Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha

Stable Identifier
Homo sapiens
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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
17434750 Expression and purification of catalytically active human PHD3 in Escherichia coli

Bergquist, J, Fedulova, N, Hanrieder, J, Emrén, LO

Protein Expr Purif 2007
12538644 Multiple splice variants of the human HIF-3 alpha locus are targets of the von Hippel-Lindau E3 ubiquitin ligase complex

Lee, EH, Chung, J, Maynard, MA, Qi, H, Ohh, M, Conaway, JW, Kondo, Y, Hara, S, Conaway, RC

J Biol Chem 2003
11292861 Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation

Gielbert, J, Gaskell, SJ, Maxwell, PH, Mukherji, M, Pugh, CW, Mole, DR, Kriegsheim, Av, Jaakkola, P, Tian, YM, Wilson, MI, Hebestreit, HF, Schofield, CJ, Ratcliffe, PJ

Science 2001
15474027 Determination and comparison of specific activity of the HIF-prolyl hydroxylases

Tuckerman, JR, Mole, DR, Hewitson, KS, Tian, YM, Zhao, Y, Pugh, CW, Ratcliffe, PJ

FEBS Lett 2004
12788921 Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor

Hirsilä, M, Günzler, V, Koivunen, P, Myllyharju, J, Kivirikko, KI

J Biol Chem 2003
12351678 Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor

Günzler, V, Sorokina, I, Gervasi, DC, Haberberger, T, Ivan, M, Kaelin WG, Jr, Kondo, K, Conaway, JW, Yang, H, Michelson, KS, Conaway, RC

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

Gleadle, JM, Tian, YM, Raval, RR, Harris, AL, Turley, H, Pugh, CW, Ratcliffe, PJ, Appelhoff, RJ

J Biol Chem 2004
19208626 Erythrocytosis-associated HIF-2alpha mutations demonstrate a critical role for residues C-terminal to the hydroxylacceptor proline

McMullin, MF, Furlow, PW, Percy, MJ, Lappin, TR, Bierl, C, Master, SR, Sutherland, S

J Biol Chem 2009
11292862 HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing

Lane, WS, Asara, JM, Kim, W, Salic, A, Valiando, J, Ivan, M, Kaelin WG, Jr, Ohh, M, Kondo, K, Yang, H

Science 2001
18184961 A gain-of-function mutation in the HIF2A gene in familial erythrocytosis

McMullin, MF, Furlow, PW, Li, X, Lucas, GS, Percy, MJ, Lappin, TR

N Engl J Med 2008
12615973 Intracellular localisation of human HIF-1 alpha hydroxylases: implications for oxygen sensing

Stengel, P, Klinger, M, Acker, H, Hellwig-Bürgel, T, Fandrey, J, Wotzlaw, C, Metzen, E, Berchner-Pfannschmidt, U, Huang, WQ, Marxsen, JH, Stolze, I, Jelkmann, W

J Cell Sci 2003
12912907 HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia

Benizri, E, Pouysségur, J, Ginouvès, A, Volmat, V, Roux, D, Berra, E

EMBO J 2003
21335549 Differential sensitivity of HIF hydroxylation sites to hypoxia and hydroxylase inhibitors

Willam, C, Lee, MK, Yeoh, KK, Tian, YM, Edelmann, MJ, Kessler, BM, Kramer, HB, Schofield, CJ, Pugh, CW, Ratcliffe, PJ, Eriksson, T

J Biol Chem 2011
11598268 A conserved family of prolyl-4-hydroxylases that modify HIF

McKnight, SL, Bruick, RK

Science 2001
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