Phospholipid and sphingolipid metabolism in Leishmania

Zhang, Kai; Beverley, Stephen M.

doi:10.1016/j.molbiopara.2009.12.004

Cited by 121 publications

(134 citation statements)

References 135 publications

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“…Leishmania PE species often contain the cyclopropyl fatty acid C19Δ [41, 42]. Several PE species were identified and confirmed by accurate mass spectrometry (S5 Fig, S3 Table), by parent ion ES-MS-MS of 295 m/z corresponding to the C19Δ fragment (S6A Fig) and by daughter ion fragmentation by ES-MS-MS (S6B–S6G Fig).…”

Section: Resultsmentioning

confidence: 96%

Different Mutations in a P-type ATPase Transporter in Leishmania Parasites are Associated with Cross-resistance to Two Leading Drugs by Distinct Mechanisms

et al. 2016

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Leishmania infantum is an etiological agent of the life-threatening visceral form of leishmaniasis. Liposomal amphotericin B (AmB) followed by a short administration of miltefosine (MF) is a drug combination effective for treating visceral leishmaniasis in endemic regions of India. Resistance to MF can be due to point mutations in the miltefosine transporter (MT). Here we show that mutations in MT are also observed in Leishmania AmB-resistant mutants. The MF-induced MT mutations, but not the AmB induced mutations in MT, alter the translocation/uptake of MF. Moreover, mutations in the MT selected by AmB or MF have a major impact on lipid species that is linked to cross-resistance between both drugs. These alterations include changes of specific phospholipids, some of which are enriched with cyclopropanated fatty acids, as well as an increase in inositolphosphoceramide species. Collectively these results provide evidence of the risk of cross-resistance emergence derived from current AmB-MF sequential or co-treatments for visceral leishmaniasis.

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Section: Resultsmentioning

confidence: 96%

Different Mutations in a P-type ATPase Transporter in Leishmania Parasites are Associated with Cross-resistance to Two Leading Drugs by Distinct Mechanisms

et al. 2016

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“…This may be due to the fatty acid composition of PE and lysoPE produced by yeast versus Leishmania . In fact, yeast PC fatty acids are of medium length while Leishmania produces PC species with long to very long fatty acids (Tables 2 and 3; data not shown; [3]). It is unclear as to which subspecies of PC are produced via the methylation or the de novo pathway in Leishmania .…”

Section: Resultsmentioning

confidence: 99%

“…Phosphatidylcholine (PC) is the most abundant lipid of the Leishmania biological membrane, representing 30–40% of total cellular lipids [1,2,3]. Structurally, it contains unusually long unsaturated fatty acid chains that are believed to confer a higher degree of resistance towards host-derived oxidants [3].…”

Section: Introductionmentioning

confidence: 99%

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Characterization of Leishmania major phosphatidylethanolamine methyltransferases LmjPEM1 and LmjPEM2 and their inhibition by choline analogs

Bibis

Dahlstrom

Zhu

et al. 2014

Molecular and Biochemical Parasitology

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Phosphatidylcholine (PC) is the most abundant phospholipid in the membranes of the human parasite Leishmania. It is synthesized via two metabolic routes, the de novo pathway that starts with the uptake of choline, and the threefold methylation of phosphatidylethanolamine. Choline was shown to be dispensable for Leishmania; thus, the methylation pathway likely represents the primary route for PC production. Here, we have identified and characterized two phosphatidylethanolamine methyltransferases, LmjPEM1 and LmjPEM2. Both enzymes are expressed in promastigotes as well as in the vertebrate form amastigotes, suggesting that these methyltransferases are important for the development of the parasite throughout its life cycle. These enzymes are maximally expressed during the log phase of growth which correlates with the demand of PC synthesis during cell multiplication. Immunofluorescence studies combined with cell fractionation have shown that both methyltransferases are localized at the endoplasmic reticulum membrane. Heterologous expression in yeast has demonstrated that LmjPEM1 and LmjPEM2 complement the choline auxotrophy phenotype of a yeast double null mutant lacking phosphatidylethanolamine methyltransferase activity. LmjPEM1 catalyzes the first, and to a lesser extent, the second methylation reaction. In contrast, LmjPEM2 has the capacity to add the second and third methyl group onto phosphatidylethanolamine to yield (lyso)PC; it can also add the first methyl group, albeit with very low efficiency. Finally, we have demonstrated using inhibition studies with choline analogs that miltefosine and octadecyltrimethylammonium bromide are potent inhibitors of this metabolic pathway.

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“…IPCS (Inositol phosphorylceramide synthase) has been identified as an important drug target in the sphingolipid metabolism of several organisms like fungi, yeast and protozoans like Leishmania and Trypanosoma 29 . Systems biology has played a major role in defining the relative importance of IPCS in the sphingolipid metabolism of Leishmania , a protozoan responsible for causing an infectious disease leishmaniasis.…”

Section: Discussionmentioning

confidence: 99%

Molecular docking and molecular dynamics simulation study of inositol phosphorylceramide synthase – inhibitor complex in leishmaniasis: Insight into the structure based drug design

Mandlik

Singh

2016

F1000Res

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Inositol phosphorylceramide synthase (IPCS) has emerged as an important, interesting and attractive target in the sphingolipid metabolism of Leishmania. IPCS catalyzes the conversion of ceramide to IPC which forms the most predominant sphingolipid in Leishmania. IPCS has no mammalian equivalent and also plays an important role in maintaining the infectivity and viability of the parasite. The present study explores the possibility of targeting IPCS; development of suitable inhibitors for the same would serve as a treatment strategy for the infectious disease leishmaniasis. Five coumarin derivatives were developed as inhibitors of IPCS protein. Molecular dynamics simulations of the complexes of IPCS with these inhibitors were performed which provided insights into the binding modes of the inhibitors. In vitro screening of the top three compounds has resulted in the identification of one of the compounds (compound 3) which shows little cytotoxic effects. This compound therefore represents a good starting point for further in vivo experimentation and could possibly serve as an important drug candidate for the treatment of leishmaniasis.

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Phospholipid and sphingolipid metabolism in Leishmania

Cited by 121 publications

References 135 publications

Different Mutations in a P-type ATPase Transporter in Leishmania Parasites are Associated with Cross-resistance to Two Leading Drugs by Distinct Mechanisms

Different Mutations in a P-type ATPase Transporter in Leishmania Parasites are Associated with Cross-resistance to Two Leading Drugs by Distinct Mechanisms

Characterization of Leishmania major phosphatidylethanolamine methyltransferases LmjPEM1 and LmjPEM2 and their inhibition by choline analogs

Molecular docking and molecular dynamics simulation study of inositol phosphorylceramide synthase – inhibitor complex in leishmaniasis: Insight into the structure based drug design

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