[Research Interests] [Representative Publications] RESEARCH INTERESTSResearch programs in Dr. Townsend's group are broadly in bioorganic chemistry with specific interests in natural product biosynthesis, the enzymology and molecular biology of secondary metabolism, small molecule/DNA interactions, and rational drug design. Particular emphasis has been placed on studies of biochemical reaction mechanism and synthesis, notably biomimetic synthesis, discovery of biosynthetic gene clusters and discerning their funcion, mechanistic enzymology and the applications of molecular biology and microbiology in bioorganic chemistry, inhibitor design and synthesis based on understanding of enzyme mechanisms, and the study of and the design and synthesis of sequence-specific DNA cleaving molecules. Major efforts are currently underway with: (1) the aflatoxins, a family of environmental carcinogens of wide distribution and their fundamental engines of synthesis, the polyketide synthases, (2) the b-lactam antibiotics represented classically by penicillin and cephalosporin, but more recently by the nocardicins and their precursor polypeptide synthetases, the potent b-lactamase inhibitor clavulanic acid, and the clinically-important carbapenems, (3) calicheamicin, an exceptionally potent anti-tumor antibiotic of the diynene class with promise as an immunoconjugate drug in Man, and (4) in collaboration with geneticists, microbiologists, pathologists, and oncologists in the Medical School, investigate a cascade of enzymes in Mycobacteria tuberculosis, the causative agent of TB, and closely related proteins highly expressed in human cancer cells, and design and synthesize potential inhibitors/inactivators as potential drugs. REPRESENTATIVE PUBLICATIONSKelly, W.L., and Townsend, C.A. Mutational Analysis and Characterization of Nocardicin C-9' Epimerase. J. Biol. Chem. accepted. Kelly, W.L., and Townsend, C.A. Protoplast Transformation of the Nocardicin A Producer Nocardia uniformis and Application for Mutational Analysis of nocK and nocL. submitted. Gunsior, M., Ravel, J., Challis, G.L., and Townsend, C.A. 2004. Engineering p-Hydroxyphenylpyruvate Dioxygenase to a p-Hydroxymandelate Synthase and Evidence for the Proposed Benzene Oxide Intermediate in Homogentisate Formation, Biochemistry. 43:663-674. Gunsior, M., Breazeale, S.D. Lind, A.J. Ravel, J., Janc, J.W., and Townsend, C.A. 2004. The Biosynthetic Gene Cluster for a Monocyclic b-Lactam Antibiotic, Nocardicin A, Chem. & Biol.. Gerratana, B. Stapon, A. Townsend, C. A. 2003. Inhibition and Alternate Substrate Studies on the Mechanism of Carbapenam Synthetase from Erwinia carotovora, Biochemistry. 42:7836-7847. Miller, M.T. Gerratana, B. Stapon, A. Townsend, C.A. Rosenzweig, A.C. 2003. Crystal Stucture of Carbapenem Synthetase (CarA), J. Biol. Chem. 278:40996-41002. Zhou, W. B. Simpson, P. J. McFadden, J. M. Townsend, C. A. 2003. Medghalchi, S. M. Vadlamudi, A. Pinn, M. L. Ronnett, G. V. Kuhajda, F. P. Fatty Acid Synthase Inhibition Triggers Apotosis During S Phase in Human Cells, Cancer Res. 63:7330-7337. Stapon, A. Li, R.-F. Townsend, C. A. 2003. Synthesis of (3S,5R)-carbapenam-3-carboxylic acid and its role in carbapenem biosynthesis and the stereoinversion problem, J. Amer. Chem. Soc. 125:15746-15747. Stapon, A Li, R.-F. Townsend, C. A. 2003. Carbapenem Biosynthesis: Confirmation of Stereochemical Assignments and the Role of CarC in the Ring Stereoinversion Process from L-Proline, J. Amer. Chem. Soc. 125:8486-8493. Udwary, D. W. Casillas, L. K. Townsend, C. A. 2002. Synthesis of 11-Hydroxyl O-Methylsterigmatocystin and the Role of a Cytochrome P-450 in the Final Step of Aflatoxin Biosynthesis, J. Amer. Chem. Soc. 124:5294-5303. Kelly, W. L Townsend, C. A. 2002. Role of the Cytochrome P450 NocL in Nocardicin A Biosynthesis, J. Amer. Chem. Soc. 124:8186-8187. Townsend, C. A. 2002. New Reactions in Clavulanic Acid Biosynthesis, Curr. Opin. Chem. Biol. 6:583-589. Watanabe, M. H. C. Townsend, C. A. 2002. Initial Characterization of a Type I Fatty Acid Synthase and Polyketide Synthase Multienzyme Complex NorS in the Biosynthesis of Aflatoxin B1, Chem. & Biol. 9:981-988. Kim, E. K. Landree, L. E. Borisy-Rudin, F. F. Brown, P. Tihan, T. Townsend, C. A. Witters, L. A. Moran, T. H. Kuhajda, F. J. Ronnett, G. V. 2002. Expression of FAS within Hypothalmic Neurons: A Model for Decreased Food Intake After C75 Treatment, Amer. J. Physiol.-Endrocrinol. Metab. 283:E867-E879. Udwary, D. W. Merski, M. Townsend, C. A. A Method for Prediction of Linker Regions within Large Multifunctional Proteins, and its Application to a Type I Polyketide Synthase, J. Mol. Biol. 2002, 323, 585-598. Miller, M. T. Bachmann, B. O. Townsend, C. A. Rosenzweig, A. C. 2002. The Catalytic Cycle of b-Lactam Synthetase Observed by X-Ray Crystallographic Snapshots, Proc. Nat'l Acad. Sci. 99:14752-14757. McFadden, J. M. Frehywot, G. L. Townsend, C. A. 2002. A Flexible Route to (5R)-Thiolactomycin, a Naturally-Occurring Inhibitor of Fatty Acid Synthesis, Org. Lett. 4:3859-3862. Parrish, N. M. Houston, T. A. Jones, P. B. Townsend, C. A. Dick, J. D. 2001. In Vitro Activity of a Novel Antimicrobial Compound, N-Octanesulfonylacetamide, and its Effects on Lipid and Mycolic Acid Synthesis, Antimicrob. Agents Chemother. 45:1143-1150. Zhou, J. Kelly, W. L. Bachmann, B. O. Gunsior, M. Townsend, C. A. Solomon, E. I. 2001. Spectroscopic Studies of Substrate Interactions with Clavaminate Synthase 2, a Multifunctional a-KG-Dependent Non-Heme Iron Enzyme: Correlation with Mechanisms and Reactivities, J. Amer. Chem. Soc. 123:7388-7398. Hitchman, T. S. Schmidt, E. W. Trail, F. Rarick, M. D. Linz, J. E. Townsend, C. A. 2001. Hexanoate Synthase, a Specialized Type I Fatty Acid Synthase from Aflatoxin B1 Biosynthesis . Bioorg. Chem. 29:293-307. Miller, M. T. Bachmann, B. O. Townsend, C. A. Rosenzweig, A. C. 2001. Stucture of b-Lactam Synthetase Reveals How to Synthesize Antibiotics Instead of Asparagine, Nature Struct. Biol. 8:684-689. Keller, N. P. Watanabe, C. M. H. Kelkar, H. S. Adams, T. H. Townsend, C. A. 2000. Requirement of Monooxygenase-Mediated Steps for Sterigmatocystin Biosynthesis by Aspergillus nidulans, Appl. Environ. Microbiol. 66:359-362. Challis, G. L. Ravel, J. Townsend, C. A. 2000. Predictive, Structure-Based Model of Amino Acid Recognition by Non-Ribosomal Peptide Synthetase Adenylation Domains, Chemistry & Biology 7:211-224. Pizer, E. S. Thupari, J. Han, W.-F. Pinn, M. L. Chrest, F. J. Frehywot, G. L. Townsend, C. A. Kuhajda, F. P. 2000. Malonyl-Coenzyme-A is a Potential Mediator of Cytotoxicity Induced by Fatty Acid Synthase Inhibition in Human Breast Cancer Cells and Xenografts, Cancer Res. 60:213-218. Li, R.-F. Khaleeli, N. Townsend, C. A. 2000. Expansion of the Clavulanic Acid Gene Cluster: Identification and In vivo Functional Analysis of Three New Genes Required for the Biosynthesis of Clavulanic Acid from Streptomyces clavuligerus, J. Bacteriol. 182:4087-4095. Kuhajda, F. P. Pizer, E. S. Li J. N. Mani, N. S. Frehywot, G. L. Townsend, C. A. 2000. Synthesis and Anti-tumor Activity of a Novel Inhibitor of Fatty Acid Synthase, Proc. Nat'l Acad. Sci., U.S.A. 97:3450-3454. Khaleeli, N. Busby, R. W. Townsend, C. A. 2000. Site-Directed Mutagenesis and Biochemical Analysis of the Endogeneous Ligands in the Ferrous Active Site of Clavaminate Synthase. The His-3 Variant of the 2-His-1-Carboxylate Model. Biochemistry. 39:8666-8673. Loftus, T. M. Jaworsky D. Frehywot, G. L. Townsend, C. A. Ronnett, G. Lane, M. D. Kuhajda, F. J. 2000. Inhibitors of Fatty Acid Synthase Induce Weight Loss: A Link Between Fatty Acid Synthesis and Feeding Behavior, Science. 288:2379-2381. Bachmann, B. O. Townsend, C. A. 2000. Kinetic Mechanism of the b-Lactam Synthetase of Streptomyces clavuligerus, Biochemistry. 39:11187-11193. Jones, P. B. Parrish, N. M. Houston, T. A. Stapon, A. S. Bansal, N. P. Dick, J. D. Townsend, C. A. 2000. A New Class of Anti-Tuberculosis Agents, J. Med. Chem. 2000, 43, 3304-3314. Li. R.-F. Stapon, A. Blanchfield, J. T. Townsend, C. A. Three Unusual Reactions Mediate Carbapenem and Carbapenam Biosynthesis, J. Amer. Chem. Soc. 122:9296-9297. Wu, M. Stoermer, D. Townsend, C. A. Tullius, T. D. 2000. Calicheamicin-Homeodomain Conjugate as an Efficient, Sequence-Specific DNA Cleavage and Mapping Tool, J. Amer. Chem. Soc. 122:12884-12885. Khaleeli, N. Li, R.-F. Townsend, C. A. 1999. Origin of the b-Lactam Carbons in Clavulanic Acid from an Unusual Thiamine Pyrophosphate-Mediated Reaction, J. Amer. Chem. Soc. 121:9223-9224. Casillas, L. K. Townsend, C. A. 1999. Total Synthesis of O-Methylsterigmatocystin Using N-Alkylnitrilium Salts and Carbonyl-Alkene Interconversion in a New Xanthone Synthesis. J. Org. Chem. 64:4050-4059. Graybill, T. L. Casillas, E. G. Pal, K. Townsend, C. A. 1999. Silyltriflate-Mediated Ring-Closure and Rearrangement in the Synthesis of Potential Bisfuran-Containing Intermediates of Aflatoxin Biosynthesis, J. Amer. Chem. Soc. 121:7729-7746. Iwata-Reuyl, D. Basak, A. Townsend, C. A.1999. b-Secondary Kinetic Isotope Effects in the Clavaminate Synthase-Catalyzed Oxidative Cyclization of Proclavaminic Acid and in Related Azetidinone Model Reactions, J. Amer. Chem. Soc. 121:11356-11368.
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