Figure 5
The regulation of HIF by the prolyl hydroxylase (PHD) enzyme, a putative oxygen sensor. The von Hippel-Lindau gene product (pVHL) interacts with HIF-1α and is required for the destruction of HIF-1α at the oxygen-dependent degradation domain (ODDD) under normoxic conditions. The HIF-pVHL interaction depends on both oxygen and iron availability (shown as O2 and Fe). Furthermore, HIF-1α-pVHL interaction requires enzymatic post-translational hydroxylation of HIF-1α at a single proline (shown as yellow circle labeled P564-OH). This prolyl hydroxylation also requires, besides oxygen and iron, a citric acid cycle intermediate, 2-oxoglutarate. Together with the HIF-induced activation of glucose- and iron-metabolism genes, hydroxylation creates a tight link between oxygen sensing and cellular control of metabolism. Cul-2, B, C and Rbx are signaling cofactors associated with VHL in the regulation of ODDD. Adapted from Jaakkola et al.[88].