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Gillian
Air
/ Sanjay
Bidichandani / Robert
Broyles Karla Rodgers / Robert Steinberg / Leon Unger / Paul Weigel |
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Exploration of complex carbohydrate biosynthesis in bacteria, viruses, and animals using the tools of biochemical analysis and molecular biology. Most
life on earth, from microbes to humans, utilizes the specific
interaction of proteins with carbohydrates for recognition and
adhesion between cells. Our laboratory has been studying the
biosynthesis of polysaccharides and oligosaccharides using the
tools of biochemical analysis, carbohydrate chemistry and
molecular biology. Several
projects focus on glycosaminoglycans, a class of essential
polysaccharides, which includes hyaluronan, heparin and
chondroitin. These molecules are found in extracellular space
and/or cell surfaces throughout the human body where they play
various roles in signaling, adhesion, recognition as well as
structural elements. Certain pathogenic bacteria coat themselves
with the identical or similar polymers to enhance infection;
this molecular camouflage protects the microbe as well as
potentially hijacks the host's pathways. We are cloning and manipulating the enzymes involved in the synthesis of various glycosaminoglycan polysaccharides. We have discovered several new hyaluronan synthases, the first chondroitin synthase from any source, and two novel distinct heparosan synthases. Our overall basic science goals are to understand the fundamental mechanisms of naturally occurring enzymes. As a result of this work, we have found certain modules and motifs are responsible for specific sugar transfer reactions. This knowledge has allowed us to pursue endeavors with potential commercial applications. Some of our biotechnological research is focused on: (a) the design of novel hybrid polysaccharide molecules for medical or industrial applications, (b) the formation of biocompatible coatings and surfaces for use in sensors or other implanted devices, (c) the synthesis of defined oligosaccharides that have potential for use as anticancer agents, anticoagulants, or immune system stimulators and (d) the synthesis of sugar-based targeting drug delivery systems.
Recent Publications: Almond, A, DeAngelis, P.L., and Blundell, C.D. (2006) Hyaluronan: The Local Solution Conformation Determined by NMR and Computer Modeling is Close to a Contracted Left-handed 4-Fold Helix. J. Mol. Biol. 358:1256-1269.
Williams, K.J., Halkes, K.M., Kamerling, J.P., and DeAngelis, P.L. (2006) Critical elements of oligosaccharide acceptor substrates for the Pasteurella multocida hyaluronan synthase. J. Biol. Chem. 281:5391-5397.
Blundell, C.D., Almond, A., Mahoney, D.J., DeAngelis, P.L., Campbell, I.D., and Day, A.J. (2005) Towards a structure for a hyaluronan-TSG-6 complex by modeling and NMR spectroscopy: Insights into other members of the link module superfamily. J. Biol. Chem. 280: 18189-18201.
Bodevin-Authelet, S., Kusche-Gullberg, M., Pummill, P.E., DeAngelis, P.L., and Lindahl, U. (2005) Biosynthesis of hyaluronan: Direction of chain elongation. J. Biol. Chem. 280: 8813-8818.
Blundell, C.D., DeAngelis, P.L., Day, A.J., and Almond, A. (2004) Use of 15N-NMR to resolve molecular details in isotopically-enriched carbohydrates: sequence-specific observations in hyaluronan oligomers up to decasaccharides Glycobiology. 14: 999-1009.
DeAngelis, P.L. and White, C.L. (2004) Identification of a distinct, cryptic heparosan synthase from Pasteurella multocida Types A, D and F. J. Bacteriology. 186: 8529-8532.
Jing, W. and DeAngelis, P.L. (2004) Synchronized chemoenzymatic synthesis of monodisperse hyaluronan polymers. J. Biol. Chem. 279: 42345-42349. Jing W, DeAngelis PL, 2003: Analysis of the two active sites of the hyaluronan synthase and the chondroitin synthase of Pasteurella multocida. Glycobiology 13(10):661-671. DeAngelis PL, Oatman LC, Gay DF, 2003: Rapid chemoenzymatic synthesis of monodisperse hyaluronan oligosaccharides with immobilized enzyme reactors. J Biol Chem. 278(37):35199-35203. Pummill PE, DeAngelis PL, 2003: Alteration of polysaccharide size distribution of a vertebrate hyaluronan synthase by mutation. J Biol Chem. 278:19808-19814. Epub 2003 Mar 22 DeAngelis P, 2002: Evolution of glycosaminoglycans and their glycosyltransferases: Implications for the extracellular matrices of animals and the capsules of pathogenic bacteria. Anat. Rec. 268:317-326. DeAngelis P, Gunay N, Toida T, Mao W, Linhardt R, 2002: Identification of the capsular polysaccharides of Type D and F Pasteurella multocida as unmodified heparin and chondroitin, respectively. Carbohydr Res 337:1547. Pummill PE, DeAngelis PL, 2002: Evaluation of critical structural elements of UDP-sugar substrates and certain cysteine residues of a vertebrate hyaluronan synthase. J Biol Chem 277:21610-6. DeAngelis, P.L.and White, C.L. 2002: Identification and molecular cloning of a heparosan synthase from Pasteurella multocida type D. J. Biol. Chem. 277:7209-7213. DeAngelis, P.L. 2002: Bacterial Glycosaminoglycan Glycosyltransferases. Glycobiology, MiniReview 12:9R-16R. Heldermon C., DeAngelis P.L., and Weigel P.H. 2001: Topological Organization of the Hyaluronan Synthase from Streptococcus pyogenes. J. Biol. Chem. 276:2037-2046. Pummill, P.E., Kempner, E.S., and DeAngelis, P.L. 2001: Functional Molecular Mass of a Vertebrate Hyaluronan Synthase as Determined by Radiation Inactivation Analysis. J. Biol. Chem. 276: 39832-39835. DeAngelis, P.L. and Padgett-McCue, A.J. 2000: Identification and Molecular Cloning of a Chondroitin Synthase from Pasteurella multocida Type F. J. Biol. Chem. 275:24124-24129. Jing, W. and DeAngelis, P.L. 2000: Dissection of the Two Tranferase Activities of the Pasteurella multocida Hyaluronan Synthase: Two Active Sites Exist in One Polypeptide. Glycobiology. 10:883-889. DeAngelis, P.L. 2000: Polysaccharide labeling with N-methylisatoic anhydride: generation of ultravioloet chromophores and blue fluorophores. Anal. Biochem. 284:167-169. DeAngelis, P.L. 1999: Hyaluronan Synthases: Fascinating Glycosyltransferases From Vertebrates, Bacterial Pathogens, and Algal Viruses. Cellular and Molecular Life Sciences. 56:670-682. DeAngelis, P.L. 1999: Molecular Directionality of Polysaccharide Polymerization by the Pasteurella multocida Hyaluronan synthase. J. Biol. Chem. 274:26557-26562. Graves, M.V., Burbank, D.E., Roth, R., Heuser, J., DeAngelis, P.L., and Van Etten, J.L. 1999: Hyaluronan Synthesis in Virus PBCV-1 Infected, Chlorella-like Green algae. Virology 257:15-23. DeAngelis, P.L., Jing, W., Drake, R.R., and Achyuthan, A.M. 1998: Identification and Molecular Cloning of a Unique Hyaluronan Synthase from Pasteurella multocida. J. Biol. Chem. 273:8454-8458. Landstein, D., Graves, M.V., Burbank, D.E., DeAngelis, P.L., and Van Etten, J.L. 1998: Chlorella Virus PBCV-1 Encodes Functional Glutamine: Fructose-6-Phosphate Amidotransferase and UDP-Glucose Dehydrogenase Enzymes. Virology 250:388-396. Pummill, P.E., Achyuthan, A.M., and DeAngelis, P.L. 1998: Enzymological Characterization of Recombinant Xenopus DG42, a Vertebrate Hyaluronan Synthase J. Biol. Chem. 273:4976-4981. DeAngelis, P.L. 1998: Transposon Tn916 Insertional Mutagenesis of Pasteurella multocida and Direct Sequencing of Disruption Site. Microbial Pathogenesis. 24:203-209. DeAngelis, P.L., Jing, W., Graves, M.V., Burbank, D.E., and Van Etten, J.L. 1997: Hyaluronan Synthase of Chlorella Virus PBCV-1. Science. 278:1800-1803. |
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