Irreversible Inhibition of Glutathione S-Transferase by Phenethyl Isothiocyanate (PEITC), a Dietary Cancer Chemopreventive Phytochemical

Kumari, Vandana; Dyba, Marzena A.; Holland, Ryan J.; Liang, Yu-He; Singh, Shivendra V.; Ji, Xinhua; Cheng, Xiaodong

doi:10.1371/journal.pone.0163821

Irreversible Inhibition of Glutathione S-Transferase by Phenethyl Isothiocyanate (PEITC), a Dietary Cancer Chemopreventive Phytochemical

Journal Article · Thu Sep 29 00:00:00 EDT 2016 · PLoS ONE

DOI:https://doi.org/10.1371/journal.pone.0163821· OSTI ID:1328024

Kumari, Vandana ^[1]; Dyba, Marzena A. ^[2]; Holland, Ryan J. ^[3]; Liang, Yu-He ^[4]; Singh, Shivendra V. ^[5]; ^[1]; Cheng, Xiaodong ^[6]

National Cancer Inst., Frederick, MD (United States)
National Cancer Inst., Frederick, MD (United States); Frederick National Lab. for Cancer Research, MD (United States)
Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD (United States); National Cancer Inst., Frederick, MD (United States)
Rutgers Univ., Piscataway, NJ (United States); National Cancer Inst., Frederick, MD (United States)
Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States)
Univ. of Texas Health Science Center, Houston, TX (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: Center for Cancer Research; Intramural Research Program of the National Inst. of Health (NIH); National Cancer Inst. (NCI); USPHS

OSTI ID:: 1328024

Journal Information:: PLoS ONE, Journal Name: PLoS ONE Journal Issue: 9 Vol. 11; ISSN 1932-6203

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Irreversible Inhibition of Glutathione S-Transferase by Phenethyl Isothiocyanate (PEITC), a Dietary Cancer Chemopreventive Phytochemical

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