Sensitivity of Trypanosomatid Protozoa to DFMO and Metabolic Turnover of Ornithine Decarboxylase

Carrillo, Carolina; Cejas, Silvina; Cortés, Micaela; Ceriani, Carolina; Huber, Alejandra; González, Nélida S.; Algranati, Israel D.

doi:10.1006/bbrc.2000.3996

Cited by 26 publications

(28 citation statements)

References 29 publications

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“…Recent results have indicated that monogenetic trypanosomatids as C. fasciculata were naturally resistant to DFMO even at drug concentrations of 20 or 50 mM [16]. This property was related to the high turnover of Crithidia ODC; the continuously synthesized new molecules of active enzyme seem to produce enough putrescine rapidly converted into spermidine, thus avoiding a too drastic depletion of the latter polyamine in the presence of the inhibitor.…”

Section: Resultsmentioning

confidence: 99%

“…On the contrary, Leishmania mexicana and Trypanosoma brucei, which have a rather stable ODC with a half-life longer than 8 h [19,20], are susceptible to the drug and stop their proliferation after repeated treatments with DFMO [16,21]. The measurement of endogenous polyamine pools of various parasites cultivated for a long time in the absence and presence of the inhibitor has indicated that putrescine was almost completely depleted by DFMO in Crithidia as well as in Leishmania and Trypanosoma [16].…”

Section: Introductionmentioning

confidence: 99%

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Spermidine is essential for normal proliferation of trypanosomatid protozoa

2001

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Trypanosomatid parasites containing a metabolically unstable ornithine decarboxylase (ODC) are naturally resistant to high levels of K K-difluoromethylornithine (DFMO) because this ODC inhibitor, though causing a drastic reduction of intracellular putrescine, elicits only a moderate decrease of the spermidine endogenous pool. In this study we have used a combination of DFMO with cyclohexylamine (CHA ; biscyclohexylammonium sulfate), an inhibitor of spermidine synthase, to reach a more complete depletion of spermidine. Under these conditions we have observed the arrest of proliferation not only in trypanosomatids with stable ODC but also in parasites with an enzyme of high turnover rate. In all cases the reinitiation of proliferation occurred only after the addition of exogenous spermidine, and neither putrescine nor spermine were able to induce the same effect. ß

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Spermidine is essential for normal proliferation of trypanosomatid protozoa

2001

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“…Experiments in the past showed that DFMO reduces trypanothione levels significantly in sensitive strains of trypanosomes, but no reduction of trypanothione was observed in strains with resistance to the drug since the latter produced high levels of ornithine (Carrillo et al 2000).…”

Section: Trypanosomesmentioning

confidence: 99%

“…Recently, Carrillo et al (2000) investigated the regulatory mechanisms for drug tolerance of DFMO in T. cruzi transformed with the odc gene from C. fasciculata and in Leishmania mexicana. Resistance in C. fasciculata and Phytomonas, a plant parasite, was investigated.…”

Section: Trypanosomesmentioning

confidence: 99%

“…A determination of polyamine pools in ODC-transformed T. cruzi and L. mexicana showed that DFMO caused a significant decrease in putrescine and spermidine. Spermidine depletion was higher in parasites containing an ODC with a slow turnover indicating that spermidine might decrease below critical levels, needed to maintain trypanothione concentrations for normal cell proliferation (Carrillo et al 2000).…”

Section: Trypanosomesmentioning

confidence: 99%

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Spermidine metabolism in parasitic protozoa - a comparison to the situation in prokaryotes, viruses, plants and fungi

Kaiser¹,

Gottwald²,

Wiersch³

et al. 2003

FOLIA PARASIT

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Abstract. Targeting polyamines of parasitic protozoa in chemotherapy has attracted attention because polyamines might reveal novel drug targets for antiparasite therapies (Müller et al. 2001). The biological function of the triamine spermidine in parasitic protozoa has not been studied in great detail although the results obtained mainly imply three different functions, i.e., cell proliferation, cell differentiation, and biosynthesis of macromolecules. Sequence information from the malaria genome project databases and inhibitor studies provide evidence that the current status of spermidine research has to be extended since enzymes of spermidine metabolism are present in the parasite (Kaiser et al. 2001). Isolation and characterisation of these enzymes, i.e., deoxyhypusine synthase (EC 1.1.1.249) (DHS) and homospermidine synthase (EC 2.5.1.44) (HSS) might lead to valuable new targets in drug therapy. Currently research on spermidine metabolism is based on the deposition of the deoxyhypusine synthase nucleic acid sequence in GenBank while the activity of homospermidine synthase was deduced from inhibitor studies. Spermidine biosynthesis is catalyzed by spermidine synthase (EC 2.5.1.16) which transfers an aminopropyl moiety from decarboxylated S-adenosylmethionine to putrescine. Spermidine is also an important precursor in the biosynthesis of the unusual amino acid hypusine and the uncommon triamine homospermidine in eukaryotes, in particular in pyrrolizidine alkaloid-producing plants (Ober and Hartmann 2000). Hypusine is formed by a two-step enzymatic mechanism starting with the transfer of an aminobutyl moiety from spermidine to the ε-amino group of one of the lysine residues in the precursor protein of eukaryotic initiation factor eIF5A by DHS (Lee and Park 2000). The second step of hypusinylation is completed by deoxyhypusine hydroxylase (EC 1.14.9929) (Abbruzzese et al. 1985). Homospermidine formation in eukaryotes parallels deoxyhypusine formation in the way that in an NAD + -dependent reaction an aminobutyl moiety is transferred from spermidine. In the case of homospermidine synthase, however the acceptor is putrescine. Thus the triamine homospermidine consists of two symmetric aminobutyl moieties while there is one aminobutyl and one aminopropyl moiety present in spermidine. Here, we review the metabolism of the triamine spermidine with particular focus on the biosynthesis of hypusine and homospermidine in parasitic protozoa, i.e., Plasmodium, Trypanosoma and Leishmania, compared to that in prokaryotes i.e., Escherichia coli, a phytopathogenic virus and pyrrolizidine alkaloid-producing plants (Asteraceae) and fungi.

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Targeting the polyamine biosynthetic enzymes: a promising approach to therapy of African sleeping sickness, Chagas’ disease, and leishmaniasis

2007

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Trypanosomatids depend on spermidine for growth and survival. Consequently, enzymes involved in spermidine synthesis and utilization, i.e. arginase, ornithine decarboxylase (ODC), S-adenosylmethionine decarboxylase (AdoMetDC), spermidine synthase, trypanothione synthetase (TryS), and trypanothione reductase (TryR), are promising targets for drug development. The ODC inhibitor alpha-difluoromethylornithine (DFMO) is about to become a first-line drug against human late-stage gambiense sleeping sickness. Another ODC inhibitor, 3-aminooxy-1-aminopropane (APA), is considerably more effective than DFMO against Leishmania promastigotes and amastigotes multiplying in macrophages. AdoMetDC inhibitors can cure animals infected with isolates from patients with rhodesiense sleeping sickness and leishmaniasis, but have not been tested on humans. The antiparasitic effects of inhibitors of polyamine and trypanothione formation, reviewed here, emphasize the relevance of these enzymes as drug targets. By taking advantage of the differences in enzyme structure between parasite and host, it should be possible to design new drugs that can selectively kill the parasites.

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Sensitivity of Trypanosomatid Protozoa to DFMO and Metabolic Turnover of Ornithine Decarboxylase

Cited by 26 publications

References 29 publications

Spermidine is essential for normal proliferation of trypanosomatid protozoa

Spermidine is essential for normal proliferation of trypanosomatid protozoa

Spermidine metabolism in parasitic protozoa - a comparison to the situation in prokaryotes, viruses, plants and fungi

Targeting the polyamine biosynthetic enzymes: a promising approach to therapy of African sleeping sickness, Chagas’ disease, and leishmaniasis

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