This research will develop new techniques for organic synthesis based on enzymes as catalysts. It will emphasize: 1) Synthesis of chiral synthons by kinetic resolutions employing lipases, esterases, fumarase, acylase, acetate kinase, lactate dehydrogenase and malic dehydrogenase. 2) Development of techniques for regeneration of important cofactors: coenzyme A, NAD, and 3'-phospho-5'-adenylyl sulfate (PAPS). 3) Synthesis of sugars, oligosaccharides, and polysaccharides using aldolase and complex enzyme-based schemes involving both Leloir pathways (for hyalauronic acid and glycosyl derivatives of N-acetylneuraminic acid) and non-Leloir pathways (for dextrans, glycogen, and analogs of these polymers). 4) Preparation of specific, small biochemically important molecules: N-acetylneuraminic acid, KDO, sphingosine, CoASH. 5) Exploration of techniques for assembling and controlling complex synthetic systems involving eight or more cooperating enzymes capable of performing both synthetic and cofactor-regenerating functions (""""""""artificial metabolism"""""""").

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Bio-Organic and Natural Products Chemistry Study Section (BNP)
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Harvard University
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Mack, Eric T; Snyder, Phillip W; Perez-Castillejos, Raquel et al. (2012) Dependence of avidity on linker length for a bivalent ligand-bivalent receptor model system. J Am Chem Soc 134:333-45
Mirica, Katherine A; Lockett, Matthew R; Snyder, Phillip W et al. (2012) Selective precipitation and purification of monovalent proteins using oligovalent ligands and ammonium sulfate. Bioconjug Chem 23:293-9
Mecinovic, Jasmin; Snyder, Phillip W; Mirica, Katherine A et al. (2011) Fluoroalkyl and alkyl chains have similar hydrophobicities in binding to the ""hydrophobic wall"" of carbonic anhydrase. J Am Chem Soc 133:14017-26
Snyder, Phillip W; Mecinovic, Jasmin; Moustakas, Demetri T et al. (2011) Mechanism of the hydrophobic effect in the biomolecular recognition of arylsulfonamides by carbonic anhydrase. Proc Natl Acad Sci U S A 108:17889-94
Mack, Eric T; Snyder, Phillip W; Perez-Castillejos, Raquel et al. (2011) Using covalent dimers of human carbonic anhydrase II to model bivalency in immunoglobulins. J Am Chem Soc 133:11701-15
Bilgi├žer, Ba?ar; Thomas 3rd, Samuel W; Shaw, Bryan F et al. (2009) A non-chromatographic method for the purification of a bivalently active monoclonal IgG antibody from biological fluids. J Am Chem Soc 131:9361-7
Krishnamurthy, Vijay M; Kaufman, George K; Urbach, Adam R et al. (2008) Carbonic anhydrase as a model for biophysical and physical-organic studies of proteins and protein-ligand binding. Chem Rev 108:946-1051
Mack, Eric T; Perez-Castillejos, Raquel; Suo, Zhigang et al. (2008) Exact analysis of ligand-induced dimerization of monomeric receptors. Anal Chem 80:5550-5
Bilgicer, Basar; Moustakas, Demetri T; Whitesides, George M (2007) A synthetic trivalent hapten that aggregates anti-2,4-DNP IgG into bicyclic trimers. J Am Chem Soc 129:3722-8
Krishnamurthy, Vijay M; Semetey, Vincent; Bracher, Paul J et al. (2007) Dependence of effective molarity on linker length for an intramolecular protein-ligand system. J Am Chem Soc 129:1312-20

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