Cytosolic PHD2,3 hydroxylates proline residues on HIF1A

Stable Identifier
Reaction [transition]
Homo sapiens
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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
Catalyst Activity

peptidyl-proline 4-dioxygenase activity of PHD2,3:LIMD1,AJUBA,WTIP:VHL:EloB:EloC:CUL2:RBX1 [cytosol]

Orthologous Events
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