Oxygen sensors, hydroxylases

Appelhoff RJ, Tian YM, Raval RR, Turley H, Hands AL, Pugh CW, Ratcliffe PJ, Gleadle JM. Differential function of the prolyl hydroxylases, PHDl, 2 and 3 in the regulation of hypoxia inducible factor (HIF). J. Biol. Chem. 2004 279 38458-38465. Berra E, Benizri E, Ginouves A, Vofinat V, Roux D, Pouysse-gur J. HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-la in normoxia. EMBO J. 2003 22 4082-4090. 

Figure 1 Role of prolyl hydroxylases as an oxygen-sensor regulating HIF activation. In the presence of oxygen, PHD enzymes convert specific prolyl residues in HIF-a chains to hydroxyproline. The enzymes require iron as a cofactor. Modified HIF-a chains are captured hy the pVHL ubiquitin E3 ligase complex, ubiquitylated, and destroyed by the proteasome. Under reduced oxygenation, HIF-a rapidly accumulates, enters the nucleus, dimerizes with a jS subunit, recruits coactivators, and activates transcription of genes with hypoxic response elements (HRE). HYP, hydroxyproline.

A prolyl hydroxylase-based oxygen-sensing system fits well with key attributes of the HIF system— notably that iron chelators or cobaltous ions mimic the effect of hypoxia. In particular, iron chelators remove the ferrous iron atom from the active site of the enzyme, preventing the conversion of HIF alpha subunits and thereby mimicking hypoxia. Exposure to cobaltous ions results in substitution of cobalt for the iron at the active center, also disabling the enzyme. Thus, the prolyl hydroxylase sensor accommodates the effects of cobalt and iron chelators without requiring the sensor itself to be turning over rapidly. 

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