HIF-α亚单位,它包括HIF1A(Bruick和2001 McKnight的,Ivan等人,2001,Jaakkola等人,2001),HIF2A(珀西等人,2008,Furlow等人,2009),和HIF3A(Maynard等人,2003)那are hydroxylated at proline residues by the prolyl hydroxylases PHD1 (EGLN2), PHD2 (EGLN1), and PHD3 (EGLN3) (Bruick and McKnight 2001, Berra et al. 2003, Hirsila et al. 2003, Metzen et al. 2003, Tuckerman et al. 2004, Appelhoff et al. 2004, Fedulova et al. 2007, Tian et al. 2011). The reaction requires molecular oxygen as a substrate and so it is inhibited by hypoxia. PHD2 (EGLN1) is predominantly cytosolic (Metzen et al. 2003) and is the key determinant in the regulation of HIF-alpha subunits by oxygen (Berra et al. 2003).
在脯氨酸残基下羟基化的HIF-α亚基由VHL,含有ELONGINB,ELONGIN C,CUL2和RBX1的复合物中的E3泛素连接酶。VHL泛素HIF-α,导致蛋白水解的HIF-α的破坏。缺氧抑制脯氨酸羟基化和与VHL的相互作用,稳定HIF-α,其经过核并激活基因表达。