title: Squalestatin is an inhibitor of carotenoid biosynthesis in Plasmodium falciparum.
abstract: The increasing resistance of malaria parasites to almost all available drugs calls for the characterization of novel targets and the identification of new compounds. Carotenoids are polyisoprenoids from plants, algae, and some bacteria, and they are biosynthesized by Plasmodium falciparum but not by mammalian cells. Biochemical and reverse genetics approaches were applied to demonstrate that phytoene synthase (PSY) is a key enzyme for carotenoid biosynthesis in P. falciparum and is essential for intraerythrocytic growth. The known PSY inhibitor squalestatin reduces biosynthesis of phytoene and kills parasites during the intraerythrocytic cycle. PSY-overexpressing parasites showed increased biosynthesis of phytoene and its derived product phytofluene and presented a squalestatin-resistant phenotype, suggesting that this enzyme is the primary target of action of this drug in the parasite.
authors.affiliation: Department of Parasitology, Institute of Biomedical Science, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Heloisa B
authors.initials: HB
authors.lastname: Gabriel
authors.affiliation: Department of Parasitology, Institute of Biomedical Science, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Marcia F
authors.initials: MF
authors.lastname: Silva
authors.affiliation: Department of Parasitology, Institute of Biomedical Science, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Emília A
authors.initials: EA
authors.lastname: Kimura
authors.affiliation: Department of Parasitology, Institute of Biomedical Science, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wunderlich
authors.affiliation: Department of Parasitology, Institute of Biomedical Science, University of Sao Paulo, Sao Paulo, Brazil amkatzin@icb.usp.br maurousp@gmail.com.
authors.forename: Alejandro M
authors.initials: AM
authors.lastname: Katzin
authors.affiliation: Department of Parasitology, Institute of Biomedical Science, University of Sao Paulo, Sao Paulo, Brazil amkatzin@icb.usp.br maurousp@gmail.com.
authors.forename: Mauro F
authors.initials: MF
authors.lastname: Azevedo
mesh_terms: D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology*; D002338:Carotenoids / Q000096:biosynthesis*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D000962:Antimalarials; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002338:Carotenoids; C100185:(all-E) phytoene