Reactome | Cytosolic PHD2,3 hydroxylates proline residues on HIF1A

Cytosolic PHD2,3 hydroxylates proline residues on HIF1A

Stable Identifier

R-HSA-1234177

Type

Reaction [transition]

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

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Cytosolic PHD2,3 hydroxylates proline residues on HIF1A

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Proline hydroxylases PHD2 (EGLN1) and PHD3 (EGLN3) located in the cytosol (Metzen et al. 2003) hydroxylate HIF1A at proline-402 and proline-564 (Bruick and McKnight 2001, Jaakkola et al. 2001, Ivan et al. 2001, Ivan et al. 2002, Berra et al. 2003, Hirsila et al. 2003, Appelhoff et al. 2004, Tuckerman et al. 2004, Fedulova et al. 2007, Tian et al. 2011). A portion of PHD3 (EGLN3) is also located in the nucleus (Rantanen et al. 2008). PHD1, PHD2, and PHD3 are each contained in a complex with LIMD1 and VHL (Foxler et al. 2012).
PHD activity is competitively inhibited by succinate (Selak et al, 2005; Pollard et al, 2005; Koivunen et al, 2007).

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
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
17182618	Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF Myllyharju, J, Remes, AM, Hirsilä, M, Hassinen, IE, Kivirikko, KI, Koivunen, P	J Biol Chem	2007
15987702	Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations Wortham, NC, Griffiths, JR, Moat, SJ, Pollard, PJ, Barclay, E, Barwell, J, Mitchell, M, Tomlinson, IP, Alam, NA, Hargreaves, IP, Poulsom, R, Dalgleish, A, Heales, SJ, Hodgson, SV, Hunt, T, Gleeson, MJ, McGrath, JA, Brière, JJ, Rustin, P, Chung, YL, Olpin, S	Hum Mol Genet	2005
15652751	Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase MacKenzie, ED, Boulahbel, H, Selak, MA, Pan, Y, Armour, SM, Watson, DG, Gottlieb, E, Mansfield, KD, Simon, MC, Thompson, CB	Cancer Cell	2005
22286099	The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity James, V, Webb, TM, Sharp, TV, Bjornsson, J, Foxler, DE, Longmore, GD, Petursdottir, TE, Constantin-Teodosiu, D, Ingvarsson, S, Wong, SC, Ratcliffe, PJ, Mee, M, Feng, Y, Bridge, KS	Nat. Cell Biol.	2012
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
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
18337469	Prolyl hydroxylase PHD3 activates oxygen-dependent protein aggregation Himanen, V, Metzen, E, Högel, H, Rantanen, K, Jaakkola, PM, Pursiheimo, J	Mol. Biol. Cell	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
11598268	A conserved family of prolyl-4-hydroxylases that modify HIF McKnight, SL, Bruick, RK	Science	2001
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