The Polyamine Metabolism of Filarial Worms as Chemotherapeutic Target
Parasite-specific putrescine-N-acetyltransferase and polyamine oxidase, both involved in the reversed pathway of polyamine metabolism, were demonstrated for Ascaris suum and Onchocerca volvulus. Berenil-treatment was found to be correlated with accumulation of polyamines, especially spermine, obviously due to blockaded polyamine interconversion. Furthermore it was shown that added spermine to the culture medium led to the death of worms. These specificities might be exploited for chemotherapy of filarial infections.
Polyamines are widely distributed in the nature. They are found in higher and lower eucaryotes and in procaryotes as well as in viruses (Tabor and Tabor, 1984). During the last years there have been many approaches to examine the role of polyamines in cell growth and differentiation in vertebrates (Tabor and Tabor, 1984; Pegg, 1986). The polyamine metabolism of parasites also has attracted increasing interest, e. g. in African trypanosomes the initial enzyme of polyamine synthesis — ornithine decarboxylase — has been exploited as a target for chemotherapy by using DFMO (DLα-difluoro-methylornithine) (Bacchi et al., 1980; Bacchi et al., 1983; Fairlamb et al., 1985; Giffin et al., 1986).
The polyamine metabolism of filaria and other helminths is still a neglected area of research, although there are reports about distribution pattern of polyamines and some peculiarities of polyamine metabolism in filarial worms (Srivastava et al., 1980; Wittich et al., 1987; Walter, 1988). DFMO and MGBG (methylglyoxal bis-(guanylhydrazone)), both of which are potent inhibitors of polyamine synthesis in mammals, do not significantly effect the viability of filarial worms (Wittich et al., 1987). If synthesis via ornithine as well as arginine decarboxylase could finally be denied, the absolute dependence of filarial worms on their host for a supply with polyamines would offer some leads for chemotherapy of river blindness and lymphatic fila-riasis. It should be demonstrated for filaria and other helminths that blockade and disturbance of polyamine synthesis and distribution leads to death of worms. Furthermore the enzymes involved in the interconversion pathway should be identified and their potential as targets for design and developement of enzyme inhibitors to antifilarial drugs should be studied.
KeywordsTrypanosoma Brucei Diamine Oxidase Polyamine Metabolism Polyamine Synthesis Arginine Decarboxylase
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- Bacchi, C. J., Garofalo, J., Mockenhaupt, D., McCann, P. P., Diekema, K. A., Pegg, A. E., Nathan, H. C., Mullany, E. A., Chunosoff, L., Sjoerdsma, A., Hunter, S. H., 1983, In vivo effects of-D, L-difluoromethyl-ornithine on the metabolism and morphology of trypanosoma brucei brucei, Mol. Biochem., Parasitol., 7: 209–225.CrossRefGoogle Scholar
- Ferrante, A., Ljungstrom, I., Rzepzyk, C. M., and Morgan, D. M. L., 1986, Differences in sensitivity of Schistosoma mansoni schistosomula, Dirofilaria immitis microfilariae and Nematospiroides dubius third-stage larvae to damage by polyamine oxidase-polyamine system, Infect.Immun., 53(3): 606–610.PubMedGoogle Scholar
- Giffin, B. F., McCann, P. P., Bitonti, A. J., and Bacchi, C. J., 1986, Polyamine depletion following exposure to DL-difluoromethylornithine both in vivo and in vitro initiates morphological alterations and mitochondrial activation in a monomorphic strain of trypanosoma brucei brucei, J. Protozool., 33(2): 238–243.PubMedGoogle Scholar
- McCann, P. P., Bacchi, C. J., Nathan, H. C, and Sjoerdsma, A., 1983, in “Mechanism of Drug Action”, T. P. Singer and R. N. Ordarza, eds., Academic Press, New York.Google Scholar
- Morgan, D. M. L., Bachrach, U., Assaraf, Y. G., Harari, E., and Golenser, J., 1986, The effect of purified aminoaldehydes produced by polyamine oxidation on developement in vitro of Plasmodium falciparum in normal and glucose-6-phosphate-dehydrogenase-deficient erythrocytes, Biochem. J., 236: 97–101.PubMedGoogle Scholar
- Müller, S., and Walter, R. D., 1988, Effect of berenil and spermine on viability and polyamine metabolism of filarial worms in vitro, International Symposium on Polyamines in Biochemistry and Clinical research, Sorrento, Naples, Italy, 13-17 June 1988 (Abstract).Google Scholar
- Müller, S., Wittich, R.-M., and Walter, R. D., Characteristics and function of polyamine oxidase in nematodes, Zbl. Bakt. Hyg., in press.Google Scholar
- Srivastava, D. K., Roy, T. K., and Shukla, O. P., 1980, Polyamines of helminths, Ind. J. Parasitol., 4(2): 187–189.Google Scholar
- Wittich, R.-M., and Walter, R. D., 1988, A novel putrescine (diamine) N-acetyltransferase from Onchocerca volvulus and Ascaris suum, International Symposium on Polyamines in Biochemistry and Clinical Research, Sorrento, Naples, Italy, 13-17 June 1988 (Abstract).Google Scholar