studied possible links between
metabolic pathways and HIF hydroxylases by analyzing the abilities of citric acid cycle
intermediates to inhibit purified human HIF-P4Hs and FIH. Fumarate and succinate were
identified as in vitro inhibitors of all three HIF-P4Hs, fumarate having K i values of 50–80 μm�…