David Sherman explores the biochemical pathways of marine microorganisms with the goal of finding new drug candidates for infectious diseases and cancers. He collects samples from marine and terrestrial sources around the world to build an extensive library of natural chemical compounds with potential disease-fighting capability.

Bioorganic Chemistry/Chemical Biology/Organic Chemistry/Medicinal Chemistry

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 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 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 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.

Dutta, S., Whicher, J.R., Hansen, D.A., Hale, W.A., Chemler, J.A., Congdon, G.R., Narayan, A.R., Hakansson, K., Sherman, D.H., Smith, J.L., Skiniotis, G. 2014. Structure of a modular polyketide synthase. Nature. 510(7506): 512-517. PubMed link

Whicher, J.A., Dutta, S., Hansen, D.A., Hale, W.A., Chemler, J.A., Dosey, A.M., Narayan, A.R., Hakansson, K., Sherman, D.H., Smith, J.L., Skiniotis, G. 2014. Structural rearrangements of a polyketide synthase module during its catalytic cycle. Nature. 510(7506):560-564. Pubmed link

Newmister, S.A., Sherman, D.H. 2014. Crystal structures of acyl carrier protein in complex with two catalytic partners show a dynamic role in cellular metabolism. ChemBioChem. 15(8):1079-1081. PubMed link

Walter, G.M., Raveh, A., McQuade, T. J., Arevang, C.J., Schultz, P. J., Smith, M. C., Asare, S., Cruz, P. G., Wisen, S., Matainaho, T., Sherman, D.H ., Gestwicki, J. E. 2014. High throughput screen of natural product extracts in a yeast model of polyglutamine proteotoxicity. Chem. Biol. Drug Des. 83(4):440-449. PubMed link

Negretti, S., Narayan, A.R., Chiou K.C., Kells, P.M., Stachowski, J., Hansen, D., Podust, L., Montgomery, J., Sherman, D.H. 2014. Directing group-controlled regioselcetivity in an enzymatic C-H bond oxygenation. J. Am. Chem. Soc. 136(13):4901-4904. PubMed link

Zhang, W., Liu, Y., Yan, J., Cao, S., Bai, F., Yang, Y., Huang, S., Yao, L., Anzai, Y., Kato, F., Podust, L.M., Sherman, D.H. , Li, S. 2014. New reactions and products resulting from alternative interactions between the P450 enzyme and redox partners. J. Am. Chem. Soc. 136(9):3640-3646. doi: 10.1021/ja4130302. PubMed link

Coates, R.C., Podell, S., Korobeynikov, A., Lapidus, A., Pevzner, P., Sherman, D.H., Allen, E.E., Gerwick, L., Gerwick, W.H. 2014. Characterization of cyanobacterial hydrocarbon composition and distribution of biosynthetic pathways. PLoS One 9(1):e85140 PubMed link

Larsen, M.J., Larsen, S.D., Fribley, A., Grembecka, J., Homan, K., Mapp, A., Haak, A., Nikolovska-Coleska, Z., Stuckey, J.A., Sun, D., Sherman, D.H. 2014. The role of HTS in drug discovery at the University of Michigan. Comb. Chem. High Throughput Screen. {Epub ahead of print} PubMed link

Tripathi A., Schofield, M.M., Chlipala, G.E., Schultz, P.J., Yim, I., Newmister, S.A., Nusca, T.D., Scaglione, J.B., Hanna, P.C., Tamayo-Castillo, G., Sherman, D.H. 2013. Baulamycins A and B, broad-spectrum antibiotics identified as inhibitors of siderophore biosynthesis in Staphylococcus aureus and Bacillus anthracis. J. Amer. Chem. Soc. 136(4):1579-86. PubMed link

Raveh A., Delekta P. C., Dobry, C. J., Schultz, P. J., Blakely, P. K., Tai, A. W., Matainaho, T., Irani, D. N., Sherman, D.H. , Miller, D. H. 2013. Discovery of potent broad spectrum antivirals derived from marine actinobacteria. PLoS One. 8(12):e82318 PubMed link

Whicher, J.R., Smaga, S.S., Hansen, D.A., Brown, W.C., Gerwick, W.H., Sherman, D.H., et al. 2013. Cyanobacterial polyketide synthase docking domains: a tool for engineering natural product biosynthesis. Chem. Biol. 20(11):1340-1351 PubMed link

Hansen, D.A., Rath, C.M., Eisman, E.B., Narayan, A.R., Kittendorf, J.D., Mortison, J.D., Yoon, Y.J., Sherman, D.H. 2013. Biocatalytic synthesis of pikromycin, methymycin, neomethymycin, novamethymycin, and ketomethymycin. J. Am. Chem. Soc. 135(30): 11232-11238. PubMed link

Schofield, M.M., Sherman, D.H. 2013. Meta-omic characterization of prokaryotic gene clusters for natural product biosynthesis. Curr. Opin. Biotechnol. pii:S0958-1669(13)00115-8. PubMed link

Zhang, W., Fortman, J.L., Carlson, J.C., Yan, J., Liu, Y., Bai, F., Guan, W., Jia, J., Matainaho, T., Sherman, D.H. , Li, S. 2013. Characterization of the bafilomycin biosynthetic gene cluster from Streptomyces lohii. Chembiochem. 14(3):301-306. PubMed link

Narayan, A.R., Sherman, D.H. 2013. Chemistry. Re-engineering nature's catalysts. Science. 339(6117):283-284. PubMed link

Sunderhaus, J.D., McAfoos, T.J., Finefield, J.M., Kato, H., Li, S., Tsukamoto, S., Sherman, D.H. , Williams, R.M. 2013. Synthesis and bioconversions of notoamide T: a biosynthetic precursor to stephacidin a and notoamide B. Org Lett. . 15(1): 22-25. PubMed link

Kim, E.J., Lee, J.H., Choi, H., Pereira, A.R., Ban, Y.H., Yoo, Y.J., Kim, E., Park, J.W., Sherman, D.H. , Gerwick, W.H., Yoon, Y.J. 2012. Heterologous production of 4-O-demethylbarbamide, a marine cyanobacterial natural product. Org Lett. 14(23):5824-5827. PubMed link

Majmudar, C.Y., Hojfeldt, J.W., Arevang, C.J., Pomerantz, W.C., Gagnon, J.K., Schultz, P.J., Cesa, L.C., Doss, C.H., Row, S.P., Vasquez, V., Tamayo-Castillo, G., Cierpicki, T., Brooks, C.L. 3rd., Sherman D.H ., Mapp, A.K. 2012. Sekikaic acid and lobaric acid target a dynamic interface of the coactivator CBP/p300. Angew Chem Intl Engl. 51(45):11258-62. PubMed link

Li, S., Tietz, D.R., Rutaganira, F.U., Kells, P.M., Anzai, Y. , Kato, F., Pochapsky, T.C., Sherman D.H ., Podust, L.M. 2012. Substrate recognition by the multifunctional cytochrome P450 MycG in mycinamicin hydroxylation and epoxidation reactions. J Biol Chem. 287(45):37880-90. PubMed link

Kim, D., Nah, J.H., Choi, S.S., Shin, H.S., Sherman D.H. , Kim, E.S. 2012. Biological activities of an engineered tautomycetin analogue via disruption of tmcR-encoding hydroxylase in Streptomyces sp. CK4412 J Ind Microbiol Biotechnol. 39(10):1563-8. PubMed link