Stereoselective, strong inhibition of ribonucleotide reductase from E. coli by cisplatin.
Using ribonucleotide reductase (EC 1.17.4.1) purified from E. coli clones with overproducing plasmids for the B1 and B2 subunits, respectively, studies have been carried out of the inhibition of this enzyme by cisplatin. Under anaerobic conditions, using the dithiol, reduced form of the enzyme, it was found that ribonucleotide reductase is extremely sensitive to cisplatin: greater than 90% inhibition was achieved with 2-fold molar excess of platinum reagent even at 10(-8)M enzyme. Inhibition was essentially instantaneous and irreversible to G-25 gel filtration. The site of inhibition was found to be the B1 subunit. Transplatin was much less effective. Inhibition of the enzyme by cisplatin (molar ratio cisplatin:B1 = 4.3) led to a decrease in thiol titre corresponding to approximately 1 thiol group per dimer of B1 subunits under conditions leading to 94% inactivation of the ribonucleotide reductase activity.
Smith
S L
SL
Department of Pharmacy, University of Manchester, U.K.
Douglas
K T
KT
D016190:Carboplatin; D002850:Chromatography, Gel; D002945:Cisplatin / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology*; D046911:Macromolecular Substances; D009944:Organoplatinum Compounds / Q000494:pharmacology; D010084:Oxidation-Reduction; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*
D046911:Macromolecular Substances; D009944:Organoplatinum Compounds; C034697:transplatin; D016190:Carboplatin; D012264:Ribonucleotide Reductases; D002945:Cisplatin