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

Journal Article · · PLoS ONE
 [1];  [2];  [3];  [4];  [5]; ORCiD logo [1];  [6]
  1. National Cancer Inst., Frederick, MD (United States)
  2. National Cancer Inst., Frederick, MD (United States); Frederick National Lab. for Cancer Research, MD (United States)
  3. Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD (United States); National Cancer Inst., Frederick, MD (United States)
  4. Rutgers Univ., Piscataway, NJ (United States); National Cancer Inst., Frederick, MD (United States)
  5. Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States)
  6. Univ. of Texas Health Science Center, Houston, TX (United States)
+ Show Author Affiliations

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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
Intramural Research Program of the National Inst. of Health (NIH); National Cancer Institute (NCI); Center for Cancer Research; USPHS
Grant/Contract Number:
HHSN261200800001E; RO1 CA101753
OSTI ID:
1328024
Journal Information:
PLoS ONE, Vol. 11, Issue 9; ISSN 1932-6203
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 21 works
Citation information provided by
Web of Science

References (23)

Isothiocyanates as substrates for human glutathione transferases: structure-activity studies journal October 1995
Structure and Function of Residue 104 and Water Molecules in the Xenobiotic Substrate-Binding Site in Human Glutathione S -Transferase P1-1 † , ‡ journal August 1999
Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by β-phenylethyl isothiocyanate journal September 2006
Cancer chemoprevention with dietary isothiocyanates mature for clinical translational research journal June 2012
Vegetables, Fruit, and Cancer Prevention journal October 1996
Design of a monomeric human glutathione transferase GSTP1, a structurally stable but catalytically inactive protein journal October 2002
Naturally Occurring Human Glutathione S-transferase GSTP1-1 Isoforms with Isoleucine and Valine in Position 104 Differ in Enzymic Properties journal September 1994
Structure Determination and Refinement of Human Alpha Class Glutathione Transferase A1-1, and a Comparison with the Mu and Pi Class Enzymes journal July 1993
Forward and reverse catalysis and product sequestration by human glutathione S-transferases in the reaction of GSH with dietary aralkyl isothiocyanates journal March 1995
Purification of glutathione S-transferases from human liver by glutathione-affinity chromatography journal October 1977
Diuretic drug binding to human glutathione transferase P1-1: potential role of Cys-101 revealed in the double mutant C47S/Y108V journal February 2011
Influence of the H-site residue 108 on human glutathione transferase P1-1 ligand binding: Structure-thermodynamic relationships and thermal stability journal December 2009
Determination of phenethyl isothiocyanate in human plasma and urine by ammonia derivatization and liquid chromatography–tandem mass spectrometry journal December 2003
Coot model-building tools for molecular graphics journal November 2004
Effects of Phenethyl Isothiocyanate on Acetaminophen Metabolism and Hepatotoxicity in Mice journal June 1997
[20] Processing of X-ray diffraction data collected in oscillation mode book January 1997
Intake of Cruciferous Vegetables Is Associated with Reduced Risk of Ovarian Cancer: A Meta‐analysis journal March 2015
Pharmacokinetics of Dietary Phenethyl Isothiocyanate in Rats journal September 2005
Structural Basis for Catalytic Differences between α Class Human Glutathione Transferases hGSTA1-1 and hGSTA2-2 for Glutathione Conjugation of Environmental Carcinogen Benzo[ a ]pyrene-7,8-diol-9,10-epoxide † journal August 2004
Crystal Structure of a Murine Glutathione S -Transferase in Complex with a Glutathione Conjugate of 4-Hydroxynon-2-enal in One Subunit and Glutathione in the Other:  Evidence of Signaling across the Dimer Interface † , ‡ journal September 1999
Cavin1 intrinsically disordered domains are essential for fuzzy electrostatic interactions and caveola formation journal February 2021
PHENIX: a comprehensive Python-based system for macromolecular structure solution. text January 2010
The chemical diversity and distribution of glucosinolates and isothiocyanates among plants journal January 2001

Cited By (6)

The Role of Cruciferous Vegetables and Isothiocyanates for Lung Cancer Prevention: Current Status, Challenges, and Future Research Directions journal June 2018
The structure of Trametes versicolor glutathione transferase Omega 3S bound to its conjugation product glutathionyl‐phenethylthiocarbamate reveals plasticity of its active site journal April 2019
Glucose metabolism and NRF2 coordinate the antioxidant response in melanoma resistant to MAPK inhibitors journal February 2018
Glutathione-Depleting Pro-Oxidant as a Selective Anticancer Therapeutic Agent journal June 2019
Phenethyl isothiocyanate activates leptin signaling and decreases food intake journal November 2018
Physiological relevance of covalent protein modification by dietary isothiocyanates journal January 2018

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Related Subjects

60 APPLIED LIFE SCIENCES
cysteine
crystal structure
glutathione chromatography
cancer prevention
enzyme inhibitors
dimers (chemical physics)
enzymes
nitrogen