Figure 1. Overview of the HIF system.

The figure shows the roles of HIFα NODD/CODD hydroxylation in the hypoxic response. Ordered ODD hydroxylation is tightly regulated in animals; NODD hydroxylation is more sensitive than CODD to hypoxia¹⁴,¹⁵. ODD hydroxylation significantly increases the affinity of hydroxylated HIFα for the VCB (VHL, elongins B and C) complex, thus signalling for HIFα degradation via proteosomal hydrolysis; the difference in k_d for hydroxylated versus non-hydroxylated CODD is ∼1,000-fold (33 nM versus 34 μM, respectively)³⁴. In response to hypoxia, HIFα escapes ODD hydroxylation and forms the αβ-heterodimeric HIF complex that activates the transcription of a gene array.