Specific inhibitors of poly(ADP-ribose) synthetase and mono(ADP-ribosyl)transferase.
Two classes of enzymes, poly(ADP-ribose) synthetase and mono(ADP-ribosyl)transferases, catalyze covalent attachment of multiple or single residues, respectively, of the ADP-ribose moiety of NAD+ to various proteins. In order to find good inhibitors of poly(ADP-ribose) synthetase free of side actions and applicable to in vivo studies, we made a large scale survey using an in vitro assay system, and found many potent inhibitors. The four strongest were 4-amino-1,8-naphthalimide, 6(5H)- and 2-nitro-6(5H)-phenanthridinones, and 1,5-dihydroxyisoquinoline. Their 50% inhibitory concentrations, 0.18-0.39 microM, were about two orders of magnitude lower than that of 3-aminobenzamide that is currently most popularly used. A common structural feature among all potent inhibitors, including 1-hydroxyisoquinoline, chlorthenoxazin, 3-hydroxybenzamide, and 4-hydroxyquinazoline, in addition to the four mentioned above, was the presence of a carbonyl group built in a polyaromatic heterocyclic skeleton or a carbamoyl group attached to an aromatic ring. Most of the inhibitors exhibited mixed-type inhibition with respect to NAD+. Comparative studies of the effects on poly(ADP-ribose) synthetase and mono(ADP-ribosyl)transferase from hen heterophils revealed high specificity of most of the potent inhibitors for poly(ADP-ribose) synthetase. On the other hand, unsaturated long-chain fatty acids inhibited both enzymes, and saturated long-chain fatty acids and vitamin K1 acted selectively on mono(ADP-ribosyl)transferase. The finding of many inhibitors of ADP-ribosyltransferases, especially poly(ADP-ribose) synthetase, supports the view that ADP-ribosylation of proteins may be regulated by a variety of metabolites or structural constituents in the cell.
Banasik
M
M
Department of Clinical Science and Laboratory Medicine, Kyoto University Faculty of Medicine, Japan.
Komura
H
H
Shimoyama
M
M
Ueda
K
K
D036002:ADP Ribose Transferases / Q000037:antagonists & inhibitors*; D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002417:Cattle; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D007700:Kinetics; D009243:NAD / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013950:Thymus Gland / Q000201:enzymology
D000098:Acetophenones; D001549:Benzamides; D004791:Enzyme Inhibitors; D005230:Fatty Acids, Nonesterified; D007546:Isoquinolines; D009281:Naphthalenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D011804:Quinolines; D009243:NAD; D009536:Niacinamide; C037689:benzamide; D036002:ADP Ribose Transferases; C038699:acetophenone