Oxygen homeostasis All of the major physiological systems participate in complex homeostatic mechanisms that regulate O2 supply and demand to maintain cellular oxygenation within a narrow range that balances the risks associated with O2 deficiency and excess.
Oxygen sensing by hydroxylation of HIF-1α The amino-terminal half of HIF-1α consists of basic helix-loop-helix (bHLH) and Per-ARNT-Sim homology (PAS) domains. The carboxy-terminal half contains the transactivation domains (TAD-N and TAD-C). The HIF-1α prolyl hydroxylases (HPH)/prolyl hydroxylase domain proteins (PHD) 1–3 hydroxylate Pro-402 and Pro-564. Factor inhibiting HIF-1 (FIH-1) hydroxylates Asn-803. Proline hydroxylation is required for the interaction of HIF-1α with the von Hippel-Lindau tumor-suppressor protein (VHL), which is the recognition component of an E3 ubiquitin-protein ligase that targets HIF-1α for proteasomal degradation. Asparagine hydroxylation prevents the interaction of HIF-1α with the coactivators CBP and p300. The enzymes, which contain Fe(II) at the active site, can be inactivated by desferrioxamine (DFX) and other iron chelators. O2 appears to be a rate-limiting substrate for the hydroxylases under physiological conditions, thus providing a mechanism for the direct regulation of the stability and activity of HIF-1α as a function of the cellular O2 concentration.