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Plasmodium falciparum Phospholipase C Hydrolyzing Sphingomyelin and Lysocholinephospholipids Is a Possible Target for Malaria Chemotherapy

Sphingomyelinase (SMase) is one of the principal enzymes in sphingomyelin (SM) metabolism. Here, we identified a Plasmodium falciparum gene (PfNSM) encoding a 46-kD protein, the amino acid sequence of which is ∼25% identical to that of bacteria SMases. Biochemical analyses of the recombinant protein...

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Autores principales: Hanada, Kentaro, Palacpac, Nirianne Marie Q., Magistrado, Pamela A., Kurokawa, Ken, Rai, Ganesh, Sakata, Daiji, Hara, Tomoko, Horii, Toshihiro, Nishijima, Masahiro, Mitamura, Toshihide
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2002
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2196011/
https://www.ncbi.nlm.nih.gov/pubmed/11781362
http://dx.doi.org/10.1084/jem.20010724
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author Hanada, Kentaro
Palacpac, Nirianne Marie Q.
Magistrado, Pamela A.
Kurokawa, Ken
Rai, Ganesh
Sakata, Daiji
Hara, Tomoko
Horii, Toshihiro
Nishijima, Masahiro
Mitamura, Toshihide
author_facet Hanada, Kentaro
Palacpac, Nirianne Marie Q.
Magistrado, Pamela A.
Kurokawa, Ken
Rai, Ganesh
Sakata, Daiji
Hara, Tomoko
Horii, Toshihiro
Nishijima, Masahiro
Mitamura, Toshihide
author_sort Hanada, Kentaro
collection PubMed
description Sphingomyelinase (SMase) is one of the principal enzymes in sphingomyelin (SM) metabolism. Here, we identified a Plasmodium falciparum gene (PfNSM) encoding a 46-kD protein, the amino acid sequence of which is ∼25% identical to that of bacteria SMases. Biochemical analyses of the recombinant protein GST-PfNSM, a fusion protein of the PfNSM product with glutathione-S-transferase, reveal that this enzyme retained similar characteristics in various aspects to SMase detected in P. falciparum–infected erythrocytes and isolated parasites. In addition, the recombinant protein retains hydrolyzing activity not only of SM but also of lysocholinephospholipids (LCPL) including lysophosphatidylcholine and lysoplatelet-activating factor, indicating that PfNSM encodes SM/LCPL-phospholipase C (PLC). Scyphostatin inhibited SM/LCPL-PLC activities of the PfNSM product as well as the intraerythrocytic proliferation of P. falciparum in a dose-dependent manner with ID(50) values for SM/LCPL-PLC activities and the parasite growth at 3–5 μM and ∼7 μM, respectively. Morphological analysis demonstrated most severe impairment in the intraerythrocytic development with the addition of scyphostatin at trophozoite stage than at ring or schizont stages, suggesting its effect specifically on the stage progression from trophozoite to schizont, coinciding with the active transcription of PfNSM gene.
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spelling pubmed-21960112008-04-14 Plasmodium falciparum Phospholipase C Hydrolyzing Sphingomyelin and Lysocholinephospholipids Is a Possible Target for Malaria Chemotherapy Hanada, Kentaro Palacpac, Nirianne Marie Q. Magistrado, Pamela A. Kurokawa, Ken Rai, Ganesh Sakata, Daiji Hara, Tomoko Horii, Toshihiro Nishijima, Masahiro Mitamura, Toshihide J Exp Med Original Article Sphingomyelinase (SMase) is one of the principal enzymes in sphingomyelin (SM) metabolism. Here, we identified a Plasmodium falciparum gene (PfNSM) encoding a 46-kD protein, the amino acid sequence of which is ∼25% identical to that of bacteria SMases. Biochemical analyses of the recombinant protein GST-PfNSM, a fusion protein of the PfNSM product with glutathione-S-transferase, reveal that this enzyme retained similar characteristics in various aspects to SMase detected in P. falciparum–infected erythrocytes and isolated parasites. In addition, the recombinant protein retains hydrolyzing activity not only of SM but also of lysocholinephospholipids (LCPL) including lysophosphatidylcholine and lysoplatelet-activating factor, indicating that PfNSM encodes SM/LCPL-phospholipase C (PLC). Scyphostatin inhibited SM/LCPL-PLC activities of the PfNSM product as well as the intraerythrocytic proliferation of P. falciparum in a dose-dependent manner with ID(50) values for SM/LCPL-PLC activities and the parasite growth at 3–5 μM and ∼7 μM, respectively. Morphological analysis demonstrated most severe impairment in the intraerythrocytic development with the addition of scyphostatin at trophozoite stage than at ring or schizont stages, suggesting its effect specifically on the stage progression from trophozoite to schizont, coinciding with the active transcription of PfNSM gene. The Rockefeller University Press 2002-01-07 /pmc/articles/PMC2196011/ /pubmed/11781362 http://dx.doi.org/10.1084/jem.20010724 Text en Copyright © 2002, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Original Article
Hanada, Kentaro
Palacpac, Nirianne Marie Q.
Magistrado, Pamela A.
Kurokawa, Ken
Rai, Ganesh
Sakata, Daiji
Hara, Tomoko
Horii, Toshihiro
Nishijima, Masahiro
Mitamura, Toshihide
Plasmodium falciparum Phospholipase C Hydrolyzing Sphingomyelin and Lysocholinephospholipids Is a Possible Target for Malaria Chemotherapy
title Plasmodium falciparum Phospholipase C Hydrolyzing Sphingomyelin and Lysocholinephospholipids Is a Possible Target for Malaria Chemotherapy
title_full Plasmodium falciparum Phospholipase C Hydrolyzing Sphingomyelin and Lysocholinephospholipids Is a Possible Target for Malaria Chemotherapy
title_fullStr Plasmodium falciparum Phospholipase C Hydrolyzing Sphingomyelin and Lysocholinephospholipids Is a Possible Target for Malaria Chemotherapy
title_full_unstemmed Plasmodium falciparum Phospholipase C Hydrolyzing Sphingomyelin and Lysocholinephospholipids Is a Possible Target for Malaria Chemotherapy
title_short Plasmodium falciparum Phospholipase C Hydrolyzing Sphingomyelin and Lysocholinephospholipids Is a Possible Target for Malaria Chemotherapy
title_sort plasmodium falciparum phospholipase c hydrolyzing sphingomyelin and lysocholinephospholipids is a possible target for malaria chemotherapy
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2196011/
https://www.ncbi.nlm.nih.gov/pubmed/11781362
http://dx.doi.org/10.1084/jem.20010724
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