Irreversible Inhibition of Glutathione S-Transferase by Phenethyl Isothiocyanate (PEITC), a Dietary Cancer Chemopreventive Phytochemical.
Dietary isothiocyanates abundant as glucosinolate precursors in many edible cruciferous vegetables are effective for prevention of cancer in chemically-induced and transgenic rodent models. Some of these agents, including phenethyl isothiocyanate (PEITC), have already advanced to clinical investigations. The primary route of isothiocyanate metabolism is its conjugation with glutathione (GSH), a reaction catalyzed by glutathione S-transferase (GST). The pi class GST of subunit type 1 (hGSTP1) is much more effective than the alpha class GST of subunit type 1 (hGSTA1) in catalyzing the conjugation. Here, we report the crystal structures of hGSTP1 and hGSTA1 each in complex with the GSH adduct of PEITC. We find that PEITC also covalently modifies the cysteine side chains of GST, which irreversibly inhibits enzymatic activity.
Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
Vandana
V
Kumari
Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.|Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
Marzena A
MA
Dyba
Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
Ryan J
RJ
Holland
Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
Yu-He
YH
Liang
Department of Pharmacology and Chemical Biology and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Shivendra V
SV
Singh
Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
Xinhua
http://orcid.org/0000-0001-6942-1514
X
Ji
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