Research Interests | Research Projects 2004
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Bio-Organic and Medicinal Chemistry
My current research activities are focused on:
• designing and synthesising inhibitors of the enzyme indoleamine 2,3-dioxygenase
• understanding the mechanism of formation of age related cataract
• studies on human lens UV filter compounds
• isolation, testing and structural elucidation of natural products from traditional medicinal plants
Design of inhibitors of IDO (with M. Parker and G. Polekhina, St. Vincent's Institute of Medical Research; R. Truscott, University of Wollongong
Indoleamine 2,3-dioxygenase (IDO) is an ubiquitous enzyme found in mammals. It catalyses the conversion of the essential amino acid tryptophan to N-formylkynurenine by oxidative cleavage of the 2,3-double bond. N-formylkynurenine is subsequently converted, via the kynurenine pathway, to a range of metabolites including the neurotoxin quinolinic acid.
Elevation of IDO activity, and the corresponding increase in quinolinic acid concentration in the CNS and depletion of tryptophan, has been directly implicated in the development of AIDS-Dementia Complex, a debilitating condition observed in AIDS sufferers, and of human cerebral malaria, which affects well over one million people annually. Furthermore, activation of IDO has been linked to a range of other diseases, including Huntington, Parkinson and Alzheimer's disease. Thus, inhibitors of IDO have enormous potential to play a therapeutic role in the treatment of a range of varied neurological disorders. Using a combination of techniques, including synthesis, biological testing, molecular modelling and molecular biology, we are currently exploring the rational design of potent inhibitors of IDO.
Relevant Publications
Littlejohn, T.K., Takikawa, O., Jamie, J.F., Walker, M.J. and Truscott, R.J.W.
Production of Truncated Enzymically-Active Human Indoleamine 2,3-Dioxygenase (IDO) Using Site-Directed
Mutagenesis. Excerpta Medica International Congress Series (ICS). 2003, 1233, 157-160.
Littlejohn, T.K., Takikawa, O., Skylas, D., Jamie, J.F., Walker, M.J. and Truscott, R.J.W. Expression and Purification of Recombinant Human Indoleamine 2,3-Dioxygenase. Protein Expression and Purif. 2000, 19, 22-29. (An electronic reprint is available from Idealibrary)
Southan, M.D., Truscott, R.J.W., Jamie, J.F., Pelosi, L., Walker, M.J., Maeda, H., Iwamoto, Y. and Toné, S. Structural Requirements of the Competitive Binding Site of Recombinant Human Indoleamine 2,3-dioxygenase. Med. Chem. Res. 1996, 6, 343-352.
Mechanism of formation of age related cataract (with R. Truscott, Australian Cataract Research Foundation, University of Wollongong; M. Davies, Heart Research Institute)
There are over 50 million cases of blindness worldwide and greater than 20 million of these are due to cataract, a condition that results in opacification or clouding of the lens. The most significant form of cataract is human senile nuclear cataract (age related cataract), which is the primary form of blindness in the elderly. At present the only remedy for cataract is surgical removal and replacement of the lens. The mechanism of formation of age related cataract has not been fully understood, and elucidation of the cause of cataract is an essential first step in the development of either a preventative and/or therapeutic treatment for this problem. We are currently undertaking studies that are giving us a greater insight into the mechanism of formation of age related cataract. It is anticipated that these studies will provide us with the knowledge to allow the rational development of cataract preventative drugs.
Human lens UV filter compounds (with R. Truscott, Australian Cataract Research Foundation, University of Wollongong)
The human lens contains a number of low molecular weight compounds known as UV filters. These play a role in protecting the lens and retina from UV damage. Some of these compounds have also been implicated in the normal age dependent colouration of the human lens and in modification of the lens structural proteins during the development of age related cataract. A number of studies are currently being conducted on these UV filters. This includes studies aimed at determining the true role of the UV filters in lens colouration and structural modifications upon aging; elucidation of the structure of unknown UV filters; and determining the biosynthetic origin of several UV filters.
Relevant Publications
Taylor, L.M., Aquilina, J.A., Jamie, J.F. and Truscott, R.J.W.
Glutathione and NADH, but not Ascorbate, Protect Lens Proteins From Modification by UV Filters.
Exp. Eye Res. 2002, 74, 503-511.
Taylor, L.M., Aquilina, J.A., Jamie, J.F. and Truscott, R.J.W. UV Filter Instability: Consequences for the Human Lens. Exp. Eye Res. 2002, 75, 165-175.
Vazquez, S., Aquilina, J.A., Jamie, J.F., Sheil, M.M. and Truscott, R.J.W. Novel Protein Modification of Kynurenine in Human Lenses. J. Biol. Chem. 2002, 277, 4867-4873.
Taylor, L.M., Aquilina, J.A., Willis, R.H., Jamie, J.F. and Truscott, R.J.W. Identification of a New Human Lens UV Filter Compound. FEBS Letters 2001, 509(1), 6-10.
Bova, L.M., Sweeney, M.H.J., Jamie, J.F. and Truscott, R.J.W. Major Changes in Human Ocular UV Protection With Age. Invest. Ophthalmol. Vis. Sci. 2001, 42(1), 200-205.
Manthey, M.K., Jamie, J.F. and Truscott, R.J.W. Synthesis of Human Ultraviolet Filter Compounds: O-b-D-glucopyranosides of 3-Hydroxykynurenine and 2-Amino-3-hydroxy-g-oxobenzenebutanoic Acid. J. Org. Chem. 1999, 64(11), 3930-3933. (An electronic reprint is available from ACS)
Bova, L., Jamie, J.F. and Truscott, R.J.W. UV filter Compounds in Human lenses: the Origin of AHBG. Invest. Ophthalmol. Vis. Sci. 1999, 40(13), 3237-3244.
Takikawa, O., Littlejohn, T., Jamie, J.F., Walker, M.J. and Truscott, R.J.W. Regulation of Indoleamine 2,3-Dioxygenase, The First Enzyme in UV Filter Biosynthesis in The Human Lens: Relevance for Senile Nuclear Cataract. Adv. Exp. Med. Biol. 1999, 467, 241-245.
Ethnopharmacological Study of Medicinal Plants of New South Wales (with S. Vemulpad, Health and Chiropractic, Macquarie University; J. Kohen, Biological Sciences, Macquarie University; M. Collins, Pharmacy University of Sydney)
The Australian Aboriginal people have used plants as medicine for thousands of years and have a vast reservoir of knowledge of Australia's unique flora. This traditional knowledge, however, is poorly documented and is in danger of being lost, especially in southern and eastern Australia due to dislocation and greater westernisation of Aboriginal communities. Through an unique collaboration with Aboriginal communities, this progran aims to document the traditional medicinal plant knowledge of Aboriginal communities and to identify the biologically active compounds from the traditional medicinal plants. Specifically, databases are being established for the communities on their medicinal plant usage, noting what parts of the plant are used and at which stages of growth, collection data, the use and preparation in the literature, and most importantly the preparation and application of the remedy by the communities; and chemical and biological studies are being conducted on those plants used by the communities that show significant medicinal potential. For the latter studies particular attention is being placed on plants used traditionally to treat bacterial / fungal infections or conditions derived from neurological disturbances such as pain, anxiety, depression and memory / sleep loss. Various antimicrobial assays are being carried out (e.g. disc diffusion assay, resazurin assay, fluorescein diacetate assay) on the human pathogens Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Candida albicans. Neurological assays will also be carried out on GABA and acetylcholine receptors.
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Relevant Publications
Herath, H.M.T.B., Athukoralage, P.S. and Jamie, J.F.
A New Oleanane Triterpenoid from Gordonia Ceylanica. Nat. Product Lett. 2001, 15(5),
339-344.
Lindsay, E.A., Berry, Y., Jamie, J.F. and Bremner, J.B. Antibacterial Agents from Carissa lanceolata R.Br. Phytochem. 2000, 55(5), 403-406.
Herath, H.M.T.B., Athukoralage, P.S. and Jamie, J.F. Two New Oleanane Triterpenoids From Gordonia Ceylanica and Their Conversions to Taraxarane Triterpenoids. Phytochem. 2000, 54(8), 823-827. (An electronic reprint is available from ScienceDirect)
Herath, H.M.T.B., Athukoralage, P.S. and Jamie, J.F. Triterpenoids and Steroids from Gordonia Dassanayakei. ACGC Chem. Res. Commun. 1999, 9, 3-8.
Dharmaratne, H.R.W., Perera, D.S.C., Marasinghe, G.P.K. and Jamie, J. A Chromene Acid From Calophyllum Cordato-Oblongum. Phytochem. 1999, 51(1), 111-113. (An electronic reprint is available from ScienceDirect)
Herath, H.M.T.B., Dassanayake, R.S., Priyadarshani, A.M.A., De Silva, S., Wannigama, G.P. and Jamie, J. Isoflavanoids and a Pterocarpan from Gliricidia Sepium. Phytochem. 1998, 47(1), 117-119. (An electronic reprint is available from ScienceDirect)
Dharmaratne, H.R.W., Herath, H.M.A.S. and Jamie, J.F. Anti-Inflammatory Active Agent From Zanthoxylum Rhetsa. ACGC Chem. Res. Commun. 1998, 8, 16-19.
Herath, H.M.T.B., Priyadarshani, A.M.A. and Jamie, J. Dactyloidin, A New Diaryl Nonanoid From Myristica Dactyloides. Nat. Prod. Letters. 1998, 12(2), 91-95.
Last Revised: 18-Dec-2003
