Cytosolic HIF1AN (FIH1) hydroxylates asparagine residues of Hypoxia-inducible Factor Alpha (HIF1A,HIF2A)

Stable Identifier
R-HSA-1234164
Type
Reaction [transition]
Species
Homo sapiens
Compartment
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HIF1AN (FIH, FIH-1) forms a homodimer that hydroxylates an asparagine residue on HIF1A and HIF2A (Hewitson et al. 2002, Lando et al. 2002, Metzen et al. 2003, Koivunen et al. 2004, Lancaster et al. 2004). The hydroxylation of the asparagine interferes with the interaction between HIF1A/HIF2A and p300, a histone acetylase, and therefore inhibits the ability of HIF1A/2A to activate transcription of target genes (Lando et al. 2002). Because molecular oxygen is a substrate of the reaction, hypoxia is a negative regulator of this reaction and thereby increases transcriptional activation of target genes by HIF1A/2A.

Literature References
PubMed ID Title Journal Year
14701857 Catalytic properties of the asparaginyl hydroxylase (FIH) in the oxygen sensing pathway are distinct from those of its prolyl 4-hydroxylases

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

J Biol Chem 2004
11823643 Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch

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

Science 2002
12042299 Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family

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

J Biol Chem 2002
12080085 FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor

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

Genes Dev 2002
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
15239670 Disruption of dimerization and substrate phosphorylation inhibit factor inhibiting hypoxia-inducible factor (FIH) activity

Hewitson, KS, McDonough, MA, Aplin, RT, Lancaster, DE, Schofield, CJ, Pugh, CW, McNeill, LA, Ratcliffe, PJ

Biochem J 2004
Participants
Participates
Catalyst Activity

2-oxoglutarate-dependent dioxygenase activity of FIH1:AscH-:Fe2+ dimer [cytosol]

Orthologous Events
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