Redirection of sphingolipid metabolism toward de novo synthesis of ethanolamine in Leishmania

Kai Zhang, Justine M. Pompey, Fong Fu Hsu, Phillip Key, Padmavathi Bandhuvula, Julie D. Saba, John Turk, Stephen M. Beverley

Research output: Contribution to journalArticlepeer-review

90 Scopus citations

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.

Original languageEnglish
Pages (from-to)1094-1104
Number of pages11
JournalEMBO Journal
Volume26
Issue number4
DOIs
StatePublished - Feb 21 2007

Keywords

  • Metacyclogenesis
  • Phosphatidylethanolamine
  • Sphingolipid
  • Sphingosine-1- phosphate lyase
  • Virulence

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