L-ascorbic acid: A true substrate for HIF prolyl hydroxylase?
Article Details
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Osipyants AI, Poloznikov AA, Smirnova NA, Hushpulian DM, Khristichenko AY, Chubar TA, Zakhariants AA, Ahuja M, Gaisina IN, Thomas B, Brown AM, Gazaryan IG, Tishkov VI
L-ascorbic acid: A true substrate for HIF prolyl hydroxylase?
Biochimie. 2018 Apr;147:46-54. doi: 10.1016/j.biochi.2017.12.011. Epub 2017 Dec 28.
- PubMed ID
- 29289682 [ View in PubMed]
- Abstract
L-Ascorbate (L-Asc), but not D-isoascorbate (D-Asc) and N-acetylcysteine (NAC) suppress HIF1 ODD-luc reporter activation induced by various inhibitors of HIF prolyl hydroxylase (PHD). The efficiency of suppression by L-Asc was sensitive to the nature of HIF PHD inhibitor chosen for reporter activation. In particular, the inhibitors developed to compete with alpha-ketoglutarate (alphaKG), were less sensitive to suppression by the physiological range of L-Asc (40-100muM) than those having a strong iron chelation motif. Challenging those HIF activators in the reporter system with D-Asc demonstrated that the D-isomer, despite exhibiting the same reducing potency with respect to ferric iron, had almost no effect compared to L-Asc. Similarly, no effect on reporter activation was observed with cell-permeable reducing agent NAC up to 1mM. Docking of L-Asc and D-Asc acid into the HIF PHD2 crystal structure showed interference of Tyr310 with respect to D-Asc. This suggests that L-Asc is not merely a reducing agent preventing enzyme inactivation. Rather, the overall results identify L-Asc as a co-substrate of HIF PHD that may compete for the binding site of alphaKG in the enzyme active center. This conclusion is in agreement with the results obtained recently in cell-based systems for TET enzymes and jumonji histone demethylases, where L-Asc has been proposed to act as a co-substrate and not as a reducing agent preventing enzyme inactivation.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Ascorbic acid Prolyl 3-hydroxylase 1 Protein Humans UnknownCofactorDetails Ascorbic acid Prolyl 3-hydroxylase 2 Protein Humans UnknownCofactorDetails Ascorbic acid Prolyl 3-hydroxylase 3 Protein Humans UnknownCofactorDetails Ascorbic acid Prolyl 4-hydroxylase subunit alpha-1 Protein Humans UnknownCofactorDetails