title: Genetic Characterization of Plasmodium Putative Pantothenate Kinase Genes Reveals Their Essential Role in Malaria Parasite Transmission to the Mosquito.
abstract: The metabolic machinery for the biosynthesis of Coenzyme A (CoA) from exogenous pantothenic acid (Vitamin B5) has long been considered as an excellent target for the development of selective antimicrobials. Earlier studies in the human malaria parasite Plasmodium falciparum have shown that pantothenate analogs interfere with pantothenate phosphorylation and block asexual blood stage development. Although two eukaryotic-type putative pantothenate kinase genes (PanK1 and PanK2) have been identified in all malaria parasite species, their role in the development of Plasmodium life cycle stages remains unknown. Here we report on the genetic characterization of PanK1 and PanK2 in P. yoelii. We show that P. yoelii parasites lacking either PanK1 or PanK2 undergo normal asexual stages development and sexual stages differentiation, however they are severely deficient in ookinete, oocyst and sporozoite formation inside the mosquito vector. Quantitative transcriptional analyses in wild-type and knockout parasites demonstrate an important role for these genes in the regulation of expression of other CoA biosynthesis genes. Together, our data provide the first genetic evidence for the importance of the early steps of pantothenate utilization in the regulation of CoA biosynthesis and malaria parasite transmission to Anopheles mosquitoes.
authors.affiliation: Tulane University, Department of Tropical Medicine, New Orleans, LA 70112, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Hart
authors.affiliation: Institut de Biologie Computationnelle, Université Montpellier, 34095 Montpellier, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Cornillot
authors.affiliation: Tulane University, Department of Tropical Medicine, New Orleans, LA 70112, USA.
authors.forename: Amanah
authors.initials: A
authors.lastname: Abraham
authors.affiliation: Tulane University, Department of Tropical Medicine, New Orleans, LA 70112, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Molina
authors.affiliation: Tulane University, Department of Tropical Medicine, New Orleans, LA 70112, USA.
authors.forename: Catherine S
authors.initials: CS
authors.lastname: Nation
authors.affiliation: Yale University School of Medicine, Section of Infectious Diseases, New Haven, CT 06520, USA.
authors.forename: Choukri
authors.initials: C
authors.lastname: Ben Mamoun
authors.affiliation: Tulane University, Department of Tropical Medicine, New Orleans, LA 70112, USA.
authors.forename: Ahmed S I
authors.initials: AS
authors.lastname: Aly
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000852:Anopheles / Q000469:parasitology*; D053898:Biosynthetic Pathways; D003065:Coenzyme A / Q000096:biosynthesis; D017124:Conserved Sequence; D004912:Erythrocytes / Q000469:parasitology; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D017125:Genes, Protozoan; D008018:Life Cycle Stages; D008288:Malaria / Q000235:genetics / Q000469:parasitology*; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D033661:Oocysts / Q000378:metabolism; D010271:Parasites / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010802:Phylogeny; D010961:Plasmodium / Q000201:enzymology* / Q000235:genetics* / Q000254:growth & development; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D034101:Sporozoites / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D015800:Protozoan Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase; D003065:Coenzyme A