Trypanocidal CoQ analogues: Their effect on other mitochondrial systems

Ab, Clarkson; Ej, Bienen; Pollakis, Georgios; Rw, Grady

doi:10.1016/0305-0491(89)90341-6

Cited by 18 publications

(14 citation statements)

References 8 publications

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“…Antimicrobial compounds targeting mitochondria are valuable targets for chemotherapy (Kita et al, 2003) and may be particularly relevant against trypanosomatid parasites, in which the glycolytic pathway depends on a cyanide-insensitive glycerol-3-phosphate oxidase system in the inner mitochondrial membrane (Clarkson et al, 1989). In addition, pentamidine resistance in Leishmania involves drug extrusion from the mitochondria (Basselin et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

The putrescine analogue 1,4-diamino-2-butanone affects polyamine synthesis, transport, ultrastructure and intracellular survival in Leishmania amazonensis

et al. 2008

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Polyamines are important regulators of growth and differentiation in a variety of cells, including parasitic protozoa. Promastigotes of Leishmania species have high levels of putrescine and spermidine and their growth can be inhibited by polyamine biosynthesis antagonists. The putrescine analogue 1,4-diamino-2-butanone (DAB) is microbicidal against Tritrichomonas foetus and Trypanosoma cruzi, so we tested its effects on Leishmania amazonensis proliferation, viability, organization, putrescine transport and synthesis as well as in vitro infectivity. DAB impaired promastigote proliferation dose-dependently (IC 50 144 mM) and the parasite putrescine concentration was reduced by nearly 50 %. This analogue markedly inhibited both ornithine decarboxylase activity and [H 3 ]putrescine uptake by promastigotes. Pre-treatment with DAB for 24 h led to compensatory enhancement of putrescine uptake, indicating an adaptive mechanism in DAB-treated parasites. Remarkably, DAB caused mitochondrial damage, assessed by transmission electron microscopy, and 3 h treatment with 1 mM DAB enhanced lipid peroxidation, whereas incubation with 10 mM DAB or for 24 h resulted in decreased peroxidation levels in the parasites. This effect was probably due to the loss of mitochondrial function, demonstrated by the diminished reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), not observed in macrophages. Murine macrophages infected with L. amazonensis amastigotes treated with DAB had parasite loads significantly (P,0.05) lower than controls, presumably due to interference with putrescine uptake and/or synthesis. These results suggest that putrescine may be involved in leishmanial survival, possibly by maintaining the parasite's mitochondrial function. The use of analogues to interfere with polyamine/diamine synthesis and transport may shed light on its function in intracellular parasite survival and lead to identification of new targets for leishmaniasis chemotherapy.

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Section: Discussionmentioning

confidence: 99%

The putrescine analogue 1,4-diamino-2-butanone affects polyamine synthesis, transport, ultrastructure and intracellular survival in Leishmania amazonensis

et al. 2008

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“…This is despite the presence of ubiquinone 9 (UQ-9), the product of a biosynthetic pathway beginning with the condensation of p-hydroxybenzoic acid and solanesyl diphosphate (SPP, C 45 ), in Leishmania (12)(13)(14), T. brucei (15,16), Crithida fasciculata (17), and Crithidia oncopelti (18) and the finding that, at least in L. major and T. brucei (12,16), labeled precursors (acetate and mevalonate, and mevalonate, respectively) are incorporated into UQ. These results imply the presence of a solanesyldiphosphate synthase (SPPS) in these parasites.…”

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confidence: 99%

A Solanesyl-diphosphate Synthase Localizes in Glycosomes of Trypanosoma cruzi

Ferella

Montalvetti

Rohloff

et al. 2006

Journal of Biological Chemistry

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We report the cloning of a Trypanosoma cruzi gene encoding a solanesyl-diphosphate synthase, TcSPPS. The amino acid sequence (molecular mass ϳ 39 kDa) is homologous to polyprenyl-diphosphate synthases from different organisms, showing the seven conserved motifs and the typical hydrophobic profile. TcSPPS preferred geranylgeranyl diphosphate as the allylic substrate. The final product, as determined by TLC, had nine isoprene units. This suggests that the parasite synthesizes mainly ubiquinone-9 (UQ-9), as described for Trypanosoma brucei and Leishmania major. In fact, that was the length of the ubiquinone extracted from epimastigotes, as determined by high-performance liquid chromatography. Expression of TcSPPS was able to complement an Escherichia coli ispB mutant. A punctuated pattern in the cytoplasm of the parasite was detected by immunofluorescence analysis with a specific polyclonal antibody against TcSPPS. An overlapping fluorescence pattern was observed using an antibody directed against the glycosomal marker pyruvate phosphate dikinase, suggesting that this step of the isoprenoid biosynthetic pathway is located in the glycosomes. Co-localization in glycosomes was confirmed by immunogold electron microscopy and subcellular fractionation. Because UQ has a central role in energy production and in reoxidation of reduction equivalents, TcSPPS is promising as a new chemotherapeutic target.

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“…In the mammalian host, the mitochondrion lacks cytochromes and Krebs cycle enzymes (19). Instead, the mitochondrion contributes to NADH oxidation by means of an alternative oxidase (20). A membrane potential is maintained in bloodstream forms at the expense of ATP (21) or through activity of the alternative oxidase (22).…”

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confidence: 99%