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

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.