1887

Abstract

The uptake, biosynthesis and catabolism of polyamines in the microsporidian parasite are detailed with reference to the effects of oligoamine and arylamine analogues of polyamines. , an intracellular parasite of mammalian cells, has both biosynthetic and catabolic enzymes of polyamine metabolism, as demonstrated in cell-free extracts of mature spores. The uptake of polyamines was measured in immature, pre-emergent spores isolated from host cells by Percoll gradient. Spermine was rapidly taken up and metabolized to spermidine and an unknown, possibly acetamidopropanal, by spermidine/spermine -acetyltransferase (SSAT) and polyamine oxidase (PAO). Most of the spermidine and the unknown product were found in the cell incubation medium, indicating they were released from the cell. bis(Ethyl) oligoamine analogues of polyamines, such as SL-11144 and SL-11158, as well as arylamine analogues [BW-1, a bis(phenylbenzyl) 3-7-3 analogue] blocked uptake and interconversion of spermine at micromolar levels and, in the case of BW-1, acted as substrate for PAO. The PAO activity differed from that found in mammalian cells with respect to pH optimum, substrate specificity and sensitivity to known PAO inhibitors. SL-11158 inhibited SSAT activity with a mixed type of inhibition in which the analogue had a 70-fold higher affinity for the enzyme than the natural substrate, spermine. The interest in polyamine metabolism and the biochemical effects of these polyamine analogues is warranted since they cure model infections of in mice and are potential candidates for human clinical trials.

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2004-05-01
2024-10-06
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References

  1. Ariyanayagam M. R., Fairlamb A. H. 1997; Diamine auxotrophy may be a universal feature of Trypanosoma cruzi epimastigotes. Mol Biochem Parasitol 84:111–121 [CrossRef]
    [Google Scholar]
  2. Bacchi C. J., Yarlett N. 2002; Polyamine metabolism as chemotherapeutic target in protozoan parasites. Mini Rev Med Chem 2:553–563 [CrossRef]
    [Google Scholar]
  3. Bacchi C. J., Lane S., Weiss L. M., Yarlett N., Takvorian P., Cali A., Wittner M. 2001; Polyamine synthesis and interconversion by the microsporidian Encephalitozoon cuniculi. J Eukaryot Microbiol 48:374–381 [CrossRef]
    [Google Scholar]
  4. Bacchi C. J., Weiss L. M., Lane S.9 other authors 2002; Novel synthetic polyamines are effective in the treatment of experimental microsporidiosis, an opportunistic AIDS-associated infection. Antimicrob Agents Chemother 46:55–61 [CrossRef]
    [Google Scholar]
  5. Bernacki R. J., Oberman E. J., Seweryniak K. E., Atwood A., Bergeron R. J., Porter C. W. 1995; Preclinical antitumor efficacy of the polyamine analogue N1,N11-diethylnorspermine administered by multiple injection or continuous infusion. Clin Cancer Res 1:847–857
    [Google Scholar]
  6. Bey P., Bolkenius F. N., Seiler N., Casara P. 1985; N-2,3-Butadienyl-1,4-butanediamine derivatives: potent irreversible inactivators of mammalian polyamine oxidase. J Med Chem 28:1–2 [CrossRef]
    [Google Scholar]
  7. Bitonti A. J., McCann P. P., Sjoerdsma A. 1982; Restriction of bacterial growth by inhibition of polyamine biosynthesis by using monofluoromethylornithine, difluoromethylarginine and dicyclohexylammonium sulphate. Biochem J 208:435–441
    [Google Scholar]
  8. Bitonti A. J., Dumont J. A., Bush T. L., Stemerick D. M., Edwards M. L., McCann P. P. 1990; Bis(benzyl) polyamine analogs as novel substrates for polyamine oxidase. J Biol Chem 265:382–388
    [Google Scholar]
  9. Casero R. A., Jr, Pegg A. E. 1993; Spermidine/spermine N1-acetyltransferase – the turning point in polyamine metabolism. FASEB J 7:653–661
    [Google Scholar]
  10. Casero R. A., Jr, Woster P. M. 2001; Terminally alkylated polyamine analogues as chemotherapeutic agents. J Med Chem 44:1–26 [CrossRef]
    [Google Scholar]
  11. Childs R. E., Bardsley W. G. 1975; The steady-state kinetics of peroxidase with 2,2′-azino-di-(3-ethyl-benzthiazoline-6-sulphonic acid) as chromogen. Biochem J 145:93–103
    [Google Scholar]
  12. Cohen S. S. 1998 A Guide to the Polyamines pp. 69–93 New York: Oxford University Press;
  13. Costa S. F., Weiss L. M. 2000; Drug treatment of microsporidiosis. Drug Resist Updat 3:384–399 [CrossRef]
    [Google Scholar]
  14. Coyle C., Bacchi C. J., Yarlett N., Tanowitz H. B., Wittner M., Weiss L. M. 1996; Polyamine metabolism as a therapeutic target for Microsporidia. J Eukaryot Microbiol 43:96S [CrossRef]
    [Google Scholar]
  15. Didier E. S. 1997; Effects of albendazole, fumagillin, and TNP-470 on microsporidial replication in vitro. Antimicrob Agents Chemother 41:1541–1546
    [Google Scholar]
  16. Dieterich D. T., Lew E. A., Kotler D. P., Poles M. A., Orenstein J. M. 1994; Treatment with albendazole for intestinal disease due to Enterocytozoon bieneusi in patients with AIDS. J Infect Dis 169:178–183 [CrossRef]
    [Google Scholar]
  17. Dolgikh V. V., Sokolova J. J., Issi I. V. 1997; Activities of enzymes of carbohydrate and energy metabolism of the spores of the microsporidian, Nosema grylli. J Eukaryot Microbiol 44:246–249 [CrossRef]
    [Google Scholar]
  18. Frydman B., Valasinas A. 1999; Polyamine-based chemotherapy of cancer. Exp Opin Ther Patents 9:1055–1068 [CrossRef]
    [Google Scholar]
  19. Goldberg B., Rattendi D., Lloyd D., Sufrin J. R., Bacchi C. J. 1998; Effects of intermediates of methionine metabolism and nucleoside analogs on S-adenosylmethionine transport by Trypanosoma brucei brucei and a drug-resistant Trypanosoma brucei rhodesiense. Biochem Pharmacol 56:95–103 [CrossRef]
    [Google Scholar]
  20. Green L. C., Didier P. J., Didier E. S. 1999; Fractionation of sporogonial stages of the microsporidian Encephalitozoon cuniculi by Percoll gradients. J Eukaryot Microbiol 46:434–438 [CrossRef]
    [Google Scholar]
  21. Ha H. C., Woster P. M., Casero R. A., Jr. 1998; Unsymmetrically substituted polyamine analogue induces caspase-independent programmed cell death in Bcl-2-overexpressing cells. Cancer Res 58:2711–2714
    [Google Scholar]
  22. Katinka M. D., Duprat S., Cornillot E.14 other authors 2001; Genome sequence and genome compaction of the eukaryote parasite Encephalitozoon cuniculi. Nature 414:450–453 [CrossRef]
    [Google Scholar]
  23. Katiyar S. K., Gordon V. R., McLaughlin G. L., Edlind T. D. 1994; Antiprotozoal activities of benzimidazoles and correlations with β-tubulin sequence. Antimicrob Agents Chemother 38:2086–2090 [CrossRef]
    [Google Scholar]
  24. Keithly J. S., Zhu G., Upton S. J., Woods K. M., Martinez M. P., Yarlett N. 1997; Polyamine biosynthesis in Cryptosporidium parvum and its implications for chemotherapy. Mol Biochem Parasitol 88:35–42 [CrossRef]
    [Google Scholar]
  25. Le Quesne S. A., Fairlamb A. H. 1996; Regulation of a high-affinity diamine transport system in Trypanosoma cruzi epimastigotes. Biochem J 316:481–486
    [Google Scholar]
  26. Libby P. R., Henderson M., Bergeron R. J., Porter C. W. 1989; Major increases in spermidine/spermine-N1-acetyltransferase activity by spermine analogs and their relationship to polyamine depletion and growth inhibition in L1210 cells. Cancer Res 49:6226–6231
    [Google Scholar]
  27. Marton L. J., Pegg A. E. 1995; Polyamines as targets for therapeutic intervention. Annu Rev Pharmacol Toxicol 35:55–91 [CrossRef]
    [Google Scholar]
  28. Schechter P. J., Sjoerdsma A. 1989; Therapeutic utility of selected enzyme-activated irreversible inhibitor. In Enzymes as Targets for Drug Design pp. 201–210 Edited by Palfreyman M. G., McCann P. P., Lovenberg W., Temple J. G., Sjoerdsma A. San Diego, CA: Academic Press;
    [Google Scholar]
  29. Seiler N. 1987; Inhibition of enzymes oxidizing polyamines. In Inhibition of Polyamine Metabolism pp. 49–77Edited by McCann P. P. Pegg A. E., Sjoerdsma A. Orlando, FL: Academic Press;
    [Google Scholar]
  30. Undeen A. H. 1990; A proposed mechanism for the germination of microsporidian (Protozoa: Microspora) spores. J Theor Biol 142:223–235 [CrossRef]
    [Google Scholar]
  31. Valasinas A., Sarkar A., Reddy V. K., Marton L. J., Basu H. S., Frydman B. 2001; Conformationally restricted analogues of 1N,14N-bisethylhomospermine (BE-4-4-4): synthesis and growth inhibitory effects on human prostate cancer cells. J Med Chem 44:390–403 [CrossRef]
    [Google Scholar]
  32. Visvesvara G. S., Leitch G. J., Moura H., Wallace S., Weber R., Bryan R. T. 1991; Culture, electron microscopy, and immunoblot studies on a microsporidian parasite isolated from the urine of a patient with AIDS. J Protozool 38:105S–111S [CrossRef]
    [Google Scholar]
  33. Weber R., Bryan R. T., Schwartz D. A., Owens R. L. 1994; Human microsporidian infections. Clin Microbiol Rev 7:426–461
    [Google Scholar]
  34. Weidner E., Trager W. 1973; Adenosine triphosphate in the extracellular survival of an intracellular parasite (Nosema michaelis, Microsporidia). J Cell Biol 57:586–591 [CrossRef]
    [Google Scholar]
  35. Weidner E., Findley A. M., Dolgikh V., Sokolova J. 1999; Microsporidian biochemistry and physiology. In The Microsporidia and Microsporidiosis pp. 172–195Edited by Wittner M., Weiss L. M. Washington, DC: American Society for Microbiology;
    [Google Scholar]
  36. Weiss L. M., Michalakakis E., Coyle C. M., Tanowitz H. B., Wittner M. 1994a; The in vitro activity of albendazole againstEncephalitozoon cuniculi. J Eukaryot Microbiol 41:65S [CrossRef]
    [Google Scholar]
  37. Weiss L. M., Zhu X., Cali A., Tanowitz H., Wittner M. 1994b; Utility of microsporidian rRNA in diagnosis and phylogeny: a review. Folia Parasitol (Praha) 41:81–90
    [Google Scholar]
  38. Wittner M., Weiss L. M. 1999 The Microsporidia and Microsporidiosis Washington, DC: American Society for Microbiology;
  39. Yarlett N., Lindmark D. G., Goldberg B., Moharrami M. A., Bacchi C. J. 1994; Subcellular localization of the enzymes of the arginine dihydrolase pathway in Trichomonas vaginalis and Tritrichomonas foetus. J Eukaryot Microbiol 41:554–559 [CrossRef]
    [Google Scholar]
  40. Zou Y., Wu Z., Sirisoma N., Woster P. M., Casero R. A., Jr, Weiss L. M., Rattendi D., Lane S., Bacchi C. J. 2001; Novel alkylpolyamine analogues that possess both antitrypanosomal and antimicrosporidial activity. Bioorg Med Chem Lett 11:1613–1617 [CrossRef]
    [Google Scholar]
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