Glutathionyl transferase catalyzed addition of glutathione to COMC: a new hypothesis for antitumor activity.
[reaction: see text] Data are presented indicating that the potent antitumor activity of 2-crotonyloxymethyl-(4R,5R,6R)-4,5,6-trihydroxy-2-cyclohexenone (COTC) and 2-crotonyloxymethyl-2-cyclohexenone (COMC) is not likely the result of glyoxalase I inhibition, as has long been assumed. An alternative hypothesis is presented, based on the finding that COMC is a substrate for human glutathionyl transferase, which produces a transient, highly electrophilic glutathionylated 2-exomethylenecyclohexanone that can covalently modify proteins and nucleic acids.
Hamilton
Diana S
DS
Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore, Maryland 21228, USA.
Ding
Zhebo
Z
Ganem
Bruce
B
Creighton
Donald J
DJ
D000903:Antibiotics, Antineoplastic / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D003512:Cyclohexanones / Q000737:chemistry*; D003545:Cysteine / Q000737:chemistry; D004912:Erythrocytes / Q000737:chemistry; D005978:Glutathione / Q000737:chemistry*; D005982:Glutathione Transferase / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D013056:Spectrophotometry, Ultraviolet
D000903:Antibiotics, Antineoplastic; D003512:Cyclohexanones; C073431:2-crotonyloxymethyl-2-cyclohexenone; D005982:Glutathione Transferase; D005978:Glutathione; D003545:Cysteine