title: Multisubstrate adducts as potential inhibitors of S-adenosylmethionine dependent methylases: inhibition of indole N-methyltransferase by (5'-deoxyadenosyl)[3-(3-indolyl)prop-1-yl]methylsulfonium and (5'-deoxyadenosyl)[4-(3-indolyl)but-1-yl]methylsulfonium salts.
abstract: Multisubstrate adducts of the indole N-methyltransferase reaction have been designed in which a structural moiety representing the nucleophilic methyl acceptor is attached through the sulfur atom to the 5-(methylthio)adenosine and/or methionine moieties of the methyl donor, S-adenosyl-L-methionine. Indole derivatives attached through a 4-(3-indolyl)butyl sulfide or a 3-(3-indolyl)propyl sulfide linkage to 5'-thioadenosine or homocysteine have been synthesized, together with their corresponding methylsulfonium salts. These compounds have been assayed for their ability to inhibit rabbit lung indole N-methyltransferase. The adenosylsulfonium salts (5'-deoxyadenosyl)[4-(3-indolyl)but-1-yl]methylsulfonium perchlorate and (5'-deoxyadenosyl)[3-(3-indolyl)prop-1-yl]-methylsulfonium perchlorate were found to be inhibitors of this enzyme with Ki's of 12 and 44 microM, respectively. Neither of these compounds was effective in inhibiting the methylation of 3,4-dihydroxybenzoic acid, catalyzed by purified porcine catechol O-methyltransferase.
mesh_terms: D000818:Animals; D007202:Indicators and Reagents; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology*; D007700:Kinetics; D008168:Lung / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D011817:Rabbits; D012436:S-Adenosylmethionine / Q000378:metabolism*; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
chemical_list: D007202:Indicators and Reagents; D007211:Indoles; D012436:S-Adenosylmethionine; C039364:(5'-deoxyadenosyl)(4-(3-indolyl)but-1-yl)methylsulfonium; C039363:(5'-deoxyadenosyl)(3-(3-indolyl)prop-1-yl)methylsulfonium; D008780:Methyltransferases; C031863:indole methyltransferase