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

Nilu Wansadhipathi-Kannangara, John Mina, Ssu-Ying Pan, Nilu Wansadhipathi, Catherine Bruce, Hosam Shams-Eldin, Ralph Schwarz, P.G. Steel and Paul W. Denny 2009. The Trypanosoma brucei sphingolipid synthase, an essential enzyme and drug target. Molecular and Biochemical Parasitology. 168 (2009), pp. 16-23. https://doi.org/10.1016/j.molbiopara.2009.06.002

TitleThe Trypanosoma brucei sphingolipid synthase, an essential enzyme and drug target
TypeJournal article
AuthorsNilu Wansadhipathi-Kannangara, John Mina, Ssu-Ying Pan, Nilu Wansadhipathi, Catherine Bruce, Hosam Shams-Eldin, Ralph Schwarz, P.G. Steel and Paul W. Denny
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 phorylceramide (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.

KeywordsSphingolipid
Inositol phosphorylceramide
Sphingomyelin
Trypanosoma brucei
JournalMolecular and Biochemical Parasitology
Journal citation168 (2009), pp. 16-23
ISSN1872-9428
0166-6851
Year2009
PublisherElsevier
Accepted author manuscript
File Access Level
Open (open metadata and files)
Publisher's version
File Access Level
Open (open metadata and files)
Digital Object Identifier (DOI)https://doi.org/10.1016/j.molbiopara.2009.06.002
Web address (URL)https://pubmed.ncbi.nlm.nih.gov/19545591/
Publication dates
PublishedNov 2009
Supplemental file
File Access Level
Open (open metadata and files)

Related outputs

Sphingolipid synthases of Toxoplasma gondii and other organisms
Kannangara, N. 2013. Sphingolipid synthases of Toxoplasma gondii and other organisms. PhD thesis Durham University Biophysical sciences

Sphingolipid synthesis and scavenging in the intracellular apicomplexan parasite, Toxoplasma gondii
Steven Pratt, Nilu Wansadhipathi-Kannangara, Catherine Bruce, John Mina, Hosam Shams-Eldin, Josefina Casas, Kentaro Hanada, Ralph T. Schwarz, Sabrina Sonda and Paul Denny 2012. Sphingolipid synthesis and scavenging in the intracellular apicomplexan parasite, Toxoplasma gondii. Molecular and Biochemical Parasitology. 187 (1), pp. 43-51. https://doi.org/10.1016/j.molbiopara.2012.11.007

Functional analyses of differentially expressed isoforms of the Arabidopsis Inositol phosphorylceramide synthase
John Mina, Y. Okada, Nilu Wansadhipathi-Kannangara, S. Pratt, H. Shams-Eldin, Ralph T. Schwarz, P. G. Steel, Tony Fawcett and Paul Denny 2010. Functional analyses of differentially expressed isoforms of the Arabidopsis Inositol phosphorylceramide synthase. Plant molecular biology. 73 (4-5), pp. 399-407. https://doi.org/10.1007/s11103-010-9626-3

Human antibody responses to the Plasmodium vivax Duffy Binding protein in Sri Lanka
Nilu Wansadhipathi-Kannangara, W T A Wickremarachchi, K L R L Perera, S Bandara, S Longacre, S M Handunnetti and P V Udagama-Randeniya 2005. Human antibody responses to the Plasmodium vivax Duffy Binding protein in Sri Lanka. University Joint annual academic sessions, Faculties of Science and Medicine. University of Colombo, Sri Lanka 25 - 26 Jun 2004

Comparison of the two different recombinant proteins representing region II of the Duffy binding protein of Plasmodium vivax by assaying for natural antibodies
Nilu Wansadhipathi-Kannangara, Nilu Wansadhipathi, P H Premarathne, W T A Wickremarachchi, K L R L Perera, S Bandara, S M Handunnetti and P V Udagama-Randeniya 2005. Comparison of the two different recombinant proteins representing region II of the Duffy binding protein of Plasmodium vivax by assaying for natural antibodies. Allergy and Immunology Society of Sri Lanka (and FIMSA). Medical Research Council, Sri Lanka 03 - 05 Jan 2005

Human Antibody Responses to the Plamodium vivax DBP
N. K. Wansadhipathi-Kannangara 2004. Human Antibody Responses to the Plamodium vivax DBP. University Joint annual academic sessions, Faculties of Science and Medicine. University of Colombo, Sri Lanka 25 - 26 Jun 2004

Permalink - https://westminsterresearch.westminster.ac.uk/item/w5qx2/the-trypanosoma-brucei-sphingolipid-synthase-an-essential-enzyme-and-drug-target


Share this

Usage statistics

50 total views
0 total downloads
These values cover views and downloads from WestminsterResearch and are for the period from September 2nd 2018, when this repository was created.