TY - JOUR
T1 - Identification and Characterization of a Small Molecule that Activates Thiosulfate Sulfurtransferase and Stimulates Mitochondrial Respiration
AU - Al-Dahmani, Zayana M
AU - Hadian, Mojgan
AU - Ruiz-Moreno, Angel J
AU - Maria, Sabogal-Guaqueta Angelica
AU - Batista, Fernando A
AU - Zhang, Ran
AU - Luo, Yang
AU - Sadremomtaz, Afsaneh
AU - van der Straat, Robin
AU - Spoor, Mette
AU - Dolga, Amalia M
AU - Dekker, Frank J
AU - S S, Alexander Dömling
AU - van Goor, Harry
AU - Groves, Matthew R
N1 - This article is protected by copyright. All rights reserved.
PY - 2023/11
Y1 - 2023/11
N2 - 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.
AB - 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.
U2 - 10.1002/pro.4794
DO - 10.1002/pro.4794
M3 - Article
C2 - 37800277
SN - 0961-8368
VL - 32
JO - Protein Science
JF - Protein Science
IS - 11
M1 - e4794
ER -