Identification and Characterization of a Small Molecule that Activates Thiosulfate Sulfurtransferase and Stimulates Mitochondrial Respiration

Zayana M Al-Dahmani*, Mojgan Hadian, Angel J Ruiz-Moreno, Sabogal-Guaqueta Angelica Maria, Fernando A Batista, Ran Zhang, Yang Luo, Afsaneh Sadremomtaz, Robin van der Straat, Mette Spoor, Amalia M Dolga, Frank J Dekker, Alexander Dömling S S, Harry van Goor*, Matthew R Groves*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

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Samenvatting

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 E. coli. mercaptopyruvate sulfurtransferase. Finally, we show that increasing TST activity in isolated mitochondria increases mitochondrial oxygen consumption. This article is protected by copyright. All rights reserved.

Originele taal-2English
Artikelnummere4794
Aantal pagina's18
TijdschriftProtein Science
Volume32
Nummer van het tijdschrift11
Vroegere onlinedatum6-okt.-2023
DOI's
StatusPublished - nov.-2023

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