Metabolites of alanosine, an antitumor antibiotic

Hiremagalur N. Jayaram, Anil K. Tyagi, Spurgeon Anandaraj, John A. Montgomery, James A. Kelley, Janice Kelley, Richard H. Adamson, David A. Cooney

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Abstract

The metabolism of alanosine. dl-2-amino-3-(N-hydroxy, N-nitrosamino) propionic acid (NSC-143647), a new antitumor antibiotic, was studied in mice, rats, monkeys and dogs. Urine is the principal excretory vehicle for the drug in these four species. In rats, unchanged alanosine is the principal excretory product. In the other species, a second, more acidic component accounts for the major fraction of the drug-derived radioactivity in urine; this product retains the characteristic u.v. spectrum and both carbons, 1 and 3, of alanosine: it is chromatographically and spectrally indistinguishable from the compound generated by the action of NADH and malate dehydrogenase on the product resulting from the incubation of l -alanosine with l-glutamate oxaloacetate transaminase (GOT) (EC 2.6.1.1) and α-ketoglutarate. On the basis of this evidence, this metabolite is concluded to be the α-hydroxy counterpart of l-alanosine. The antibiotic was susceptible to transamination in vitro by extract of organs rich in GOT; heart was pre-eminent in this regard, and α-ketoglutaric acid was found to be the preferred α-keto partner in the reaction. Crystalline GOT catalyzed an identical reaction in vitro, and the product, like oxaloacetic acid, was susceptible to enzymatic condensation with acetyl CoA, in the presence of citrate synthase. Inability to detect the -α- keto analogue of alanosine. 2-oxo-3-(N-hydroxy, N-nitrosamino) propionic acid, in tissues and excreta is attributed to the facile decomposition of this metabolite in vivo. In vitro, alanosine was susceptible to decarboxylation by homogenates of mouse brain and by purified l-glutamate decarboxylase (EC 4.1.1.15) from Escherichia coli. No evidence could be adduced for denitrosation of the antibiotic nor for reduction of the nitroso function in a system containing hepatic microsomes and NADPH. However, l-amino acid oxidase (EC 1.4.3.2) and high concentrations of pyridoxal phosphate catalyzed the deamination of alanosine at alkaline pH. In confirmation of the observations of Hurlbert et al,

Original languageEnglish (US)
Pages (from-to)3551-3566
Number of pages16
JournalBiochemical Pharmacology
Volume28
Issue number24
DOIs
StatePublished - Dec 15 1979

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ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

Cite this

Jayaram, H. N., Tyagi, A. K., Anandaraj, S., Montgomery, J. A., Kelley, J. A., Kelley, J., Adamson, R. H., & Cooney, D. A. (1979). Metabolites of alanosine, an antitumor antibiotic. Biochemical Pharmacology, 28(24), 3551-3566. https://doi.org/10.1016/0006-2952(79)90400-3