ArticleEukaryotic cell2006
Farnesyl diphosphate synthase is a cytosolic enzyme in Leishmania major promastigotes and its overexpression confers resistance to risedronate.
Article in Eukaryotic cell, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 34 citations in OpenAlex.
- Article
- Unravelling the myth surrounding sterol biosynthesis as plausible target for drug design against leishmaniasis.Journal of parasitic diseases : official organ of the Indian Society for Parasitology · 2021Review
- Identifying Structural Determinants of Product Specificity inBiochemistry · 2020Article
- Bisphosphonate-Based Molecules as Potential New Antiparasitic Drugs.Molecules (Basel, Switzerland) · 2020Review
- Insights about the structure of farnesyl diphosphate synthase (FPPS) and the activity of bisphosphonates on the proliferation and ultrastructure of Leishmania and Giardia.Parasites & vectors · 2020Article
- Prenylquinones in Human Parasitic Protozoa: Biosynthesis, Physiological Functions, and Potential as Chemotherapeutic Targets.Molecules (Basel, Switzerland) · 2019Review
- Farnesyl pyrophosphate synthase is essential for the promastigote and amastigote stages in Leishmania major.Molecular and biochemical parasitology · 2019Article
- Pharmacophore modeling, docking and molecular dynamics to identify Leishmania major farnesyl pyrophosphate synthase inhibitors.Journal of molecular modeling · 2018Article
- Single-target high-throughput transcription analyses reveal high levels of alternative splicing present in the FPPS/GGPPS from Plasmodium falciparum.Scientific reports · 2015Article
- Structural and thermodynamic basis of the inhibition of Leishmania major farnesyl diphosphate synthase by nitrogen-containing bisphosphonates.Acta crystallographica. Section D, Biological crystallography · 2014Article
- Therapeutic switching in leishmania chemotherapy: a distinct approach towards unsatisfied treatment needs.Journal of parasitic diseases : official organ of the Indian Society for Parasitology · 2011Article
- Rewiring and regulation of cross-compartmentalized metabolism in protists.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2010Review
- Sterol Biosynthesis Pathway as Target for Anti-trypanosomatid Drugs.Interdisciplinary perspectives on infectious diseases · 2009Article
- Farnesyl diphosphate synthase localizes to the cytoplasm of Trypanosoma cruzi and T. brucei.Experimental parasitology · 2008Article
- Farnesyl diphosphate synthase is involved in the resistance to zoledronic acid of osteosarcoma cells.Journal of cellular and molecular medicine · 2008Article
- The acidocalcisome as a target for chemotherapeutic agents in protozoan parasites.Current pharmaceutical design · 2008Review
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Farnesyl diphosphate synthase is the most likely molecular target of aminobisphosphonates (e.g., risedronate), a set of compounds that have been shown to have antiprotozoal activity both in vitro and in vivo. This protein, together with other enzymes involved in isoprenoid biosynthesis, is an attractive drug target, yet little is known about the compartmentalization of the biosynthetic pathway. Here we show the intracellular localization of the enzyme in wild-type Leishmania major promastigote cells and in transfectants overexpressing farnesyl diphosphate synthase by using purified antibodies generated towards a homogenous recombinant Leishmania major farnesyl diphosphate synthase protein. Indirect immunofluorescence, together with immunoelectron microscopy, indicated that the enzyme is mainly located in the cytoplasm of both wild-type cells and transfectants. Digitonin titration experiments also confirmed this observation. Hence, while the initial step of isoprenoid biosynthesis catalyzed by 3-hydroxy-3-methylglutaryl-coenzyme A reductase is located in the mitochondrion, synthesis of farnesyl diphosphate by farnesyl diphosphate synthase is a cytosolic process. Leishmania major promastigote transfectants overexpressing farnesyl diphosphate synthase were highly resistant to risedronate, and the degree of resistance correlated with the increase in enzyme activity. Likewise, when resistance was induced by stepwise selection with the drug, the resulting resistant promastigotes exhibited increased levels of farnesyl diphosphate synthase. The overproduction of protein under different conditions of exposure to risedronate further supports the hypothesis that this enzyme is the main target of aminobisphosphonates in Leishmania cells.
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