title: Isoprenoid precursor biosynthesis is the essential metabolic role of the apicoplast during gametocytogenesis in Plasmodium falciparum.
abstract: The malaria parasite harbors a relict plastid called the apicoplast and its discovery opened a new avenue for drug discovery and development due to its unusual, nonmammalian metabolism. The apicoplast is essential during the asexual intraerythrocytic and hepatic stages of the parasite, and there is strong evidence supporting its essential metabolic role during the mosquito stages of the parasite. Supply of the isoprenoid building blocks isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) is the essential metabolic function of the apicoplast during the asexual intraerythrocytic stages. However, the metabolic role of the apicoplast during gametocyte development, the malaria stages transmitted to the mosquito, remains unknown. In this study, we showed that production of IPP for isoprenoid biosynthesis is the essential metabolic function of the apicoplast during gametocytogenesis, by obtaining normal gametocytes lacking the apicoplast when supplemented with IPP. When IPP supplementation was removed early in gametocytogenesis, developmental defects were observed, supporting the essential role of isoprenoids for normal gametocytogenesis. Furthermore, mosquitoes infected with gametocytes lacking the apicoplast developed fewer and smaller oocysts that failed to produce sporozoites. This finding further supports the essential role of the apicoplast in establishing a successful infection in the mosquito vector. Our study supports isoprenoid biosynthesis as a valid drug target for development of malaria transmission-blocking inhibitors.
authors.affiliation: Department of Biochemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia, USA.
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Wiley
authors.affiliation: Department of Biochemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia, USA.
authors.forename: Emilio F
authors.initials: EF
authors.lastname: Merino
authors.affiliation: Department of Biochemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia, USA.
authors.forename: Priscilla M
authors.initials: PM
authors.lastname: Krai
authors.affiliation: The W. Harry Feinstone Department of Molecular Microbiology and Immunology, Malaria Research Institute, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: McLean
authors.affiliation: The W. Harry Feinstone Department of Molecular Microbiology and Immunology, Malaria Research Institute, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Abhai K
authors.initials: AK
authors.lastname: Tripathi
authors.affiliation: The W. Harry Feinstone Department of Molecular Microbiology and Immunology, Malaria Research Institute, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Vega-Rodríguez
authors.affiliation: The W. Harry Feinstone Department of Molecular Microbiology and Immunology, Malaria Research Institute, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Jacobs-Lorena
authors.affiliation: Department of Biochemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Klemba
authors.affiliation: Department of Biochemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia, USA bcassera@vt.edu.
authors.forename: Maria B
authors.initials: MB
authors.lastname: Cassera
mesh_terms: D000818:Animals; D063546:Apicoplasts / Q000378:metabolism*; D005718:Gametogenesis; D045782:Hemiterpenes / Q000096:biosynthesis*; D008018:Life Cycle Stages; D009943:Organophosphorus Compounds; D010963:Plasmodium falciparum / Q000254:growth & development / Q000378:metabolism*
chemical_list: D045782:Hemiterpenes; D009943:Organophosphorus Compounds; C004809:isopentenyl pyrophosphate; C043060:3,3-dimethylallyl pyrophosphate