Egl nine homolog 1

Definition:

Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF1B. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN1 is the most important isozyme under normoxia and, through regulating the stability of HIF1, involved in various hypoxia-influenced processes such as angiogenesis in retinal and cardiac functionality. Target proteins are preferentially recognized via a LXXLAP motif.

References:

[1]. Felipe R Lorenzo, et al. A genetic mechanism for Tibetan high-altitude adaptation. Nat Genet. 2014 Sep;46(9):951-6. [Content Brief]

[2]. Yun Su, et al. Prolyl hydroxylase-2 (PHD2) exerts tumor-suppressive activity in pancreatic cancer. Cancer. 2012 Feb 15;118(4):960-72. [Content Brief]

[3]. Ken-ichi Yasumoto, et al. Role of the intracellular localization of HIF-prolyl hydroxylases. Biochim Biophys Acta. 2009 May;1793(5):792-7. [Content Brief]

[4]. A C Epstein, et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001 Oct 5;107(1):43-54. [Content Brief]

[5]. Abdullah Ozer, et al. The candidate tumor suppressor ING4 represses activation of the hypoxia inducible factor (HIF). Proc Natl Acad Sci U S A. 2005 May 24;102(21):7481-6. [Content Brief]

[6]. Jianhe Huang, et al. Sequence determinants in hypoxia-inducible factor-1alpha for hydroxylation by the prolyl hydroxylases PHD1, PHD2, and PHD3. J Biol Chem. 2002 Oct 18;277(42):39792-800. [Content Brief]

[7]. Mircea Ivan, et al. Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13459-64. [Content Brief]

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