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:
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}.
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.
Awards:
2008 AAAS Fellow
2009 American Chemistry Society Arthur C. Cope Scholar Award
