TY - JOUR
T1 - Redirection of sphingolipid metabolism toward de novo synthesis of ethanolamine in Leishmania
AU - Zhang, Kai
AU - Pompey, Justine M.
AU - Hsu, Fong Fu
AU - Key, Phillip
AU - Bandhuvula, Padmavathi
AU - Saba, Julie D.
AU - Turk, John
AU - Beverley, Stephen M.
PY - 2007/2/21
Y1 - 2007/2/21
N2 - 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.
AB - 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.
KW - Metacyclogenesis
KW - Phosphatidylethanolamine
KW - Sphingolipid
KW - Sphingosine-1- phosphate lyase
KW - Virulence
UR - http://www.scopus.com/inward/record.url?scp=33847209549&partnerID=8YFLogxK
U2 - 10.1038/sj.emboj.7601565
DO - 10.1038/sj.emboj.7601565
M3 - Article
C2 - 17290222
AN - SCOPUS:33847209549
SN - 0261-4189
VL - 26
SP - 1094
EP - 1104
JO - EMBO Journal
JF - EMBO Journal
IS - 4
ER -