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Center For Protein Structure And Function
 
Overview
 
Genome sequences are not sufficient to provide an understanding of how living systems work, because the DNA sequences must be expressed as proteins, which fold into their specific three-dimensional structures that determine how they function. Some proteins may also be chemically modified after synthesis or be converted from inactive to active forms. In addition, different proteins may be synthesized in different tissues or at different stages of development. Thus understanding of living processes requires understanding of structure and function relationships in proteins.

For this reason, the "Center for Protein Structure and Function (CPSF)" was founded as a Center for Excellence of the Faculty of Science, Mahidol University 2001, to serve as an interdisciplinary research laboratory for elucidating the molecular basis of protein action. CPSF consists of 6 staff members from three departments of the faculty, headed by Professor M.R. Jisnuson Svasti. It is well equipped with modern equipment provided by the faculty, including X-ray crystallography and stop-flow enzyme kinetics and is linked with the Laboratory of Biochemistry at the Chulabhorn Research Institute, which has facilities for protein sequencing and proteomics.

 
Networking
     Staff members of CPSF have extensive research networks both locally and overseas. In Thailand, there is extensive research collaboration with staff from: a) various departments and institutes at Mahidol University; b) other universities, such as Kasetsart University, Suranaree University of Technology, Khon Kaen University, Prince of Songkhla University, Srinakarintwirot Prasarnmitr University, Naresuan University, Mahasarakham University, Mae Fah Luang University; c) various research institutions, such as the National Center for Genetic Engineering and Biotechnology (BIOTEC) and the Chulabhorn Research Institute. Overseas, CPSF staff also collaborate with laboratories in U.S.A., Canada, Belgium, Italy, Sweden and Taiwan. In 2006, a Protein Society of Thailand was founded to link protein scientists throughout Thailand: this society has attracted much interest, and its annual meetings are attended by some 400 staff and students.
 
Research
    CPSF has six major research areas, funded by various agencies such as the Thailand Research Fund, BIOTEC, and Mahidol University. These are:
 
Plant glycosidase enzymes
       Glycosidase enzymes hydrolyze carbohydrate compounds, such as oligosaccharides and glycosides, which can function in cellular recognition, or act as components of drugs, flavors and scents. The beta-glucosidases are interesting as models for studying structure and function relationships, since they catalyze similar reactions, but show different catalytic properties. Novel enzyme and substrate combinations have been isolated from Thai plants. The special properties of certain enzymes are being used to develop enzymatic methods for synthesis of glycosides and oligosaccharides. The three-dimensional structures of bacterial chitinase, rice beta-glucosidase, and cassava linamarase are being determined by X-ray crystallography.
 
Drug targets in malaria
 
     A potential strategy for treatment of malaria is to inhibit enzymes required by malarial parasites, that are absent from the human host. The three-dimensional structures of P. falciparum dihydrofolate reductase-thymidylate synthetase complex and P. vivax dihydrofolate reductase, involved in pyrimidine biosynthesis, have been determined in collaboration with researchers at BIOTEC. This not only improves understanding of the structural basis of drug resistance, but also assists in the design of anti-malarial drugs. Another target enzyme is parasite plasmepsin, which degrades hemoglobin in the red blood cell, where understanding of three-dimensional structure will also be important for design of specific inhibitors. Mechanistic studies are also being performed on serine hydroxymethyltransferase (SHMT), a PLP-dependent enzyme, which plays an indispensable role in nucleic acid biosynthesis in malarial parasites, so specific inhibitors of this enzyme also have potential as anti-malarial drugs.
 
Enzymes in the synthesis of penicillin derivatives
       Antibiotics in the penicillin group are being imported at considerable cost. Work on enzymes, involved in the synthesis of penicillin derivatives, have potential applications in developing synthetic processes locally. One enzyme, D-phenylglycine aminotransferase, which catalyzes an unusual stereo-inversion reaction project, has been crystallized, and its three-dimensional structure is being determined to elucidate the reaction mechanism. Another project attempts to modify the specificity of the enzyme penicillin G acylase from B. megaterium by protein engineering, to generate a novel enzyme cephalosporin acylase for synthesis of cephalosporin antibiotics.
 
Mechanistic studies of flavoprotein oxygenase enzymes
 
    These oxygenases have flavin as coenzymes and catalyze the addition of oxygen or hydroxyl groups to substrates producing more soluble or readily degradable compounds. Of special interest are the oxygenases acting on aromatic compounds, since they may be useful for bioremediation of aromatic waste. The thermodynamic and catalytic properties of several enzymes are being studied, including 2-methyl-3-hydroxypyridine-5-carboxylic acid oxygenase and p-hydroxyphenylacetate hydroxylase. Recent studies involve a luciferase-flavin reductase system, which causes light emission in bacteria, and has potential application for the development of biosensors.
 
Sericin-specific proteinase enzyme
       Silk fibres from Bombyx mori silkworms consist of a major fibrous protein fibroin and other minor proteins called sericin, which cover the fibroin fiber with sticky layers to form the cocoon. Degumming of sericin is necessary for preparation of soft, shiny, and whitened silk ready for dying, but traditional practice, using alkaline solutions and high temperatures, is difficult to control. A search is being made for proteinase(s) from microorganisms, which digest sericin without degrading fibroin, which will allow milder enzymatic degumming.
 
Awards
     The results of research at CPSF have been published in journals with high impact factors. In addition, CPSF staff members have won numerous awards at national level, namely: Outstanding Scientist of Thailand Award, Distinguished Researcher Award, Outstanding Lecturer Award of Thailand, 3 Young Scientist Awards, UNESCO-L’Oreal Fellowship, and Mahidol University Prize for Research.
 
Selected Publications
 
1. Siripurkpong, P., Yuvaniyama, J.et al. (2002) Active Site Contribution to Specificity of the Aspartate Proteases Plasmepsins I and II. J Biol Chem 277, 41009-13.
 
2. Yuvaniyama, J., et al. (2003) Insights into Antifolate Resistance from Malarial DHFR-TS Structures. Nature Struct Biol 10 (5), 357–65.
 
3. Srisomsap, C., et al. (2004) Proteomic Analysis of Cholangiocarcinoma Cell Line. Proteomics 4, 1135-1144.
 
4. P. Kongsaeree, et al. Crystal structure of dihydrofolate reductase from Plasmodium vivax: Pyrimethamine Displacement Linked with Mutation-induced Resistance. Proc Natl Acad Sci USA (2005), 102, 13046-51.
 
5. Sucharitakul, J., Chaiyen, P., et al. (2006) Kinetic Mechanisms of the Oxygenase from a Two-component Enzyme, p-Hydroxyphenyl Acetate 3-Hydroxylase from Acinetobacter baumannii. J Biol Chem 281(25), 17044-53.
 
6. Alfieri, A. et al. (2007) Structure of the Monooxygenase Component of a Two-component Flavoprotein monooxygenase Proc. Natl. Acad. Sci. U.S.A. 104, 1177-1182.
 
7. Hommalai, G., Withers, S.G., Chuenchor, W., Cairns, J.R.K and Svasti, J. (2007) Enzymatic synthesis of cello-oligosaccharides by rice BGlu1 beta-glucosidase glycosynthase mutants. Glycobiology 2007, Apr 3; [Epub ahead of print]
 
For further information, contact: scjsv@mahidol.ac.th or scjyv@mahidol.ac.th
 
 

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