Functional modification of rat liver ribosomes by the in vitro action of N-methyl-N'-nitro-N-nitrosoguanidine.
The mechanism by which N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) inhibits protein synthesis has been studied in a rat liver cell free system. Using preformed aminoacyl-tRNA it was observed that incorporation of amino acid into polyribosomal protein was inhibited in the presence of low concentration of MNNG. This inhibition was not reversed by increasing the concentration of soluble factors. Transfer RNAs modified previously by treatment with MNNG and subsequently esterified with amino acids were transferred to polyribosomes with the same efficiency as those species which were not modified. Polyribosomes, on the other hand, lost activity to incorporate amino acids after pretreatment with MNNG. This inactivation was dependent on the concentration of MNNG with which polyribosomes were treated. When poly(U) was used with MNNG-treated polyribosomes, its translation, after correction for endogenous translation, was also found to be significantly low as compared to the case with untreated polyribosomes. Purified ribosomes stripped of endogenous mRNA when treated with increasing concentrations of MNNG progressively lost ability to support polyphenylalanine synthesis programmed by poly(U). The treated ribosomes, however, neither inhibited the activity of control ribosomes nor induced any loss of fidelity of translation by poly(U). It is concluded that MNNG inhibits protein synthesis through functional inactivation of ribosomes resulting from direct modification of ribosomal proteins possibly involving nitroguanidination of lysine residues.
Bhattacharya
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Bagewadikar
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D000818:Animals; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008239:Lysine; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology*; D011072:Poly U / Q000378:metabolism; D011132:Polyribosomes / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D012346:RNA, Transfer, Amino Acyl / Q000378:metabolism; D051381:Rats; D012270:Ribosomes / Q000187:drug effects*
D012346:RNA, Transfer, Amino Acyl; D008769:Methylnitronitrosoguanidine; D011072:Poly U; D008239:Lysine