David H Kwan, PhD

Education

Enzymes in synthetic biology

Enzymes are extraordinary biocatalysts –they are the machinery within cell factories crafted by Nature over aeons of evolution. The aims of my research are focused upon using techniques in synthetic biology as a means of exploiting enzymes, developing them as tools in industrial biocatalysis, as well as targeting them within pathogenic microbes to disable them with specific inhibitor drugs as therapeutics to treat infectious diseases.

Enzyme engineering

Using techniques like directed evolution, we can engineer enzymes to optimize them towards our desired activities by mimicking the natural selection process in the laboratory. To this end we are pursuing research towards discovering and engineering enzyme biocatalysts for the production of anticancer anthracycline glycoside drugs and other therapeutic drugs from the same class of natural products for use in a wide range of health applications. We also aim to establish, using synthetic biology, new methods for producing biorenewable hydrocarbons as alternatives to petroleum products and to engineer, through directed evolution, efficient enzyme biocatalysts for doing so.

Screening enzyme inhibitors as antimicrobial drugs

We aim to develop and apply high-throughput enzyme activity-based methods for discovering drugs against Mycobacteria tuberculosis using an in vitro reconstituted biosynthetic pathway of mycobacterial cell wall components by which to assay enzyme inhibitors.

Opportunities

Kwan, D.H., Jin, Y., Jiang, J., Chen, H.M., Kötzler, M.P., Overkleeft, H.S., Davies, G.J., and Withers, S.G. (2016) "Chemoenzymatic synthesis of 6-phospho-cyclophellitol as a novel probe of 6-phospho-β-glucosidases" FEBS Letters, 590, 461-468

Volkers, G. Worral, L.J., Kwan, D.H., Yu. C.-C., Baumann, L., Lameignere, E., Scott, N.E., Wakarchuk, W.W., Foster,L. J., Withers, S.G., and Strynadka, N.C.J. (2015) “Structure of human ST8SiaIII sialyltransferase provides first insights into the molecular detailsof polysialylation of human cell surfaces” Nature Structural and Molecular Biology, 22, 627-635

Kwan, D.H.,Ernst, S., Kötzler, M.P., and Withers, S.G. (2015) “Chemoenzymatic synthesis of a type 2 blood group A tetrasaccharide and the development of high-throughput assays enables a platform for screening blood group antigen-cleaving enzymes” Glycobiology, 25, 806-811

Kwan,D.H., Constantinescu, I., Chapanian, R., Higgins,M.A., Kötzler, M.P., Samain, E., Boraston A.B., Kizhakkedathu, J., and Withers,S.G.* (2015) “Towards efficient enzymes for the generation of universal bloodthrough structure-guided directed evolution”Journal of the American Chemical Society, 137, 5695-5705

Chapanian, R., Kwan, D.H., Constantinescu, I., Shaikh, F.A., Rossi, N.A.A., Withers, S.G., and Kizhakkedathu, J.* (2014) “Enhancement of Biological Reactions on Cell Surfaces via Macromolecular Crowding” Nature Communications, 5, Article number: 4683, DOI: 10.1038/ncomms5683

Kwan, D.H.,and Withers, S.G.* (2014) “Periplasmic de-acylase helps bacteria don their biofilm coat” Proceedings of the National Academy of Sciences of the USA, 111, 10904-10905

Yu, C.-C., Hill, T., Kwan, D.H., Wakarchuk, W.W., Lin, C.-C., and Withers, S.G.* (2014) “A plate based high-throughput activity assay for polysialyltransferase from Neisseria meningitides” Analytical Biochemistry, 444, 67-74

Yu, C.-C., Huang, L.-D., Kwan, D.H.,Wakarchuk, W.W., Withers, S.G., and Lin, C.-C.* (2013) “A glyco-gold nanoparticle based assay for α-2,8-polysialyltransferase from Neisseria meningitides” Chemical Communications, 49, 10166-10168

Kwan, D.H.and Withers, S.G.* (2011) “Towards efficient enzymatic glycan synthesis: Directed evolution and enzyme engineering”Journal of Carbohydrate Chemistry, 30,181-205

Kwan, D.H.*and Schulz, F. (2011) “The stereochemistry of complex polyketide biosynthesis by modular polyketide synthases” Molecules, 16, 6092-6115

Kwan, D.H.,Tosin, M., Schläger, N., Schulz, F., and Leadlay, P.F.* (2011) “Insights into the stereospecificity of ketoreduction in a modular polyketide synthase” Organic and Biomolecular Chemistry, 9, 2053-2056

Kwan, D.H.,Chen, H.-M., Ratananikom, K., Hancock, S.M. Watanabe, Y., Kongsaeree, P.T.,Samuels, A.L., and Withers, S.G.* (2011) “Self-immobilizing fluorogenic imaging agents of enzyme activity” Angewandte Chemie International Edition, 50,300-303

Kwan, D.H.*,and Leadlay, P.F. (2010) “Mutagenesis of a modular polyketide synthase enoylreductase domains reveals insights into catalysis and stereospecificity” ACS Chemical Biology, 5, 829-838

Kwan, D.H.,Sun, Y., Schulz, F., Hong, H., Popovic, B., Sim-Stark, C.C., Haydock, S.F., and Leadlay, P.F.* (2008) “Prediction and manipulation of the stereochemistry of enoylreduction in modular polyketide synthases” Chemistry and Biology, 15,1231-1240