Identification and characterization of a small molecule that activates thiosulfate sulfurtransferase and stimulates mitochondrial respiration.

Autor: Al-Dahmani ZM; Department of Pharmacy and Drug Design, University of Groningen, Groningen, The Netherlands.; Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, The Netherlands., Hadian M; Department of Pharmacy and Drug Design, University of Groningen, Groningen, The Netherlands., Ruiz-Moreno AJ; Department of Pharmacy and Drug Design, University of Groningen, Groningen, The Netherlands., Maria SA; Department of Pharmacy, Molecular Pharmacology, University of Groningen, Groningen, The Netherlands., Batista FA; Department of Pharmacy and Drug Design, University of Groningen, Groningen, The Netherlands.; Department of Microbiology Structure, Institute of Pasteur, Paris, France., Zhang R; Department of Pharmacy and Drug Design, University of Groningen, Groningen, The Netherlands., Luo Y; Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, The Netherlands.; Department of Pharmacy, Molecular Pharmacology, University of Groningen, Groningen, The Netherlands., Sadremomtaz A; Department of Pharmacy and Drug Design, University of Groningen, Groningen, The Netherlands.; Department of Nanoengineering, University of North Carolina Agriculture and Technical State, Greensboro, North Carolina, USA.; Department of Nanoengineering, Joint School of Nanoscience and Nanoengineering, Greensboro, North Carolina, USA., van der Straat R; Department of Pharmacy and Drug Design, University of Groningen, Groningen, The Netherlands., Spoor M; Department of Pharmacy and Drug Design, University of Groningen, Groningen, The Netherlands., Dolga AM; Department of Pharmacy, Molecular Pharmacology, University of Groningen, Groningen, The Netherlands., Dekker FJ; Department of Pharmaceutical Gene Modulation, University of Groningen, Groningen, The Netherlands., S S AD; Department of Pharmacy and Drug Design, University of Groningen, Groningen, The Netherlands., van Goor H; Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, The Netherlands., Groves MR; Department of Pharmacy and Drug Design, University of Groningen, Groningen, The Netherlands.
Jazyk: angličtina
Zdroj: Protein science : a publication of the Protein Society [Protein Sci] 2023 Nov; Vol. 32 (11), pp. e4794.
DOI: 10.1002/pro.4794
Abstrakt: The enzyme Thiosulfate sulfurtransferase (TST, EC 2.8.1.1), is a positive genetic predictor of diabetes type 2 and obesity. As increased TST activity protects against the development of diabetic symptoms in mice, an activating compound for TST may provide therapeutic benefits in diabetes and obesity. We identified a small molecule activator of human TST through screening of an inhouse small molecule library. Kinetic studies in vitro suggest that two distinct isomers of the compound are required for full activation as well as an allosteric mode of activation. Additionally, we studied the effect of TST protein and the activator on TST activity through mitochondrial respiration. Molecular docking and molecular dynamics (MD) approaches supports an allosteric site for the binding of the activator, which is supported by the lack of activation in the Escherichia coli. mercaptopyruvate sulfurtransferase. Finally, we show that increasing TST activity in isolated mitochondria increases mitochondrial oxygen consumption.
(© 2023 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)
Databáze: MEDLINE
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