title: Redirection of sphingolipid metabolism toward de novo synthesis of ethanolamine in Leishmania.
abstract: In most eukaryotes, sphingolipids (SLs) are critical membrane components and signaling molecules. However, mutants of the trypanosomatid protozoan Leishmania lacking serine palmitoyltransferase (spt2-) and SLs grow well, although they are defective in stationary phase differentiation and virulence. Similar phenotypes were observed in sphingolipid (SL) mutant lacking the degradatory enzyme sphingosine 1-phosphate lyase (spl-). This epistatic interaction suggested that a metabolite downstream of SLs was responsible. Here we show that unlike other organisms, the Leishmania SL pathway has evolved to be the major route for ethanolamine (EtN) synthesis, as EtN supplementation completely reversed the viability and differentiation defects of both mutants. Thus Leishmania has undergone two major metabolic shifts: first in de-emphasizing the metabolic roles of SLs themselves in growth, signaling, and maintenance of membrane microdomains, which may arise from the unique combination of abundant parasite lipids; Second, freed of typical SL functional constraints and a lack of alternative routes to produce EtN, Leishmania redirected SL metabolism toward bulk EtN synthesis. Our results thus reveal a striking example of remodeling of the SL metabolic pathway in Leishmania.
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO 63110, and Children's Hospital Oakland Research Institute, Center for Cancer Research, CA, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhang
authors.forename: Justine M
authors.initials: JM
authors.lastname: Pompey
authors.forename: Fong-Fu
authors.initials: FF
authors.lastname: Hsu
authors.forename: Phillip
authors.initials: P
authors.lastname: Key
authors.forename: Padmavathi
authors.initials: P
authors.lastname: Bandhuvula
authors.forename: Julie D
authors.initials: JD
authors.lastname: Saba
authors.forename: John
authors.initials: J
authors.lastname: Turk
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Beverley
mesh_terms: D000446:Aldehyde-Lyases / Q000172:deficiency / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D005075:Biological Evolution; D053898:Biosynthetic Pathways / Q000235:genetics*; D003001:Cloning, Molecular; D019856:Ethanolamine / Q000378:metabolism*; D005260:Female; D005528:Foot / Q000382:microbiology / Q000473:pathology; D018320:Leishmania major / Q000235:genetics* / Q000378:metabolism* / Q000472:pathogenicity / Q000648:ultrastructure; D013058:Mass Spectrometry; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D017422:Sequence Analysis, DNA; D051102:Serine C-Palmitoyltransferase / Q000172:deficiency / Q000235:genetics; D013107:Sphingolipids / Q000378:metabolism*
chemical_list: D013107:Sphingolipids; D019856:Ethanolamine; D051102:Serine C-Palmitoyltransferase; D000446:Aldehyde-Lyases; C022649:sphingosine 1-phosphate lyase (aldolase)