Inhibition of the Oxygen-Sensing Asparaginyl Hydroxylase Factor Inhibiting Hypoxia-Inducible Factor: A Potential Hypoxia Response Modulating Strategy
- PMID: 34029087
- DOI: 10.1021/acs.jmedchem.1c00415
Inhibition of the Oxygen-Sensing Asparaginyl Hydroxylase Factor Inhibiting Hypoxia-Inducible Factor: A Potential Hypoxia Response Modulating Strategy
Abstract
Factor inhibiting hypoxia-inducible factor (FIH) is a JmjC domain 2-oxogluarate and Fe(II)-dependent oxygenase that catalyzes hydroxylation of specific asparagines in the C-terminal transcriptional activation domain of hypoxia-inducible factor alpha (HIF-α) isoforms. This modification suppresses the transcriptional activity of HIF by reducing its interaction with the transcriptional coactivators p300/CBP. By contrast with inhibition of the HIF prolyl hydroxylases (PHDs), inhibitors of FIH, which accepts multiple non-HIF substrates, are less studied; they are of interest due to their potential ability to alter metabolism (either in a HIF-dependent and/or -independent manner) and, provided HIF is upregulated, to modulate the course of the HIF-mediated hypoxic response. Here we review studies on the mechanism and inhibition of FIH. We discuss proposed biological roles of FIH including its regulation of HIF activity and potential roles of FIH-catalyzed oxidation of non-HIF substrates. We highlight potential therapeutic applications of FIH inhibitors.
Similar articles
-
Kinetic Investigations of the Role of Factor Inhibiting Hypoxia-inducible Factor (FIH) as an Oxygen Sensor.J Biol Chem. 2015 Aug 7;290(32):19726-42. doi: 10.1074/jbc.M115.653014. Epub 2015 Jun 25. J Biol Chem. 2015. PMID: 26112411 Free PMC article.
-
Catalytic properties of the asparaginyl hydroxylase (FIH) in the oxygen sensing pathway are distinct from those of its prolyl 4-hydroxylases.J Biol Chem. 2004 Mar 12;279(11):9899-904. doi: 10.1074/jbc.M312254200. Epub 2003 Dec 29. J Biol Chem. 2004. PMID: 14701857
-
Substrate requirements of the oxygen-sensing asparaginyl hydroxylase factor-inhibiting hypoxia-inducible factor.J Biol Chem. 2004 Apr 2;279(14):14391-7. doi: 10.1074/jbc.M313614200. Epub 2004 Jan 20. J Biol Chem. 2004. PMID: 14734545
-
Protein Hydroxylation by Hypoxia-Inducible Factor (HIF) Hydroxylases: Unique or Ubiquitous?Cells. 2019 Apr 26;8(5):384. doi: 10.3390/cells8050384. Cells. 2019. PMID: 31035491 Free PMC article. Review.
-
Regulation of HIF: asparaginyl hydroxylation.Novartis Found Symp. 2006;272:37-49; discussion 49-53, 131-40. Novartis Found Symp. 2006. PMID: 16686428 Review.
Cited by
-
Hypoxia-induced signaling in the cardiovascular system: pathogenesis and therapeutic targets.Signal Transduct Target Ther. 2023 Nov 20;8(1):431. doi: 10.1038/s41392-023-01652-9. Signal Transduct Target Ther. 2023. PMID: 37981648 Free PMC article. Review.
-
Structure-guided optimisation of N-hydroxythiazole-derived inhibitors of factor inhibiting hypoxia-inducible factor-α.Chem Sci. 2023 Oct 27;14(43):12098-12120. doi: 10.1039/d3sc04253g. eCollection 2023 Nov 8. Chem Sci. 2023. PMID: 37969593 Free PMC article.
-
Factor-inhibiting HIF (FIH) promotes lung cancer progression.JCI Insight. 2023 Oct 23;8(20):e167394. doi: 10.1172/jci.insight.167394. JCI Insight. 2023. PMID: 37707961 Free PMC article.
-
Biochemical and Structural Insights into FIH-Catalysed Hydroxylation of Transient Receptor Potential Ankyrin Repeat Domains.Chembiochem. 2023 Feb 14;24(4):e202200576. doi: 10.1002/cbic.202200576. Epub 2023 Jan 9. Chembiochem. 2023. PMID: 36448355 Free PMC article.
-
NAXE deficiency: A neurometabolic disorder of NAD(P)HX repair amenable for metabolic correction.Mol Genet Metab. 2022 Jun;136(2):101-110. doi: 10.1016/j.ymgme.2022.04.003. Epub 2022 Apr 18. Mol Genet Metab. 2022. PMID: 35637064 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Miscellaneous
