Reaction: hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2 = hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2
Other name(s): HIF hydroxylase
Systematic name: hypoxia-inducible factor-L-asparagine, 2-oxoglutarate:oxygen oxidoreductase (4-hydroxylating)
Comments: Contains iron, and requires ascorbate. Catalyses hydroxylation of an asparagine in the C-terminal transcriptional activation domain of HIF-α, the α subunit of the transcriptional regulator HIF (hypoxia-inducible factor), which reduces its interaction with the transcriptional coactivator protein p300. The requirement of oxygen for the hydroxylation reaction enables animals to respond to hypoxia.
Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, PDB, CAS registry number:
References:
1. Mahon, P.C., Hirota, K. and Semenza, G.L. FIH-1: a novel protein that interacts with HIF-1α and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev. 15 (2001) 2675-2686. [PMID: 11641274]
2. Hewitson, K.S., McNeill, L.A., Riordan, M.V., Tian, Y.M., Bullock, A.N., Welford, R.W., Elkins, J.M., Oldham, N.J., Bhattacharya, S., Gleadle, J.M., Ratcliffe, P.J., Pugh, C.W. and Schofield, C.J. Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family. J. Biol. Chem. 277 (2002) 26351-26355. [PMID: 12042299]
4. Lando, D., Peet, D.J., Whelan, D.A., Gorman, J.J. and Whitelaw, M.L. Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science 295 (2002) 858-861. [PMID: 11823643]
5. Koivunen, P., Hirsila, M., Gunzler, V., Kivirikko, K.I. and Myllyharju, J. Catalytic properties of the asparaginyl hydroxylase (FIH) in the oxygen sensing pathway are distinct from those of its prolyl 4-hydroxylases. J. Biol. Chem. 279 (2004) 9899-9904. [PMID: 14701857]
6. Elkins, J.M., Hewitson, K.S., McNeill, L.A., Seibel, J.F., Schlemminger, I., Pugh, C.W., Ratcliffe, P.J. and Schofield, C.J. Structure of factor-inhibiting hypoxia-inducible factor (HIF) reveals mechanism of oxidative modification of HIF-1 α. J. Biol. Chem. 278 (2003) 1802-1806. [PMID: 12446723]