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

TitleSphingolipid synthases of Toxoplasma gondii and other organisms
TypePhD thesis
AuthorsKannangara, N.
Abstract

Toxoplasma gondii is an obligate intracellular protozoan parasite of the phylum Apicomplexa, and toxoplasmosis is an important disease in immuno-compromised individuals - especially AIDS patients, organ transplant recipients and patients receiving anti-cancer chemotherapy. Toxoplasmosis also has economic importance as it results in spontaneous abortion in economically important animals. Due to emerging drug resistance and the possible side effects of the existing therapeutics there is a necessity to explore new drug targets. Sphingolipids are essential components of eukaryotic cell membranes and signal transduction pathways. Mammals produce sphingomyelin (SM) via a SM synthase, whereas yeast, plants and some protozoa utilise an inositol phosphorylceramide (IPC) synthase to produce IPC. IPC synthases have no mammalian equivalent and have been proposed as targets for anti-fungals and anti-protozoals. In this study sphingolipid scavenging from the host was shown to be non-essential for Toxoplasma proliferation indicating de novo synthesis is key. To investigate this pathway in the parasite an orthologue of the SM synthase from the related apicomplexan Plasmodium falciparum was identified in the genome database as being encoded by a single copy gene. Subsequently it was characterized as a functional orthologue of the yeast AUR1p (IPC synthase), with mass spectrometry identifying this lipid species in parasite extracts for the first time. Like AUR1p and the human SM synthase, the Toxoplasma sphingolipid synthase (Tg SLS) is Golgi localized. However, unlike AUR1p Tg SLS is resistant to the inhibitor aureobasidin A and also facilitates production of a minor complex sphingolipid suggested to be SM. Further study characterized the sphingolipid synthases from the Trypanosoma species (protozoan Kinetoplastida) and the plant Arabidopsis. Bioinformatic and phylogenetic analyses of these and previously characterized SM and IPC synthases, indicate them to be a family of evolutionarily related, but functionally diverse, enzymes. Many of these may prove to be targets for pharmaceutical or herbicidal intervention.

KeywordsToxoplasma gondii
Sphingolipid synthase
Sphingolipid
Sphingomyelin
Inositol phosphoryl ceramide
Year2013
Publication dates
Published19 Oct 2011
Web address (URL)http://etheses.dur.ac.uk/3204/

Related outputs

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

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

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

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