Catalysis of the covalent binding of 3-hydroxyamino-1-methyl-5H-pyrido[4,3-b]indole to DNA by a L-proline- and adenosine triphosphate-dependent enzyme in rat hepatic cytosol.
An enzymatic mechanism involved in the activation of 3-hydroxyamino-1-methyl-5H-pyrido[4,3-b]indole (N-hydroxy-Trp-P-2), a mutagenic intermediate of a tryptophan pyrolysate, was studied in vitro. In hepatic cytosol supplemented with adenosine triphosphate and L-proline, N-hydroxy-Trp-P-2 was converted to a form which reacts readily with DNA. The enzyme responsible for the activation was partially purified and identified as prolyl transfer RNA synthetase as judged by their cofactor requirements, inhibition by pyrophosphate or adenosine monophosphate, and copurification of their activities. The prolyl transfer RNA-dependent covalent binding of N-hydroxy-Trp-P-2 to DNA of hepatic cytosol was highest in rats, followed by mice, hamsters, rabbits, and guinea pigs in that order. The capacity for the binding of N-hydroxy-Trp-P-2 was largely consistent with their prolyl transfer RNA synthetase activity. With regard to the ultimate form of N-hydroxy-Trp-P-2 for the covalent binding, a possible formation of N,O-prolyl-3-amino-1-methyl-5H-pyrido[4,3-b]indole was proposed.
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000604:Amino Acyl-tRNA Synthetases / Q000378:metabolism; D000818:Animals; D002243:Carbolines / Q000378:metabolism*; D006224:Cricetinae; D003600:Cytosol / Q000201:enzymology*; D004247:DNA / Q000378:metabolism*; D005260:Female; D006168:Guinea Pigs; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007211:Indoles / Q000378:metabolism*; D008099:Liver / Q000201:enzymology*; D008297:Male; D008647:Mesocricetus; D051379:Mice; D011392:Proline / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D013329:Structure-Activity Relationship
D002243:Carbolines; D007211:Indoles; C027210:3-hydroxyamino-1-methyl-5H-pyrido(4,3-b)indole; D000255:Adenosine Triphosphate; D004247:DNA; D011392:Proline; D000604:Amino Acyl-tRNA Synthetases; C100134:prolyl T RNA synthetase