Faculty
 |
David H. Sherman |
My research efforts over the past decade have evolved into several programs that are distinct in focus, yet coalesce into an overriding theme that include molecular genetic, biochemical and bioorganic chemical studies of microbial natural product biosynthesis. Metabolic engineering and combinatorial biosynthesis are powerful approaches for harnessing the tremendous metabolic capabilities of microorganisms, including primary and secondary pathways. New genomic-based technologies are enhancing considerably our ability to understand and manipulate complex biosynthetic systems and will enable vast new opportunities in medicine and industry. My laboratory is exploring fundamental aspects of the systems described below, as well as pursuing drug discovery opportunities in the area of infectious diseases and cancer.
Molecular genetic analysis:
Molecular genetic analysis of terrestrial and marine natural products biosynthesis. A large number of novel natural products are being discovered from terrestrial and novel marine microbes. These exciting sources of new chemical entities will provide a wealth of unique information about the organization, structure, and regulation of genes involved in secondary metabolism. The focus over the past five decades has been entirely on secondary metabolite pathways of terrestrial microorganisms. Since novel classes of microorganisms that produce important secondary metabolites are being discovered from marine sources, it is clear that there will be exciting new information to be learned from these novel organisms at the genetic level. Our focus currently includes marine cyanobacteria, actinomycetes and myxobacteria.
Biochemistry, enzymology, and bioorganic chemistry:
Biochemistry, enzymology, and bioorganic chemistry of proteins involved in biosynthesis of terrestrial and marine natural products. The unique chemistry operating to construct complex terrestrial and marine natural products provides a certain and virtually limitless source of novel enzymes and resistance proteins. The genes that specify the biosynthesis of these compounds will provide a readily accessible source of novel biocatalysts that perform interesting and potentially novel chemical reactions. As new classes of marine natural products are elucidated, the corresponding organisms identified and the gene clusters characterized, it will be possible to use the versatile tools of genetic engineering to over-express, purify and characterize fully the unique chemical catalysts that have evolved in the terrestrial and marine environments.
Combinatorial biology:
Combinatorial biology of marine natural product biosynthetic genes. Over the past few years it has become evident that powerful new molecular methods exist for the reconfiguration and expression of genes involved in natural product biosynthesis. There is huge potential to create novel organic molecules through deliberate in vivo and in vitro engineering of these pathways for production of human and veterinary pharmaceuticals, specialty chemicals, and high value biomaterials. Relatively few systems exist that can be readily tapped to provide the needed metabolic diversity for the creation of new pathways. Perhaps the single most important new source of this metabolic potential will be provided by natural product biosynthetic genes derived from marine microorganisms. We will continue to pursue aggressively novel metabolic pathways from micro- and macro-organisms, including sponge symbionts and other invertebrates.
Selected Publications:
Lee, J.Y., Passalacqua, K.D., Hanna, P.C., Sherman, D.H. Regulation of Petrobactin and Bacillibactin Biosynthesis in Bacillus anthracis under Iron and Oxygen Variation. 2011. PLos One. 6(6): e20777
Gu, L., Eisman, E.B., Dutta, S., Franzmann, T.M., Walter, S., Gerwick, W.H., Skiniotis, G., Sherman, D.H. 2011. Tandem acyl carrier proteins in the Curacin biosynthetic pathway promote consecutive multienzyme reactions with a synergistic effect. Angew. Chem. Intl.Ed. Engl. 50(12): 2795-2798.
Sunderhaus, J.D., Sherman, D.H., Williams, R.M. 2011. Studies on the biosynthesis fo the Stephacidin and Notoamide Natura Products: A Stereochemical and Genetic Conundrum. Isr. J. Chem. 51(3): 442-452.
Gehret, J.J., Gu, L., Gerwick, W.H., Wipf, P., Sherman, D.H., Smith, J.L. 2011. Terminal alkene formation by the thioesterase of Curacin a biosynthesis: Structure of a decarboxylating thioesterase. J. Biol. Chem. 286(16); 14445-14454
Singh, S., Chang, A., Goff, R.D., Bingman, C.A., Grushow, S., Sherman, D.H., Phillips, G.N. Jr., Thorson, J.S. Structural Characterization of the mitomycin 7-O-methyltransferase. 2011. Proteins. 79(7): 2181-2188. Doi: 10.1002/prot.23040.
Carlson, J.C., Li, S., Gunatilleke, S.S., Anzai, Y., Burr, D.A., Podust, L.M., Sherman, D.H. 2011. Tirandamycin biosynthesis is mediated by co-dependent oxidative enzymes. Nature Chemistry. 3(8): 628-633. Doi: 10.1038/nchem.1087.
Finefield, J.M., Kato, H., Greshock, T.J., Sherman, D.H., Tsukamoto, S., Wiliams, R.M. Biosynthetic studies of the notoamides: isotopic synthesis of stephacidin a and incorporation into notamide B and sclerotiamide. 2011. Org. Lett. 13(15): 3802-3805.
Finefield, J.M., Sherman, D.H., Tsukamoto, S., Williams, R.M. Studies on the biosynthesis of the notoamides: synthesis of an isotopomer of 6-hydroxydeoxybrevianamide e and biosynthetic incorporation into notoamide j. 2011. J. Org. Chem. 76(15): 5954-5958.
Ding, Y., Rath, C.M., Bolduc, K.L, Hakansson, K., Sherman, D.H. 2011. Chemoenzymatic Synthesis of Cryptophycin Anticancer Agents by an Ester Bond Forming NRPS Module. J. Am. Chem. Soc. August 8 {Epub ahead of print}
Jones, A.C., Monroe, E.A., Eisman, E.B., Gerwick, L., Sherman, D.H., Gerwick, W.H. 2010. The unique mechanistic transformations involved in the biosynthesis of modular natural products from marine cyanobacteria. Nat. Prod. Rep. 27(7): 1048-1065.
Scaglione, J.B., Akey, D.L., Sullivan, R., Kittendorf, J.D., Rath, C.M., Kim, E.S., Smith, J.L., Sherman, D.H. 2010. Biochemical and Structural Characterization of the Tautomycetin Thioesterase: Analysis of a Stereoselective Polyketide Hydrolase. Angew. Chem. Int. Ed. Engl. 49(33):5726-5730.
Khare, D., Wang, B., Gu, L., Razelun, J., Sherman, D.H., Gerwick, W.H., Hakansson, K., Smith, J.L. 2010. Conformational switch triggered by {alpha}-ketoglutarate in a halogenase of Curacin A biosynthesis. Proc. Natl Acad. Sci. USA. 107(32): 14099-14104.
Ding, Y., Wet, J.R., Cavalcoli, J., Greshock, T.J., Miller, K.A., Finefield, J.M., Sunderhaus, J.D., McAfoos, T.J., Tsukamoto, S., Williams, R.M., Sherman, D.H. 2010. Genome-based Characterization of Two Prenylation Steps in the Assembly of the Stephacidin and Notoamide Anticancer Agents in a Marine-Derived Aspergillus sp. J. Am. Chem. Soc. 132(36):12733-12740.
Himpsl S.D., Pearson, M.M., Arewang, C.J., Nusca, T.D., Sherman, D.H., Mobley, H.L. 2010. Proteobactin and a yersiniabactin-related siderophore mediate iron acquisition in Proteus mirabilis. Mol. Microbiol. 78(1): 138-157
Buchholz, T.J., Rath, C.M., Lopanik, N.B., Gardner, N.P., Hakansson, K., Sherman, D.H. 2010. Polyketide beta-branching in Bryostatin Biosynthesis: Identification of Surrogate Acetyl-ACP Donors for BryR, an HMG-ACP Synthase. Chem & Biol. 17(10): 1092-1100.
Mortison, J.D., Sherman, D.H. 2010. Frontiers and Opportunities in Chemoenzymatic Synthesis. J. Org. Chem. 75(21): 7041-7051.
McAffos, T.J., Li, S., Tsukamoto, S., Sherman, D.H., Williams, R.M. Studies on the biosynthesis of the Stephacidins and Notoamides. Total synthesis of Notoamide S. 2010. Heterocycles. 82(1): 461-472.
Tsukada, S.I., Anzai, Y., Li, S., Kinoshita, K. Sherman, D.H., Kato, F. 2010. Gene Targeting for O-methyltransferase genes, mycE and mycF, on the chromosome of Micromonospora griseorubida producing Mycinamicin with a disruption cassette containing the bacteriophage phiC31 attB attachment site. FEMS Microbiol. Lett. Jan 11. {Epub ahead of print}
Akey, D.L., Razelun, J.R., Tehranisa, J., Sherman, D.H., Gerwick, W.H., Smith, J.L. 2010. Crystal structures of Dehydratase Domains form the Curacin Polyketide Biosynthetic Pathway. Structure. 18(1): 94-105. NIHMSID: NIHMS166452
Carlson, J.C., Fortman, J.L., Anzai, Y., Li, S., Burr, D.A., Sherman, D.H. 2010. Identification of the Tirandamycin Biosynthetic Gene Cluster form Streptomyces sp. 307-309. ChemBioChem 11(4): 564-572.
Carlson, P.E., Dixon, S.D., Janes, B.K., Carr, K.A., Nusca, T.D., Anderson, E.C., Keene, S.E., Sherman, D.H., Hanna, P.C. 2010. Genetic analysis of petrobactin transport in Bacillus anthracis. Mol. Microbiol. Jan. 5.
Carlson, J.C., Li, S., Burr, D.A., Sherman, D.H. 2009. Isolation and Characterization of Tirandamycins from a Marine-derived Streptomyces sp. J. Nat. Prod. 72(11): 2076-2079.
Sherman, D.H. 2009. Biochemistry: Enzyme’s black box cracked open. Nature. 461(7267): 1068-1069.
Gu, L., Wang, B., Kulkamid, A., Gehret, J.J., Lloyd, K.R., Gerwick, L., Gerwick, W.H., Wipf, P., Hakansson, K., Smith, J.L., Sherman, D.H. 2009. Polyketide Decarboxylative Chain Termination Preceded by O-Sulfonation in Curacin A Biosynthesis. J. Am. Chem. Soc. 131(44): 16033-16035.
Li, S., Chaulagain, M.F., Knauff, A.R., Podust, L.M., Montgomery, J., and Sherman, D.H. 2009. Selective oxidation of carbolide C-H bonds by an engineered macrolide P450 mono-oxygenase. PNAS. 106(44):18463-18468. PMCID: PMC2774028
Mortison, J.D., Kittendorf, J.D., Sherman, D.H. 2009. Synthesis and Biochemical Analysis of Complex Chain-Elongation Intermediates for Interrogation of Molecular Specificity in the Erythromycin and Pikromycin Polyketide Synthases. J. Am. Chem. Soc. 131(43): 15784-15793. PMCID: PMC2796446
Kim, B.G., Lee, M.J., Seo, J., Hwang, Y. B., Lee, M.Y., Han, K., Sherman, D.H., Kim, E.-S. 2009. Identification of functionally clustered nystatin-like biosynthetic genes in a rare actinomycetes, Pseudonocardia autotrophica. J. Ind. Microbiol. Biotechnol. 36(11):1425-1434.
Li, M.H, Ung, P.M., Zajkowski, J., Garneau-Tsodikova, S., and Sherman, D.H. 2009. Automated genome mining for natural products. BMC Bioinformatics. 10:185. PMCID: PMC2712472.
Gu, L., Wang, B., Kulkarni, A., Geders, T.W., Grindberg, R.V., Gerwick, L., Hakansson, K., Wipf, P., Smith, J.L., Gerwick, W.H., Sherman, D.H. 2009. Metamorphic enzyme assembly in polyketide diversification. Nature. 459(7247): 731-735.
Yan, J. Gupta, S., Sherman, D.H., Reynolds, K.A. 2009. Functional Dissection of a Multimodular Polypeptide of the Pikromycin Polyketide Synthase into Monomodules by Using a Matched Pair of Heterologous Docking Domains. ChemBioChem. 10(9):1537-1543.
Li, S., Anzai, Y., Kinoshita, K., Kato, F., Sherman, D.H. 2009. Functional Analysis of MycE and MycF: Two O-Methlytransferases Involved in the Biosynthesis of Mycinamicin Macrolide Antibiotics. ChemBioChem. 10(8):1297-1301. Hu, P.J., Sherman, D.H. 2009. DANSing with Caenorhabditis elegans. Proc. Natl. Acad. Sci. U.S.A. 106(19):7685-7686. PMCID: PMC2683097.
Li, S., Ouellet, H., Sherman, D.H. and Podust, L.M. 2009. Analysis of transient and catalytic desosamine binding pockets in cytochrome P450 PikC from Streptomyces venezuelae. J. Biol. Chem. Jan. 4 {Epub ahead of print}
Buchholz, T.J., Geders, T.W., Bartley, F.E. 3rd, Reynolds, K.A., Smith, J.L., and Sherman, D.H. 2009. Structural basis for binding specificity between subclasses of modular polyketide synthase docking domains. Chem. Biol. 4(1):41-52.
Park, S.H., Choi, S.S., Kim, Y.J., Chang, Y.K., Sherman, D.H., Kim, E.-S. 2009. Functional expression of SCO7832 stimulates tautomycetin production via pathway-specific regulatory gene overexpression in Streptomyces sp. CK4412. J. Ind. Microbiol. Biotechnol. 36(7):993-998.
Jayapal, K. P., Philp, R.J., Kok, Y.-J., Yap, Miranda G.S., Sherman, D.H. Griffin, T.J., Hu, W.-S. 2008. Uncovering genes with divergent mRNA-protein dynamics in Streptomyces coelicolor. PLoS ONE. 3(5):e2097.
Ding, Y., Gruschow, S., Greshock, T.J., Finefield, J.M., Sherman, D.H., Williams, R.M. 2008. Detection of VM55599 and Preparaherquamide from Aspergillus japonicus and Penicillium fellutanum: Biosynthetic Implications. J. Nat. Prod. 71(9):1574-1578.
Smith, J. L. and Sherman, D. H. 2008. An enzyme assembly line. Science. 321(5894):1304-1305.
Anzai, Y., Li, S., Chaulagain, M. R., Kinoshita, K., Kato, F., Montgomery, J., and Sherman, D. H. 2008. Functional analysis of MycCI and MycG, cytochrome P450 enzymes involved in biosynthesis of mycinamicin macrolide antibiotics. Chem. Biol. 15(9):950-959.
Hur, Y.A., Choi, S.S., Sherman, D.H., and Kim, E.S. 2008. Identification of TmcN as a pathway-specific positive regulator of tautomycetin biosynthesis in Streptomyces sp. CK4412. Microbiology. 154(Pt 10):2912-2919.
Ding, Y., Greshock T.J., Miller, K. A., Sherman, D.H., Williams, R.M. 2008. Premalbrancheamide: Synthesis, Isotopic Labeling, Biosynthetic Incorporation, and Detection in Cultures of Malbranchea aurantiaca. Org. Lett. 10(21):4863-4866.
Pfleger, B.F., Kim, Y., Nusca, T.D., Maltseva, N., Lee, J.Y., Rath, C.M., Scaglione, J.B., Janes, B.K., Anderson, E.C., Bergman, N.H., Hanna, P.C., Joachimiak, A., Sherman, D.H. 2008. Structural and functional analysis of AsbF: origin of the stealth 3,4-dihydroxybenzoic acid subunit for petrobactin biosynthesis. Proc. Natl. Acad. Sci. 105(44): 17133-17138.
Lopanik, N. B., Shields, J. A., Buchholz, T. J., Rath, C. M., Hothersoll, J., Haygood, M. G., Håkansson, K., Thomas, C. M., and Sherman, D. H. 2008. In vivo and in vitro trans-acylation by BryP, the putative bryostatin pathway acyltransferase derived from an uncultured marine symbiont. Chem. Biol. 15(11): 1175-1186.
Kittendorf, J. D. and Sherman, D. H. 2008. The methymycin/pikromycin biosynthetic pathway: A model for metabolic diversity in natural product biosynthesis. Bioorg. & Med. Chem. Nov. 5 {Epub ahead of print}.
Awards:
2009 American Chemistry Society Arthur C. Cope Scholar Award
2008 AAAS Fellow
