L-ascorbic acid: a true substrate for HIF prolyl hydroxylase?

Osipyants, A.I.; Poloznikov, A.A.; Smirnova, N.A.; Hushpulian, D.M.; Khristichenko, A.Y.; Chubar, T.A.; Zakhariants, A.A.; Gaisina, I.N.; Brown, A.M.; Gazaryan, I.G.; Tishkov, V.I.

Авторы: Osipyants A.I., Poloznikov A.A., Smirnova N.A., Hushpulian D.M., Khristichenko A.Yu, Chubar T.A., Zakhariants A.A., Gaisina I.N., Brown A.M., Gazaryan I.G., Tishkov V.I.
Журнал: Biochimie
Том: 147
Номер: 1
Год издания: 2018
Издательство: Elsevier BV
Местоположение издательства: Netherlands
Первая страница: 46
Последняя страница: 54
DOI: 10.1016/j.biochi.2017.12.011
Аннотация: The effect of L-ascorbate, D-isoascorbate and N-acetylcysteine (NAC) on the HIF1 ODD-luc reporter activation by various inhibitors of HIF prolyl hydroxylase was analyzed. The inhibition of reporter activation by L-ascorbic acid was sensitive to the nature of HIF prolyl hydroxylase inhibitor chosen for reporter activation. In particular, the inhibitors developed to compete with alpha-ketoglutarate (KG), were less sensitive to inhibition in the physiological range of L-ascorbate (40-100 M) than those having a strong iron chelation motif. Challenging those HIF activators in the reporter system with D-isoascorbic acid demonstrated that the latter, despite the fact of exhibiting the same reducing potency with respect ferric iron, had almost no or much weaker effect than L-ascorbic acid. Similarly, no quenching of reporter activation was observed with cell-permeable reducing agent NAC. Docking of L-ascorbic acid and D-isoascorbic aci into the HIF PHD2 crystal structure showed interference of Tyr310 with respect to D-isoascorbate. The overall results can be interpreted only if one assumes true co-substrate nature of L-ascorbic acid and its competition for the binding site of KG in the enzyme active center. This conclusion is in agreement with the results obtained recently in cell-based systems for TET enzyme and jumonji histone demethylase, where L-ascorbate is supposed to act as a true co-substrate and not as a reducing agent preventing enzyme inactivation.
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L-ascorbic acid: a true substrate for HIF prolyl hydroxylase?статья

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