Oxygen is absolutely critical for the survival of mammalian cells. Hypoxia induced factor (HIF) is a transcriptional complex that plays a central role in mammalian oxygen homeostasis. There are 3-types of alpha subunits (HIF1-3alpha) and one HIF-beta subunits. However, the three HIF-alpha subunits are regulated by oxygen in a similar fashion, i.e. by regulated stabilization of the alpha-subunits. Under normal conditions, HIF-alpha Prolines are hydroxylated at Pro-402 and Pro-564. This allows binding of von Hippel-Lindau (VHL), the substrate recognition component of the E3 ubiquinated ligase complex, subsequent ubiquitination and degradation of HIF-alpha by the proteasome. Under hypoxic conditions, hydroxylation of HIF-alpha is inhibited and this prevents HIF-alpha degradation. The enzymes responsible for HIF-hydroxylation are known as HIF-prolyl hydroxylases (PHD1-3 or HPH1, HPH2, and HPH3). The three PHDs have been identified to hydroxylate the motif, LXXLAP* with *P being the hydroxyproline. PHD2 (human 426 aa, chromosome 1q42-q43, also known as Egl nine homolog 1, EGLN1, (Hypoxia-inducible factor prolyl hydroxylase 2) (HIF-prolyl hydroxylase 2) (HIF-PH2) (HPH-2) (Prolyl hydroxylase domain-containing protein 2) PHD2 (SM-20) (PNAS-118 / PNAS-137) is widely expressed. Alternatively spliced isoforms 2 is missing 337-358 aa. It is activated by hypoxia in some cells and tissues.
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