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

作者：Zeyana M. Al‐Dahmani, Mojgan Hadian, Angel J. Ruiz‐Moreno, Sabogal‐Guaqueta Angelica Maria, Fernando de Assis 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 · 发表于：Protein Science · 年份：2023 · DOI：10.1002/pro.4794 · 被引用次数：4 · 研究领域：Sulfur-Based Synthesis Techniques、Genomics, phytochemicals, and oxidative stress、Nitrogen and Sulfur Effects on Brassica

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.