Farnesyl diphosphate synthase localizes to the cytoplasm of Trypanosoma cruzi and T. brucei

Ferella, Marcela; Li, Zhu-Hong; Andersson, Björn; Docampo, Roberto

doi:10.1016/j.exppara.2008.02.013

Cited by 20 publications

(14 citation statements)

References 37 publications

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“…Overall, these data confirm that sitamaquine accumulates in acidic vesicles such as acidocalcisomes and that there is no correlation between uptake and sensitivity to sitamaquine in Leishmania parasites. This conclusion is similar to those obtained from studies of the mechanism of action of drugs that accumulate in acidocalcisomes: diamidines against Trypanosoma brucei (17,19) and N-alkyl and N-aryl-biphosphonates against parasites of the order Kinetoplastida and the phylum Apicomplexa (8,11). Thus, the accumulation of drugs in acidocalcisomes may not predict in vitro activity and seems to be a widespread phenomenon.…”

Section: Resultssupporting

confidence: 73%

Sitamaquine Sensitivity in Leishmania Species Is Not Mediated by Drug Accumulation in Acidocalcisomes

López-Martín

Pérez‐Victoria

Carvalho

et al. 2008

Antimicrob Agents Chemother

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Sitamaquine (WR6026), an 8-aminoquinoline derivative, is a new antileishmanial oral drug. As a lipophilic weak base, it rapidly accumulates in acidic compartments, represented mainly by acidocalcisomes. In this work, we show that the antileishmanial action of sitamaquine is unrelated to its level of accumulation in these acidic vesicles. We have observed significant differences in sitamaquine sensitivity and accumulation between Leishmania species and strains, and interestingly, there is no correlation between them. However, there is a relationship between the levels of accumulation of sitamaquine and acidotropic probes, acidocalcisomes size, and polyphosphate levels. The Leishmania major AP3␦-null mutant line, in which acidocalcisomes are devoid of their usual polyphosphate and proton content, is unable to accumulate sitamaquine; however, both the parental strain and the AP3␦-null mutants showed similar sensitivities to sitamaquine. Our findings provide clear evidence that the antileishmanial action of sitamaquine is unrelated to its accumulation in acidocalcisomes.

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Section: Resultssupporting

confidence: 73%

Sitamaquine Sensitivity in Leishmania Species Is Not Mediated by Drug Accumulation in Acidocalcisomes

López-Martín

Pérez‐Victoria

Carvalho

et al. 2008

Antimicrob Agents Chemother

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“…The cell suspension was diluted to ;1 mg of total protein per milliliter, and increasing amounts of digitonin (0.01-5 mg/mg total protein) were used in digitonin assays according to Ferella et al (2008).…”

Section: Digitonin Permeabilization Assaymentioning

confidence: 99%

A novel phosphatase cascade regulates differentiation in Trypanosoma brucei via a glycosomal signaling pathway

Szöőr

Burchmore²,

Matthews³

2010

Genes Dev.

118

137

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In the mammalian bloodstream, the sleeping sickness parasite Trypanosoma brucei is held poised for transmission by the activity of a tyrosine phosphatase, TbPTP1. This prevents differentiation of the transmissible “stumpy forms” until entry into the tsetse fly, whereupon TbPTP1 is inactivated and major changes in parasite physiology are initiated to allow colonization of the arthropod vector. Using a substrate-trapping approach, we identified the downstream step in this developmental signaling pathway as a DxDxT phosphatase, TbPIP39, which is activated upon tyrosine phosphorylation, and hence is negatively regulated by TbPTP1. In vitro, TbPIP39 promotes the activity of TbPTP1, thereby reinforcing its own repression, this being alleviated by the trypanosome differentiation triggers citrate and cis-aconitate, generating a potentially bistable regulatory switch. Supporting a role in signal transduction, TbPIP39 becomes rapidly tyrosine-phosphorylated during differentiation, and RNAi-mediated transcript ablation in stumpy forms inhibits parasite development. Interestingly, TbPIP39 localizes in glycosomes, peroxisome-like organelles that compartmentalize the trypanosome glycolytic reactions among other enzymatic activities. Our results invoke a phosphatase signaling cascade in which the developmental signal is trafficked to a unique metabolic organelle in the parasite: the glycosome. This is the first characterized environmental signaling pathway targeted directly to a peroxisome-like organelle in any eukaryotic cell.

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“…Phosphonocarboxylates can also be approached by routes commonly used for preparing bisphosphonates such as Arbuzov-Michaelis reaction of trialkyl phosphite with a-bromoesters, 131 reaction of diethyl phosphite with a-ketoesters, 129 and reaction of enolates and chlorodialkyl phosphites. 132 In addition, the insertion of carboxylic function can be performed by using lithium alkylphosphonate and diethyl carbonate 133 or CO 2 . 134 Another methods include alkylation of trialkyl phosphonoacetate 135 and functionalization of trialkyl 2-phosphonoacrylate via Michael-type addition.…”

Section: Non-bisphosphonate Derivativesmentioning

confidence: 99%

Chemical approaches to inhibitors of isoprenoid biosynthesis: targeting farnesyl and geranylgeranyl pyrophosphate synthases

et al. 2017

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Farnesyl diphosphate synthase localizes to the cytoplasm of Trypanosoma cruzi and T. brucei

Cited by 20 publications

References 37 publications

Sitamaquine Sensitivity in Leishmania Species Is Not Mediated by Drug Accumulation in Acidocalcisomes

Sitamaquine Sensitivity in Leishmania Species Is Not Mediated by Drug Accumulation in Acidocalcisomes

A novel phosphatase cascade regulates differentiation in Trypanosoma brucei via a glycosomal signaling pathway

Chemical approaches to inhibitors of isoprenoid biosynthesis: targeting farnesyl and geranylgeranyl pyrophosphate synthases

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