1) Biosynthesis and uptake of phospholipids in protozoan parasites.

2) The enzymology of biosynthetic enzymes in parasites.

3) Lipidomics and focussed metabolomics of pathogens.

4) Carbohydrate synthesis and “simple” chemistry towards drugs for neglected disease.

5) Structure, function & biosynthesis of parasite glycoconjugates including GPI anchors.

Lipid biosynthesis in protozoan parasites



There are currently no effective treatments against many of the debilitating and
fatal diseases caused by insect-transmitted protozoan parasites such as
Trypanosoma brucei (African sleeping sickness), Trypanosoma cruzi (ChagasÂ’s)
Leshmania, Plasmodium (malaria) and Toxoplasma. The cell-surfaceÂ’s of these
parasites are covered in glycosylphosphatidylinositol (GPI) anchors and related
molecules (1). T. brucei biosynthesis of  GPI anchors are required for their
abundant variant surface glycoprotein which protects them against the harsh
environment of the bloodstream (see figure). This GPI anchor biosynthesis is a
proven genetic and chemical target for therapeutic drugs (2-4). Our research is
concerned with the biosynthetic pathways of the building blocks required for GPI
assembly (PI, PE, Dol-P-Man and Mys-CoA) these must also be essential for the
parasiteÂ’s survival (see Figure).
We are finding significant exploitable differences between human and parasitic
biosynthetic pathways and enzymes (5-6). Inhibitor studies and chemical
 synthesis followed by screening of focussed compounds libraries for lead
 compounds will ultimately result in therapeutic drugs against these Third World
 diseases.

The multi-disciplinary research approach involves:

(a) In vivo and in vitro biosynthetic studies, to investigate how the parasites
de novo synthesise their lipids and GPIs.

(b) Bioinformatics, molecular biology and molecular parasitology are used to
clone novel genes, allowing gene-knockout and/or RNAi approaches to genetically
validate them as drug targets (3).

(c) Biochemical phenotyping of these modified parasites using labelling methods,
quantification of metabolites and proteins, enzymatic assays, various mass spec
methods and lipidomic approaches to help us understand the parasiteÂ’s
responses.

(d) Recombinant expression and development of enzymatic assays, ultimately for
high-throughput screening, in conjunction with the design and chemical
synthesis of biosynthetic inhibitors as drug leads (4).


References



1. Ferguson, M.A.J. et al (1999) Biochim. Biophys. Acta 1455: 327-340

2. Nagamune, K. et al (2000) Proc. Natl. Acad. Sci. U.S.A. 97: 10336-10341.


3. Chang, T. et al (2004) J. Biol. Chem. 277: 50176-50182

4. Smith, T.K. et al (2004) EMBO J. 23: 4701-4708.


5. Smith, T.K. et al (2001) EMBO J. 20: 3322-3332.


6. Smith, T.K. et al (2002) J. Biol. Chem. 277: 37147-37153

Personal Statement

Smith has over 20 years experience working with T. brucei and related parasites. Since establishing my research group in Dundee (2003), I have gained a standing within the parasitology field for undertaking lipidomic analysis to aid phenotyping of genetically or chemically manipulated parasites. Since moving (Oct. 2007) and establishing the first ever Cat 3 facility in St Andrews, I was able to consolidate and expand my studies into other areas of parasite lipid metabolism, using the world-class facilities and collaborations in Chemistry, Biology and Medicine available at St Andrews. The University completed building of a new £35 million medical school in 2010 and through collaborative efforts we obtained £5 million from the Wellcome Trust towards a new £13 million purpose built Biomedical Science Research Complex which we moved into in Jan 2012. My group occupies biochemistry and chemistry labs as well as a larger Cat 3 suite within this new this new complex. The building also has a purpose built floor for analytical instrumentation, including my own 4000 Q-trap mass spectrometer (Wellcome Trust). This is an ideal instrument for lipidomics that is bringing about a step change in the undertaking and completion of future and on-going collaborative lipidomic analysis by the Smith group. These are not just of protozoa, but include numerous other pathogens, bacteria, yeast and viruses as well as model cell-lines of human disease and organisms and other diverse samples as salmon, fruit flies and plant tissues.

OTHER ACTIVITES:

Review Grants for WT, BBSRC, EPSRC, MRC, ARC/DAAD, EU. Romania Science Board, Hong Kong Science Board, Austrian Science Board, French Science Board

On the Biochem J. Editorial advisory panel (2011-)

On the Editorial Board of Molecular and Biochemical Parasitology (2013-)

On the Editorial Board of IUBMB Life (2013-)

On the Editorial Board of BioMed Research International “Parasitology“ (2013-)

Guest Editor for a Special Issue of Biochemistry Research International (2010/2011)

Guest Editor for a Special Issue of Journal of Lipids (2011/2012)

Also regularly review papers for the following: EMBO, JBC, PNAS, BJ, Biochemistry, Mol Micro, BJ, FEBS, Mol Bio Parasitology, Parasitology, Int Parasitology, Chemical Biology, ChemMedChem and Drug Design and many many others.

Head of Cat 3 labs in St Andrews University 03/13 to date

Member of the University Safety Committee 03/08 to date

Member of the BSRC and University GMO Committees 03/08 to date

Departmental Radition Saftey Officer for BSRC and Purdie complex 10/11 to date

First Aider 08/12 to date

Member of the Biology PhD Recruitment Committee, St Andrews 09/08 to date

A founding committee member of the Scottish Metabolomics Consortium 12/07 to date

Member of the Infectious Disease Research Network

Academic consultant for Mylnefield lipid analysis Ltd 08/13-