Reactome | Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha

Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha

Stable Identifier

R-HSA-1234176

Type

Pathway

Species

Homo sapiens

Compartment

cytosol, nucleoplasm

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Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha

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HIF-alpha subunits, comprising HIF1A (Bruick and McKnight 2001, Ivan et al. 2001, Jaakkola et al. 2001), HIF2A (Percy et al. 2008, Furlow et al. 2009), and HIF3A (Maynard et al. 2003), are hydroxylated at proline residues by the prolyl hydroxylases PHD1 (EGLN2), PHD2 (EGLN1), and PHD3 (EGLN3) (Bruick and McKnight 2001, Berra et al. 2003, Hirsila et al. 2003, Metzen et al. 2003, Tuckerman et al. 2004, Appelhoff et al. 2004, Fedulova et al. 2007, Tian et al. 2011). The reaction requires molecular oxygen as a substrate and so it is inhibited by hypoxia. PHD2 (EGLN1) is predominantly cytosolic (Metzen et al. 2003) and is the key determinant in the regulation of HIF-alpha subunits by oxygen (Berra et al. 2003).
HIF-alpha subunits hydroxylated at proline residues are bound by VHL, an E3 ubiquitin ligase in a complex containing ElonginB, Elongin C, CUL2, and RBX1. VHL ubiquitinates HIF-alpha, resulting in destruction of HIF-alpha by proteolysis. Hypoxia inhibits proline hydroxylation and interaction with VHL, stabilizing HIF-alpha, which transits to the nucleus and activates gene expression.

Literature References

PubMed ID	Title	Journal	Year
12538644	Multiple splice variants of the human HIF-3 alpha locus are targets of the von Hippel-Lindau E3 ubiquitin ligase complex Maynard, MA, Qi, H, Chung, J, Lee, EH, Kondo, Y, Hara, S, Conaway, RC, Conaway, JW, Ohh, M	J Biol Chem	2003
17434750	Expression and purification of catalytically active human PHD3 in Escherichia coli Fedulova, N, Hanrieder, J, Bergquist, J, Emrén, LO	Protein Expr Purif	2007
11292861	Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation Jaakkola, P, Mole, DR, Tian, YM, Wilson, MI, Gielbert, J, Gaskell, SJ, Kriegsheim, Av, Hebestreit, HF, Mukherji, M, Schofield, CJ, Maxwell, PH, Pugh, CW, Ratcliffe, PJ	Science	2001
15474027	Determination and comparison of specific activity of the HIF-prolyl hydroxylases Tuckerman, JR, Zhao, Y, Hewitson, KS, Tian, YM, Pugh, CW, Ratcliffe, PJ, Mole, DR	FEBS Lett	2004
12788921	Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor Hirsilä, M, Koivunen, P, Günzler, V, Kivirikko, KI, Myllyharju, J	J Biol Chem	2003
12351678	Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor Ivan, M, Haberberger, T, Gervasi, DC, Michelson, KS, Günzler, V, Kondo, K, Yang, H, Sorokina, I, Conaway, RC, Conaway, JW, Kaelin WG, Jr	Proc Natl Acad Sci U S A	2002
15247232	Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor Appelhoff, RJ, Tian, YM, Raval, RR, Turley, H, Harris, AL, Pugh, CW, Ratcliffe, PJ, Gleadle, JM	J Biol Chem	2004
19208626	Erythrocytosis-associated HIF-2alpha mutations demonstrate a critical role for residues C-terminal to the hydroxylacceptor proline Furlow, PW, Percy, MJ, Sutherland, S, Bierl, C, McMullin, MF, Master, SR, Lappin, TR	J Biol Chem	2009
11292862	HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing Ivan, M, Kondo, K, Yang, H, Kim, W, Valiando, J, Ohh, M, Salic, A, Asara, JM, Lane, WS, Kaelin WG, Jr	Science	2001
18184961	A gain-of-function mutation in the HIF2A gene in familial erythrocytosis Percy, MJ, Furlow, PW, Lucas, GS, Li, X, Lappin, TR, McMullin, MF	N Engl J Med	2008
12615973	Intracellular localisation of human HIF-1 alpha hydroxylases: implications for oxygen sensing Metzen, E, Berchner-Pfannschmidt, U, Stengel, P, Marxsen, JH, Stolze, I, Klinger, M, Huang, WQ, Wotzlaw, C, Hellwig-Bürgel, T, Jelkmann, W, Acker, H, Fandrey, J	J Cell Sci	2003
12912907	HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia Berra, E, Benizri, E, Ginouvès, A, Volmat, V, Roux, D, Pouysségur, J	EMBO J	2003
21335549	Differential sensitivity of HIF hydroxylation sites to hypoxia and hydroxylase inhibitors Tian, YM, Yeoh, KK, Lee, MK, Eriksson, T, Kessler, BM, Kramer, HB, Edelmann, MJ, Willam, C, Pugh, CW, Schofield, CJ, Ratcliffe, PJ	J Biol Chem	2011
11598268	A conserved family of prolyl-4-hydroxylases that modify HIF Bruick, RK, McKnight, SL	Science	2001