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 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.
Bonnett, S.A., Rath, C.M., Shareef, A.R., Joels, J.R., Chemler, J.A., Hakansson, K., Reynolds, K., Sherman, D.H. 2011. Acyl-CoA subunit selectivity in the pikromycin polyketide synthase PikAIV: steady-state kinetics and active-site occupancy analysis by FTICR-MS. Chem. Biol. 18(9): 1075-1081.
Akey, D.L., Li, S., Konwerski, J.R., Confer, L.A., Bernard, S.M., Anzai, Y., Kato, F., Sherman, D.H., Smith, J.L. 2011. A New Structural Form in the SAM/Metal-Dependent O-Methyltransferase Family: MycE from the Mycinamicin Biosynthetic Pathway. J. Mol. Biol. 413(2): 438-450.
Rath, C.M., Janto, B., Earl, J., Ahmed, A., Hu, F.Z., Hiller, L., Dahlgren, M., Kreft, R., Yu, F., Wolff, J.J., Kweon, H.K., Christiansen, M.A., Hakansson, K., Williams, R.M., Ehrlich, G.D., Sherman, D.H. 2011. Meta-omic Characterization of the Marine Invertebrate Microbial Consortium That Produces the Chemotherapeutic Natural Product ET-743. ACS Chem. Biol. 6(11):1244-1256.
Cruz, P.G., Auld, D.S., Schultz, P.J., Lovell, S., Battaile, K.P., Macarthur, R., Shen, M., Tamayo-Castillo, G., Inglese, J., Sherman, D.H. 2011. Titration-based screening forevaluation of natural product extracts: identification of an aspulvinone family of luciferase inhibitors. Chem Biol. 18(11):1442-1452.
Shareef, A.R., Sherman, D.H., Montogmery, J. 2012. Nickel-Catalyzed Regiodivergent Approach to Macrolide Motifs. Chem Sci. 3(3):892-895.
Li S, Finefield JM, Sunderhaus JD, McAfoos TJ, Williams RM, Sherman DH. 2011. Biochemical Characterization of NotB as an FAD-Dependent Oxidase in the Biosynthesis of Notoamide Indole Alkaloids.Am Chem Soc. 134(2): 788-791.
Gehret, J.J., Gu, L., Geders, T.W., Brown, W.C., Gerwick, L., Gerwick, W.H., Sherman, D.H., Smith, J.L. 2011. Structure and activity of DmmA, a marine haloalkane dehalogenase. Protein Sci. 21(2):239-248.
Busche, A.E., Gottstein, D., Hein, C., Ripin, N., Pader, I., Tufar, P., Eisman, E.B., Gu, L., Walsh, C.T., Loehr, F., Sherman, D.H., Güntert, P., Dötsch, V. 2011. Characterization of molecular interactions between ACP and halogenase domains in the curacin A polyketide synthase. ACS Chem Biol. 17;7(2):378-386.
Finefield, J.M., Frisvad, J.C., Sherman, D.H., Williams, R.M. 2012. Fungal Origins of the Bicyclo[2.2.2]diazaoctane Ring System of Prenylated Indole Alkaloids. Nat Prod. 75(4): 812-833.
Chemler, J.A., Buchholz, T.J., Geders, T.W., Akey, D.L., Rath, C.M., Chlipala, G.E., Smith, J.L., Sherman, D.H. 2012. Biochemical and Structural Characterization of Germicidin Synthase: Analysis of a Type III Polyketide Synthase that Employs Acyl-ACP as a Starter Unit Donor. J AM Chem Soc. 134(17): 7359-7366.
Nusca, T.D., Kim, Y., Maltseva, N., Eschenfeldt, W.H., Stols, L., Schofield, M.M., Scaglione, J.B., Dixon, S.D., Oves-Costales, D., Challis, G.L., Hanna, P.C., Pfleger, B.F., Joachimiak, A., Sherman, D.H. 2012. Functional and structural analysis of the siderophore synthetase AsbB through reconstitution of the petrobactin biosynthetic pathway from Bacillus anthracis. J Biol Chem. 287(19): 16058-16072.
Finefield, J.M., Sherman, D.H., Kreitman, M., Williams, R.M. 2012. Enantiomeric natural products: occurrence and biogenesis. Angew Chem Int Ed Engl. 51(20):4802-36.
Lee, M.J., Kong, D., Han, K., Sherman, D.H., Bai, L., Deng, Z., Lin, S., Kim, E.S. 2012. Structural analysis and biosynthetic engineering of a solubility-improved and less-hemolytic nystatin-like polyene in Pseudonocardia autotrophica. Appl Microbiol Biotechnol. 95(1): 157-168.
Anzai, Y., Tsukada, S., Sakai, A., Masuda, R., Harad, C., Domek, A., Li, S., Kinoshit, K., Sherman, D.H., Kato, F. 2012. Function of the cytochrome P450 enzymes MycCl and MycG in Micromonospora griseorubida, a producer of the macrolide antibiotic mycinamicin. Antimicrob Agents Chemother 56(7):3648-56.
Li, S., Anand, K., Tran, H., Yu, F., Finefield, J.M., Sunderhaus, J.D., McAfoos, T.J., Tsukamoto, S., Williams, R.M., Sherman, D.H. 2012. Comparative analysis of the biosynthetic systems for fungal bicyclo[2.2.2]diazaoctane indole alkaloids: the (+)/(−)-notoamide, paraherquamide and malbrancheamide pathways. Med Chem Commun. 3(8):987-996
Jacob, R.T., Larsen, M.J., Larsen, S.D., Kirchhoff, P.D., Sherman, D.H. Neubig, R.R. 2012. MScreen: An Integrated Compound Management and High-Throughput Screening Data Storage and Analysis System. J Biomol Screen17(8):1080-7.
Podust, L.M., Sherman, D.H. 2012. Diversity of P450 enzymes in the biosynthesis of natural products. Nat Prod Rep. 29(10):1251-66.
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.
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.
Majmudar, C.Y., Højfeldt, J.W., Arevang, C.J., Pomerantz, W.C., Gagnon, J.K., Schultz, P.J., Cesa, L.C., Doss, C.H., Rowe, S.P., Vásquez, 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 Int Ed Engl. 51(45):11258-62.
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.
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.
Narayan, A.R., Sherman, D.H. 2013. Chemistry. Re-engineering nature's catalysts. Science 339(6117):283-284.
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.
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.
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.
2009 American Chemistry Society Arthur C. Cope Scholar Award
2008 AAAS Fellow