Back to Search
Start Over
Inhibition of the Oxygen-Sensing Asparaginyl Hydroxylase Factor Inhibiting Hypoxia-Inducible Factor: A Potential Hypoxia Response Modulating Strategy
- Source :
- Journal of medicinal chemistry. 64(11)
- Publication Year :
- 2021
-
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.
- Subjects :
- Gene isoform
Oxygenase
Alpha (ethology)
Hydroxylation
01 natural sciences
Hypoxia-Inducible Factor-Proline Dioxygenases
Mixed Function Oxygenases
Substrate Specificity
03 medical and health sciences
Hypoxia response
chemistry.chemical_compound
Downregulation and upregulation
Drug Discovery
Humans
p300-CBP Transcription Factors
030304 developmental biology
0303 health sciences
Chemistry
Metabolism
Hypoxia-Inducible Factor 1, alpha Subunit
0104 chemical sciences
Cell biology
Oxygen
Repressor Proteins
010404 medicinal & biomolecular chemistry
Hypoxia-inducible factors
Molecular Medicine
I-kappa B Proteins
Asparagine
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 64
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....aef6a8a62ab68e50395d85621eacd273