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Figure 2: Regulation of HIF-1α by Oxygen-Dependent Hydroxylation. HIF function is continuously regulated by the concentration of molecular oxygen, representing an essential part of physiological feedback loop. In this feedback loop, oxygen sensing is achieved by oxygen-dependent hydroxylation of specific amino acid residuals of HIF-α. Hydroxylation of two prolyl residuals leads to ubiquitination and proteasome-dependent degradation of HIF-α. Hydroxylation of an asparagine residual located at the CAD by FIH impairs its interaction with coactivator p300 or CBP, thus repressing the transactivation activity. Note that the hydroxylation reactions require ferrous ion and ascorbic acid as cofactors, and 2-oxoglutarate as cosubstrate.