Role of Human Glutathione Transferases in Biotransformation of the Nitric Oxide Prodrug JS-K [post]

Birgitta Sjödin, Bengt Mannervik
2021 unpublished
Nitric oxide (NO) plays a prominent physiological role as a low-molecular-mass signal molecule involved in diverse biological functions. Great attention has been directed to pharmacologically modulating the release of NO for various therapeutic applications. We have focused on O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K) as an example of diazeniumdiolate prodrugs with potential for cancer chemotherapy. JS-K is reportedly activated by glutathione
more » ... ugation by glutathione transferase (GST), but the scope of activities among the numerous members of the GSTome is unknown. We demonstrate that all human GSTs tested except GST T1-1 are active with JS-K as a substrate, but their specific activities are notably spanning a 100-fold range. The most effective enzyme was the mu class member GST M2-2 with a specific activity of 273 ± 5 µmol min-1 mg-1 and the kinetic parameters Km 48 ± 4 µM, kcat 501 ± 29 s-1, kcat/Km 10 x106 M-1 s-1. The abundance of the GSTs as an ensemble and their high catalytic efficiency indicate that release of NO occurs rapidly in normal tissues such that other mechanisms play a major role in the tumor-killing effect of JS-K.
doi:10.21203/ fatcat:pzlr4b7dtfhahoay3ksdow4m5a