Abstract
Formycin B is a potent inhibitor of growth of the promastigote forms of Leishmania tropica, L. mexicana, L. braziliensis, and L. donovani. The metabolic products formed in these organisms are formycin B 5'-monophosphate and formycin A 5'-mono-, di-, and triphosphates, with formycin A 5'-triphosphate predominating. In addition, formycin A is extensively incorporated into RNA. From the metabolic profile, we conclude that formycin B is first converted to the 5'-monophosphate by the nucleoside phosphotransferase found in Leishmania and is subsequently converted to cytotoxic adenosine nucleotide analogs of formycin A that become incorporated into RNA. The metabolism and mechanism of formycin B appears to be qualitatively similar to that of allopurinol riboside, but quantitative differences and species selectivity suggest that these agents may have a different spectrum of activity as potential anti-leishmanial agents.
Full text
PDF
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Caldwell I. C., Henderson J. F., Paterson A. R. The metabolism of formycin, an adenosine analogue. Can J Biochem. 1969 Oct;47(10):901–908. doi: 10.1139/o69-142. [DOI] [PubMed] [Google Scholar]
- Carson D. A., Chang K. P. Phosphorylation and anti-leishmanial activity of formycin B. Biochem Biophys Res Commun. 1981 Jun 16;100(3):1377–1383. doi: 10.1016/0006-291x(81)91976-8. [DOI] [PubMed] [Google Scholar]
- Darlix J. L., Fromageot P., Reich E. Analysis of transcription in vitro using purine nucleotide analogs. Biochemistry. 1971 Apr 27;10(9):1525–1531. doi: 10.1021/bi00785a003. [DOI] [PubMed] [Google Scholar]
- Ishizuka M., Sawa T., Hori S., Takayama H., Takeuchi T. Biological studies on formycin and formycin B. J Antibiot (Tokyo) 1968 Jan;21(1):5–12. doi: 10.7164/antibiotics.21.5. [DOI] [PubMed] [Google Scholar]
- Khym J. X. An analytical system for rapid separation of tissue nucleotides at low pressures on conventional anion exchangers. Clin Chem. 1975 Aug;21(9):1245–1252. [PubMed] [Google Scholar]
- Majima R., Tsutsumi K., Suda H., Shimura K. The effect of formycin on the processing of transfer RNA precursors in the posterior silk gland of Bombyx mori. J Biochem. 1977 Oct;82(4):1161–1166. doi: 10.1093/oxfordjournals.jbchem.a131789. [DOI] [PubMed] [Google Scholar]
- Nelson D. J., LaFon S. W., Tuttle J. V., Miller W. H., Miller R. L., Krenitsky T. A., Elion G. B., Berens R. L., Marr J. J. Allopurinol ribonucleoside as an antileishmanial agent. Biological effects, metabolism, and enzymatic phosphorylation. J Biol Chem. 1979 Nov 25;254(22):11544–11549. [PubMed] [Google Scholar]
- Nelson D. J., Lafon S. W., Jones T. E., Spector T., Berens R. L., Marr J. J. The metabolism of formycin B in Leishmania donovani. Biochem Biophys Res Commun. 1982 Sep 16;108(1):349–354. doi: 10.1016/0006-291x(82)91873-3. [DOI] [PubMed] [Google Scholar]
- Pogolotti A. L., Jr, Santi D. V. High-pressure liquid chromatography--ultraviolet analysis of intracellular nucleotides. Anal Biochem. 1982 Nov 1;126(2):335–345. doi: 10.1016/0003-2697(82)90524-3. [DOI] [PubMed] [Google Scholar]
- Spector T., Jones T. E., Elion G. B. Specificity of adenylosuccinate synthetase and adenylosuccinate lyase from Leishmania donovani. Selective amination of an antiprotozoal agent. J Biol Chem. 1979 Sep 10;254(17):8422–8426. [PubMed] [Google Scholar]
- Spector T., Miller R. L. Mammalian adenylosuccinate synthetase. Nucleotide monophosphate substrates and inhibitors. Biochim Biophys Acta. 1976 Sep 14;445(2):509–517. doi: 10.1016/0005-2744(76)90104-2. [DOI] [PubMed] [Google Scholar]
- Umezawa H., Sawa T., Fukagawa Y., Homma I., Ishizuka M. Studies on formycin and formycin B in cells of Ehrlich carcinoma and E. coli. J Antibiot (Tokyo) 1967 Nov;20(6):308–316. [PubMed] [Google Scholar]
- Ward D. C., Cerami A., Reich E., Acs G., Altwerger L. Biochemical studies of the nucleoside analogue, formycin. J Biol Chem. 1969 Jun 25;244(12):3243–3250. [PubMed] [Google Scholar]