Mitochondrion; Respiratory chain complexes; Cardiolipin; Phospholipid synthesis; Trypanosoma brucei; Phosphatidylserine; Phosphatidylethanolamine
Farine Luce, Jelk Jennifer, Choi Jae-Yeon, Voelker Dennis R., Nunes Jon, Smith Terry K., Bütikofer Peter (2017), Phosphatidylserine synthase 2 and phosphatidylserine decarboxylase are essential for aminophospholipid synthesis in Trypanosoma brucei Phosphatidylserine metabolism of T. brucei, in Molecular Microbiology
, 104(3), 412-427.
Gottier Petra, Gonzalez-Salgado Amaia, Menon Anant K., Liu Yuk-Chien, Acosta-Serrano Alvaro, Bütikofer Peter (2017), RFT1 Protein Affects Glycosylphosphatidylinositol (GPI) Anchor Glycosylation, in Journal of Biological Chemistry
, 292(3), 1103-1111.
Eltschinger Sandra, Bütikofer Peter, Altmann Michael (2016), Evolution of the Protein Synthesis Machinery and Its Regulation, in Greco Hernández (ed.), 277-311.
Klionsky Daniel J., Abdelmohsen Kotb, Abe Akihisa, Abedin Md Joynal, Abeliovich Hagai, Arozena Abraham Acevedo, Adachi Hiroaki, Adams Christopher M., Adams Peter D., Adeli Khosrow, Adhihetty Peter J., Adler Sharon G., Agam Galila, Agarwal Rajesh, Aghi Manish K., Agnello Maria, Agostinis Patrizia, Aguilar Patricia V., Aguirre-Ghiso Julio, Airoldi Edoardo M., Ait-Si-Ali Slimane, Akematsu Takahiko, Akporiaye Emmanuel T., Al-Rubeai Mohamed, Albaiceta Guillermo M. (2016), Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition), in AUTOPHAGY
, 12(1), 1-222.
Chauhan Neha, Farine Luce, Pandey Kalpana, Menon Anant K., Bütikofer Peter (2016), Lipid topogenesis — 35 years on, in Biochim Biophys Acta
, 1861, 757-766.
Imhof Simon, Vu Xuan Lan, Bütikofer Peter, Roditi Isabel (2015), A Glycosylation Mutant of Trypanosoma brucei Links Social Motility Defects In Vitro to Impaired Colonization of Tsetse Flies In Vivo., in Eukaryotic Cell
, 14(6), 588-92.
de Macedo Juan P., Burkard Gabriela Schumann, Niemann Moritz, Barrett Michael P., Vial Henri, Maeser Pascal, Roditi Isabel, Schneider Andre, Buetikofer Peter (2015), An Atypical Mitochondrial Carrier That Mediates Drug Action in Trypanosoma brucei, in PLOS PATHOGENS
, 11(5), e1004875.
Serricchio Mauro, Schmid Adrien W., Steinmann Michael E., Sigel Erwin, Rauch Monika, Julkowska Daria, Bonnefoy Serge, Fort Cecile, Bastin Philippe, Buetikofer Peter (2015), Flagellar membranes are rich in raft-forming phospholipids, in BIOLOGY OPEN
, 4(9), 1143-1153.
Farine Luce, Niemann Moritz, Schneider Andre, Buetikofer Peter (2015), Phosphatidylethanolamine and phosphatidylcholine biosynthesis by the Kennedy pathway occurs at different sites in Trypanosoma brucei, in SCIENTIFIC REPORTS
, 5, 16787.
Shameer Sanu, Logan-Klumpler Flora J., Vinson Florence, Cottret Ludovic, Merlet Benjamin, Achcar Fiona, Boshart Michael, Berriman Matthew, Breitling Rainer, Bringaud Fredrric, Butikofer Peter, Cattanach Amy M., Bannerman-Chukualim Bridget, Creek Darren J., Crouch Kathryn, de Koning Harry P., Denise Hubert, Ebikeme Charles, Fairlamb Alan H., Ferguson Michael A. J., Ginger Michael L., Hertz-Fowler Christiane, Kerkhoven Eduard J., Maeser Pascal, Michels Paul A. M. (2015), TrypanoCyc: a community-led biochemical pathways database for Trypanosoma brucei, in NUCLEIC ACIDS RESEARCH
, 43(D1), 637-644.
Gonzalez-Salgado Amaia, Steinmann Michael, Major Louise L., Sigel Erwin, Reymond Jean-Louis, Smith Terry K., Buetikofer Peter (2015), Trypanosoma brucei Bloodstream Forms Depend upon Uptake of myo-Inositol for Golgi Complex Phosphatidylinositol Synthesis and Normal Cell Growth, in EUKARYOTIC CELL
, 14(6), 616-624.
Schmidt Remo S., Buetikofer Peter (2014), Autophagy in Trypanosoma brucei: Amino Acid Requirement and Regulation during Different Growth Phases, in PLOS ONE
, 9(4), e93875.
The World Health Organisation has classified human African sleeping sickness as neglected tropical disease and has implemented several programs to control its spread and transmission. The disease is caused by the protozoan parasite, Trypanosoma brucei, which is transmitted between mammalian hosts by the tsetse insect vector. Because of a threat of emerging resistance against key drugs against African trypanosomes, and because currently available drugs show potentially life-threatening toxicity and efficacy problems, major efforts to identify novel trypanosome candidate target molecules or pathways for drug development are needed.T. brucei has also emerged as valuable model organism to study general biological processes, such as antigenic variation, glycosylphosphatidylinositol-anchoring, membrane and organelle formation, and cell differentiation. Trypanosomes can easily be propagated in vitro and are amenable to reverse genetic approaches, including inducible RNAi-mediated silencing of gene expression and gene knock-out by homologous recombination. During the last decade, we have worked on the elucidation of pathways involved in lipid modifications of proteins and de novo synthesis of phospholipids in T. brucei. We have experimentally established the enzymatic reaction sequences leading to the production of phosphatidylethanolamine (PE), a major membrane phospholipid in T. brucei, and more recently, of phosphatidylglycerol (PG) and cardiolipin (CL), two signature lipids of mitochondria. Our results have demonstrated that de novo formation of PE, PG and CL is essential for growth of T. brucei procyclic (insect) and bloodstream form parasites in culture, validating the enzymes and metabolites involved in these pathways as potential drug targets.It is well known that PE, PG and CL are required for proper function of several mitochondrial membrane proteins, in particular those belonging to the respiratory chain. In addition, they are involved in the formation and/or stability of high molecular mass protein complexes of the inner mitochondrial membrane. The availability in our laboratory of inducible knock-out and knock-down trypanosomes deficient in de novo PE, PG and CL synthesis will allow us to study the roles of these phospholipids in protein function and stability in a controlled, i.e. inducible and time-dependent, and thus more detailed way than in other eukaryotic model organisms. We plan to characterize the substrate specificity of T. brucei cardiolipin synthase, the first ever exerimentally identified prokaryotic-type CL synthase in a eukaryote, and study if the trypanosome enzyme is able to complement CL synthase-deficient yeast or bacterial strains. In addition, we aim to partially purify and characterize the protein complexes associated with CL synthase and phosphatidylglycerophosphate synthase and investigate the effects of CL and PG depletion on T. brucei mitochondrial membrane complex formation.Another focus of the grant application addresses the localization of key enzymes involved in de novo PE synthesis and proposes to determine the contributions of different routes, such as the CDP-ethanolamine pathway, phosphatidylserine decarboxylation and degradation of sphingolipids, to PE formation in T. brucei.