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Sphingolipid synthesis and scavenging in the intracellular apicomplexan parasite, Toxoplasma gondii

Sphingolipid synthesis and scavenging in the intracellular apicomplexan parasite, Toxoplasma gondii
Sphingolipid synthesis and scavenging in the intracellular apicomplexan parasite, Toxoplasma gondii
Sphingolipids are essential components of eukaryotic cell membranes, particularly the plasma membrane, and are involved in a diverse array of signal transduction pathways. Mammals produce sphingomyelin (SM) as the primary complex sphingolipid via the well characterised SM synthase. In contrast yeast, plants and some protozoa utilise an evolutionarily related inositol phosphorylceramide (IPC) synthase to synthesise IPC. This activity has no mammalian equivalent and IPC synthase has been proposed as a target for anti-fungals and anti-protozoals. However, detailed knowledge of the sphingolipid biosynthetic pathway of the apicomplexan protozoan parasites was lacking. In this study bioinformatic analyses indicated a single copy orthologue of the putative SM synthase from the apicomplexan Plasmodium falciparum (the causative agent of malaria) was a bona fide sphingolipid synthase in the related model parasite, Toxoplasma gondii (TgSLS). Subsequently, TgSLS was indicated, by complementation of a mutant cell line, to be a functional orthologue of the yeast IPC synthase (AUR1p), demonstrating resistance to the well characterised AUR1p inhibitor aureobasidin A. In vitro, recombinant TgSLS exhibited IPC synthase activity and, for the first time, the presence of IPC was demonstrated in T. gondii lipid extracts by mass spectrometry. Furthermore, host sphingolipid biosynthesis was indicated to influence, but be non-essential for, T. gondii proliferation, suggesting that whilst scavenging does take place de novo sphingolipid synthesis may be important for parasitism.
toxoplasma, sphingolipid, inositol phosphorylceramide synthase, host–parasite interaction
0166-6851
43-51
Pratt, Steven
d0232710-1625-4d92-a104-186b9745a695
Wansadhipathi-Kannangara, Nilu K.
a2c031cf-a6b1-4ccf-af88-c41cedda3c00
Bruce, Catherine R.
6a4230d5-af4f-4488-acc3-073b4a24919b
Mina, John G.
7141c6c8-1c1d-44ea-8763-0f5916dad545
Shams-Eldin, Hosam
4db2a951-cea0-4ba7-a5bd-728627aead66
Casas, Josefina
689d8cc0-bca6-44c6-8615-28a0f955478a
Hanada, Kentaro
c7aa02ef-ec85-45fa-91c8-36d470fadc94
Schwarz, Ralph T.
9008395e-9695-43a1-aa96-66ec3bf5ef3f
Sonda, Sabrina
e6978d56-b6d5-46b3-9ce1-f155b4bd92b5
Denny, Paul W.
01634b01-03d4-4b8a-b559-cd17b88d6efb
Pratt, Steven
d0232710-1625-4d92-a104-186b9745a695
Wansadhipathi-Kannangara, Nilu K.
a2c031cf-a6b1-4ccf-af88-c41cedda3c00
Bruce, Catherine R.
6a4230d5-af4f-4488-acc3-073b4a24919b
Mina, John G.
7141c6c8-1c1d-44ea-8763-0f5916dad545
Shams-Eldin, Hosam
4db2a951-cea0-4ba7-a5bd-728627aead66
Casas, Josefina
689d8cc0-bca6-44c6-8615-28a0f955478a
Hanada, Kentaro
c7aa02ef-ec85-45fa-91c8-36d470fadc94
Schwarz, Ralph T.
9008395e-9695-43a1-aa96-66ec3bf5ef3f
Sonda, Sabrina
e6978d56-b6d5-46b3-9ce1-f155b4bd92b5
Denny, Paul W.
01634b01-03d4-4b8a-b559-cd17b88d6efb

Pratt, Steven, Wansadhipathi-Kannangara, Nilu K., Bruce, Catherine R., Mina, John G., Shams-Eldin, Hosam, Casas, Josefina, Hanada, Kentaro, Schwarz, Ralph T., Sonda, Sabrina and Denny, Paul W. (2013) Sphingolipid synthesis and scavenging in the intracellular apicomplexan parasite, Toxoplasma gondii. Molecular and Biochemical Parasitology, 187 (1), 43-51. (doi:10.1016/j.molbiopara.2012.11.007). (PMID:23246819)

Record type: Article

Abstract

Sphingolipids are essential components of eukaryotic cell membranes, particularly the plasma membrane, and are involved in a diverse array of signal transduction pathways. Mammals produce sphingomyelin (SM) as the primary complex sphingolipid via the well characterised SM synthase. In contrast yeast, plants and some protozoa utilise an evolutionarily related inositol phosphorylceramide (IPC) synthase to synthesise IPC. This activity has no mammalian equivalent and IPC synthase has been proposed as a target for anti-fungals and anti-protozoals. However, detailed knowledge of the sphingolipid biosynthetic pathway of the apicomplexan protozoan parasites was lacking. In this study bioinformatic analyses indicated a single copy orthologue of the putative SM synthase from the apicomplexan Plasmodium falciparum (the causative agent of malaria) was a bona fide sphingolipid synthase in the related model parasite, Toxoplasma gondii (TgSLS). Subsequently, TgSLS was indicated, by complementation of a mutant cell line, to be a functional orthologue of the yeast IPC synthase (AUR1p), demonstrating resistance to the well characterised AUR1p inhibitor aureobasidin A. In vitro, recombinant TgSLS exhibited IPC synthase activity and, for the first time, the presence of IPC was demonstrated in T. gondii lipid extracts by mass spectrometry. Furthermore, host sphingolipid biosynthesis was indicated to influence, but be non-essential for, T. gondii proliferation, suggesting that whilst scavenging does take place de novo sphingolipid synthesis may be important for parasitism.

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e-pub ahead of print date: 16 December 2012
Published date: January 2013
Keywords: toxoplasma, sphingolipid, inositol phosphorylceramide synthase, host–parasite interaction
Organisations: Faculty of Medicine

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Local EPrints ID: 373079
URI: http://eprints.soton.ac.uk/id/eprint/373079
ISSN: 0166-6851
PURE UUID: 14e5cdbb-bde2-405d-86c5-6c6884731c8a

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Date deposited: 06 Jan 2015 15:01
Last modified: 18 Nov 2019 20:28

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Contributors

Author: Steven Pratt
Author: Nilu K. Wansadhipathi-Kannangara
Author: Catherine R. Bruce
Author: John G. Mina
Author: Hosam Shams-Eldin
Author: Josefina Casas
Author: Kentaro Hanada
Author: Ralph T. Schwarz
Author: Sabrina Sonda
Author: Paul W. Denny

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