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

Abstract：

: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.

journal_name

Mol Biochem Parasitol

journal_title

Molecular and biochemical parasitology

authors

Bibis SS,Dahlstrom K,Zhu T,Zufferey R

doi

10.1016/j.molbiopara.2014.08.005

subject

Has Abstract

pub_date

2014-09-01 00:00:00

pages

90-9

issue

eissn

0166-6851

issn

1872-9428

pii

S0166-6851(14)00114-5

journal_volume

196

pub_type

杂志文章

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