hypoxia-inducible factor-asparagine dioxygenase;
HIF hydroxylase

Oxidoreductases;
Acting on paired donors, with O2 as oxidant and incorporation or reduction of oxygen. The oxygen incorporated need not be derived from O2;
With 2-oxoglutarate as one donor, and incorporation of one atom of oxygen into each donor

hypoxia-inducible factor-L-asparagine, 2-oxoglutarate:oxygen oxidoreductase (4-hydroxylating)

hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2 = hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2

hypoxia-inducible factor-L-asparagine;
2-oxoglutarate [CPD:C00026];
O2 [CPD:C00007]

Contains iron, and requires ascorbate. Catalyses hydroxylation of an asparagine in the C-terminal transcriptional activation domain of HIF-alpha, the alpha 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.

1  [PMID:11641274]

Mahon PC, Hirota K, Semenza GL

FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity.

Genes. Dev. 15 (2001) 2675-86.

2  [PMID:12042299]

Hewitson KS, McNeill LA, Riordan MV, Tian YM, Bullock AN, Welford RW, Elkins JM, Oldham NJ, Bhattacharya S, Gleadle JM, Ratcliffe PJ, Pugh CW, Schofield CJ

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) 26351-5.

3  [PMID:12432100]

Dann CE 3rd, Bruick RK, Deisenhofer J

Structure of factor-inhibiting hypoxia-inducible factor 1: An asparaginyl hydroxylase involved in the hypoxic response pathway.

Proc. Natl. Acad. Sci. U. S. A. 99 (2002) 15351-6.

4  [PMID:11823643]

Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML

Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch.

Science. 295 (2002) 858-61.

5  [PMID:14701857]

Koivunen P, Hirsila M, Gunzler V, Kivirikko KI, 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) 9899-904.

6  [PMID:12446723]

Elkins JM, Hewitson KS, McNeill LA, Seibel JF, Schlemminger I, Pugh CW, Ratcliffe PJ, Schofield CJ

Structure of factor-inhibiting hypoxia-inducible factor (HIF) reveals mechanism of oxidative modification of HIF-1 alpha.

J. Biol. Chem. 278 (2003) 1802-6.