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The Trypanosoma brucei sphingolipid synthase, an essential enzyme and drug target

The Trypanosoma brucei sphingolipid synthase, an essential enzyme and drug target
The Trypanosoma brucei sphingolipid synthase, an essential enzyme and drug target
Sphingolipids are important components of eukaryotic membranes, particularly the plasma membrane, and are involved in a diverse array of signal transduction processes. In the Eukaryota the biosynthetic pathway for the formation of these lipid species is largely conserved. However, in contrast to mammals which produce sphingomyelin (SM), several pathogenic fungi and protozoa synthesize inositol phosphorylceramide (IPC) as the primary phosphosphingolipid. This process is catalyzed by the enzyme IPC synthase, a recognized target for anti-fungals encoded by the AUR1 gene in yeast. Recently, functional orthologues of the AUR1p have been identified in a group of insect vector-borne pathogenic protozoa, the Kinetoplastida, which are responsible for a range of so-called neglected diseases. Of these the Trypanosoma brucei species are the causative agents of human African trypanosomiasis in many of the most under-developed regions of Africa. The available treatments for these diseases are limited, of decreasing efficacy, and often demonstrate severe side-effects. Against this background the T. brucei sphingolipid synthase, an orthologue of the yeast AUR1p, may represent a promising target for novel anti-protozoals. Our studies identify an isoform of this protein as a novel bi-functional enzyme capable of catalyzing the synthesis of both IPC and SM, both known to be present in the parasite. Furthermore, the synthase is essential for parasite growth and can be inhibited by a known anti-fungal at low nanomolar levels in vitro. Most notably this drug demonstrates trypanocidal activity against cultured bloodstream form parasites. Thus, the T. brucei sphingolipid synthase represents a valid and promising drug target.
0166-6851
16-23
Mina, J.G.
a239b57a-b3cb-41fe-965d-8211ca14a10e
Denny, P.W.
41626b4a-6f75-460f-a2a0-2018a93ef8aa
Ssu-Ying, P.
725b2ae2-93ae-4423-bac3-29b3686975d5
Wansadhipathi-Kannangara, N.K.
a2c031cf-a6b1-4ccf-af88-c41cedda3c00
Mina, J.G.
a239b57a-b3cb-41fe-965d-8211ca14a10e
Denny, P.W.
41626b4a-6f75-460f-a2a0-2018a93ef8aa
Ssu-Ying, P.
725b2ae2-93ae-4423-bac3-29b3686975d5
Wansadhipathi-Kannangara, N.K.
a2c031cf-a6b1-4ccf-af88-c41cedda3c00

Mina, J.G., Denny, P.W., Ssu-Ying, P. and Wansadhipathi-Kannangara, N.K. (2009) The Trypanosoma brucei sphingolipid synthase, an essential enzyme and drug target. Molecular and Biochemical Parasitology, 168 (1), 16-23. (doi:10.1016/j.molbiopara.2009.06.002). (PMID:19545591 )

Record type: Article

Abstract

Sphingolipids are important components of eukaryotic membranes, particularly the plasma membrane, and are involved in a diverse array of signal transduction processes. In the Eukaryota the biosynthetic pathway for the formation of these lipid species is largely conserved. However, in contrast to mammals which produce sphingomyelin (SM), several pathogenic fungi and protozoa synthesize inositol phosphorylceramide (IPC) as the primary phosphosphingolipid. This process is catalyzed by the enzyme IPC synthase, a recognized target for anti-fungals encoded by the AUR1 gene in yeast. Recently, functional orthologues of the AUR1p have been identified in a group of insect vector-borne pathogenic protozoa, the Kinetoplastida, which are responsible for a range of so-called neglected diseases. Of these the Trypanosoma brucei species are the causative agents of human African trypanosomiasis in many of the most under-developed regions of Africa. The available treatments for these diseases are limited, of decreasing efficacy, and often demonstrate severe side-effects. Against this background the T. brucei sphingolipid synthase, an orthologue of the yeast AUR1p, may represent a promising target for novel anti-protozoals. Our studies identify an isoform of this protein as a novel bi-functional enzyme capable of catalyzing the synthesis of both IPC and SM, both known to be present in the parasite. Furthermore, the synthase is essential for parasite growth and can be inhibited by a known anti-fungal at low nanomolar levels in vitro. Most notably this drug demonstrates trypanocidal activity against cultured bloodstream form parasites. Thus, the T. brucei sphingolipid synthase represents a valid and promising drug target.

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Published date: 1 November 2009
Organisations: Faculty of Medicine

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Local EPrints ID: 373078
URI: https://eprints.soton.ac.uk/id/eprint/373078
ISSN: 0166-6851
PURE UUID: 520d4ef4-b379-45e1-a472-db8f4e2cccff

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Date deposited: 12 Jan 2015 09:00
Last modified: 17 Jul 2017 21:36

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Contributors

Author: J.G. Mina
Author: P.W. Denny
Author: P. Ssu-Ying
Author: N.K. Wansadhipathi-Kannangara

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