Meta-iodobenzylguanidine (MIBG), a novel high-affinity substrate for cholera toxin that interferes with cellular mono(ADP-ribosylation).
Meta-iodobenzylguanidine (MIBG) is a guanidine analogue of the neurotransmitter norepinephrine. Radioiodinated [131I]MIBG is clinically used as a tumor-targeted radiopharmaceutical in the diagnosis and treatment of adrenergic tumors. Moreover, non-radiolabelled MIBG exerts several cell-biological effects, tentatively ascribed to interference with cellular mono(ADP-ribosyl) transferases (Smets, L.A., Bout, B. and Wisse, J. (1988) Cancer Chemother. Pharmacol. 21, 9-13; Smets, L.A., Metwally, E.A.G., Knol, E. and Martens, M. (1988) Leukemia Res. 12, 737-743). In the present study it was investigated whether MIBG could serve as an acceptor for the ribosyl transferase activity of cholera toxin and of erythrocyte membranes. MIBG appeared a substrate for the cholera toxin-catalyzed transfer of the ADP-ribose moiety of NAD to arginine-like residues with the highest affinity for this enzyme reported as yet (Km = 6.5 microM). MIBG was also ADP-ribosylated by the mono(ADP-ribosyl)transferase(s) of turkey erythrocyte membranes. Moreover, the drug appeared a potent affector of the ADP-ribose linkage to membrane proteins by these enzymes. Interference by MIBG was stronger than by related guanyltyramine, the monoamine precursors of MIBG, meta-iodobenzylamine had no effect at all. In contrast, the drug failed to affect endogenous, O-linked poly(ADP-ribose) polymerase, induced in nuclei of S49-leukemia cells by deoxyribonuclease. Since MIBG is the first described drug that specifically interferes with the cellular N-linked mono(ADP-ribosyl) transferase reactions, it may be an important tool to elucidate the physiological role of this posttranscriptional protein modification.
Loesberg
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Department of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam.
van Rooij
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Smets
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D019797:3-Iodobenzylguanidine; D036002:ADP Ribose Transferases; D000246:Adenosine Diphosphate Ribose / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002772:Cholera Toxin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004910:Erythrocyte Membrane / Q000378:metabolism; D007462:Iodobenzenes / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009243:NAD / Q000378:metabolism; D009702:Nucleoside Diphosphate Sugars / Q000096:biosynthesis*; D011064:Poly Adenosine Diphosphate Ribose / Q000096:biosynthesis*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D014422:Turkeys; D014439:Tyramine / Q000031:analogs & derivatives / Q000494:pharmacology
D007462:Iodobenzenes; D008565:Membrane Proteins; D009702:Nucleoside Diphosphate Sugars; D009243:NAD; D000246:Adenosine Diphosphate Ribose; D011064:Poly Adenosine Diphosphate Ribose; D019797:3-Iodobenzylguanidine; C046038:N-guanyltyramine; D002772:Cholera Toxin; D036002:ADP Ribose Transferases; D011065:Poly(ADP-ribose) Polymerases; D014439:Tyramine