PubMed · 8646528
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L H Pearl, R Savva. 1996. The problem with pyrimidines.. https://doi.org/10.1038/nsb0696-485
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2-Nitropropane, an industrial chemical and a hepatocarcinogen in rats, induces aryl sulfotransferase-mediated liver DNA and RNA base modifications [Sodum, R. S., Sohn, O. S., Nie, G., and Fiala, E. S. (1994) Chem. Res. Toxicol. 7, 344-351]. Two of these modifications were previously identified as 8-aminoguanine and 8-oxoguanine. We now report that the base moiety of the so far unidentified third nucleic acid modification, namely RX1 in RNA and DX1 in DNA, is 2-hydrazinohypoxanthine (N2-aminoguanine). 2-Hydrazinoinosine and 2-hydrazinodeoxyinosine, synthesized by adapting published procedures, cochromatographed with RX1 and DX1 of liver RNA and DNA, respectively, from 2-nitropropane-treated rats. 2-Hydrazinoinosine and 2-hydrazinodeoxyinosine are unstable in solution like the in vivo products RX1 and DX1. At neutral pH, hypoxanthine nucleoside is the major product of decomposition, while at pH 10 or above, xanthine nucleoside is also formed. RX1 and DX1 could be generated in the anaerobic reactions of hydroxylamine-O-sulfonic acid, an intermediate in the proposed activation pathway of 2-nitropropane, with guanine nucleosides. These results provide further evidence for the activation of 2-nitropropane and other carcinogenic secondary nitroalkanes to a reactive species capable of aminating nucleic acids and proteins.
Thermolysin is remarkably activated in the presence of high concentrations (1-5 M) of neutral salts and its activity is enhanced 15 times by 4 M NaCl at pH 7.0 and 25 degrees C [Inouye, K. (1992) J. Biochem. 112, 335-340]. In this study, the effects of nitration and amination of tyrosyl residues in thermolysin on its halophilic properties were examined. Nitration and successive amination inactivate thermolysin progressively as the degree of modification increases. When 16 tyrosyl residues were nitrated, the activity decreased to 10% of that of the native enzyme, whereas it recovered to 30% when they were aminated. The decrease in the activity by the nitration and amination was shown to be brought about only by a decrease in the molecular activity, kcat; the Michaelis constant, Km, was unaltered. When 14 tyrosyl residues of thermolysin were nitrated, the degree of activation by 4 M NaCl at pH 7.0 decreased from 15 to 10, and this decreased further to 5 when the pH of the reaction medium was raised to 8.5. However, when the nitrated tyrosyl residues were reduced to aminotyrosyl residues, the degree of activation was restored to that of the native enzyme. The change in the degree of activation by nitration and amination of thermolysin could be due to the change in the ionization of tyrosyl residues, and it was suggested that removing negative charges from tyrosyl residues of thermolysin enhances its halophilicity.
In this paper we report that a hydrazinopeptide synthesized using solid-phase N-electrophilic amination with N-Boc-3-(4-cyanophenyl)oxaziridine reacted with a lipophilic peptide aldehyde to give the corresponding hydrazone plus an unexpected 1,3,4-oxadiazolidinopeptide containing two peptide aldehyde units. This methodology allows the synthesis of large lipopeptides.