Inhibition of QDPR synergistically modulates intracellular tetrahydrobiopterin profiles in cooperation with methotrexate.

Autor: Hara S; School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan; Department of Emergency and Intensive Care Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan. Electronic address: hara.s.ab@m.titech.ac.jp., Kono H; School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan., Suto N; Drug Discovery Initiative, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan., Kojima H; Drug Discovery Initiative, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan., Kishimoto K; Research and Development Center, SHIRATORI Pharmaceutical Co., Ltd, Narashino, Japan., Yoshino H; Research and Development Center, SHIRATORI Pharmaceutical Co., Ltd, Narashino, Japan., Niiyama S; Department of Emergency and Intensive Care Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan., Kakihana Y; Department of Emergency and Intensive Care Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan., Ichinose H; School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan. Electronic address: hichinos@bio.titech.ac.jp.
Jazyk: angličtina
Zdroj: Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2024 Jul 12; Vol. 717, pp. 150059. Date of Electronic Publication: 2024 May 04.
DOI: 10.1016/j.bbrc.2024.150059
Abstrakt: Tetrahydrobiopterin (BH4) is an essential cofactor for dopamine and serotonin synthesis in monoaminergic neurons, phenylalanine metabolism in hepatocytes, and nitric oxide synthesis in endothelial and immune cells. BH4 is consumed as a cofactor or is readily oxidized by autooxidation. Quinonoid dihydropteridine reductase (QDPR) is an enzyme that reduces quinonoid dihydrobiopterin (qBH2) back to BH4, and we have previously demonstrated the significance of QDPR in maintaining BH4 in vivo using Qdpr-KO mice. In addition to the levels of BH4 in the cells, the ratios of oxidized to reduced forms of BH4 are supposed to be important for regulating nitric oxide synthase (NOS) via the so-called uncoupling of NOS. However, previous studies were limited due to the absence of specific and high-affinity inhibitors against QDPR. Here, we performed a high-throughput screening for a QDPR inhibitor and identified Compound 9b with an IC 50 of 0.72 μM. To understand the inhibition mechanism, we performed kinetic analyses and molecular dynamics simulations. Treatment with 9b combined with methotrexate (MTX), an inhibitor of another BH4-reducing enzyme, dihydrofolate reductase (DHFR), significantly oxidized intracellular redox states in HepG2, Jurkat, SH-SY5Y, and PC12D cells. Collectively, these findings suggest that 9b may enhance the anticancer and anti-autoimmune effects of MTX.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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