Faculty

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., Janes B.K., Passalacqua K.D., Pfleger B., Bergman N.H., Liu H., Håkansson K., Somu R.V., Aldrich C.C., Cendrowski S., Hanna P.C., Sherman, D.H. 2007. Biosynthetic analysis of the petrobactin siderophore pathway from Bacillus anthracis. J. Bacteriol. 189:1698-1710.

   Sudek S., Lopanik N.B., Waggoner L.E., Hildebrand M., Anderson C., Liu H., Patel A., Sherman, D.H. and Haygood M.G. 2007. Identification of the putative bryostatin polyketide synthase gene cluster from “Candidatus Endobugula sertula”, the uncultivated microbial symbiont of the marine bryozoan Bugula neritina. J. Nat. Prod. 70:67-74.

   Li S., Grüschow S., Dordick J.S., and Sherman D.H. 2007. Molecular analysis of the role of tyrosine 224 in the active site of Streptomyces coelicolor RppA, a bacterial type III polyketide synthase. J. Biol. Chem. 282:12765-72.

   Pfleger B. F., Lee, J.Y., Somu, R.V., Aldrich, C.C., Hanna, P.C., and D. H. Sherman. 2007. Characterization and analysis of early enzymes for petrobactin biosynthesis in Bacillus anthracis. Biochemistry 46:4147-4157.

   Choi S.-S., Hur Y.-A., Sherman D.H., and E.-S. Kim. 2007. Isolation of the biosynthetic gene cluster for tautomycetin, a linear polyketide T cell-specific immunomodulator from Streptomyces sp. CK4412. Microbiology 153:1095-1102.

   Liu H., Håkansson K., Lee J.Y., and Sherman D.H. 2007. Collision-activated dissociation, infrared multiphoton dissociation, and electron capture dissociation of the Bacillus anthracis siderophore petrobactin and its metal ion complexes. Journal of the American Society for Mass Spectrometry 18:842-849.
Passalacqua K.D., Bergman N.H., Lee J.Y., Sherman D.H., and Hanna P.C. 2007. The global transcriptional responses of Bacillus anthracis Sterne (34F2) and DsodA1 to paraquat reveal metal ion homeostasis imbalances during endogenous superoxide stress. J Bacteriol. 189:3996-4013.

   Grüschow S., Buchholz T.J., Seufert W., Dordick J.S., and Sherman D.H. 2007. Substrate profile analysis and ACP-mediated acyl transfer in Streptomyces coelicolor type III polyketide synthases. Chembiochem. 8:863-868.

   Grüschow S., Chang L.C., Mao Y., and Sherman D.H. 2007. Hydroxyquinone O-methylation in mitomycin biosynthesis. J. Amer. Chem. Soc. 129:6470-6476.

   Kwon S. J., Lee M.-Y., Ku B., Sherman D. H., and Dordick J. S. 2007. High-throughput, microarray-based Synthesis of natural product analogs via in vitro metabolic pathway construction.  ACS Chemical Biology 2:419-25.

   Sitachitta N., Lopanik N. B., Mao, Y., Sherman D.H. 2007. Analysis of a parallel branch in the mitomycin biosynthetic pathway involving the mitN-encoded aziridine N-methyltransferase. J. Biol. Chem. 282:20941-7.

   Oh, H.-S.,  Yun, J.-S., Nah, K.-H., Kang, H.-Y. and Sherman D. H. 2007. Synthesis of the tetraketide lactones from the pikromycin biosynthetic pathway. Eur. J. Org. Chem. 3369–3379.

   Jayapal, K.P., Lian, W., Glod, F., Sherman, D.H. and Hu, W.S. 2007. Comparative genomic hybridizations reveal absence of large Streptomyces coelicolor genomic islands in Streptomyces lividans.  BMC Genomics 2007 Jul 10;8(1):229.

   Beck Z. Q., Burr D. A. and Sherman D. H.. 2007. Characterization of the b-methylaspartate-a-decarboxylase (CrpG) from the cryptophycin biosynthetic pathway. ChemBioChem 8: 1373-1375.

   Kittendorf J. D., Beck B. J., Buchholz T. J. and Sherman D. H. 2007. Interrogating the molecular basis for multiple macrolactone ring formation by the pikromycin polyketide synthase. Chemistry & Biology 14: 944-954.

   Seufert, W., Beck, Z. Q. and Sherman, D. H. 2007. Enzymatic release and macrolactonization of cryptophycins from safety-catch solid support. Angewandte Chemie (in press)

   Li, S., Podust, L. M. and Sherman, D. H. 2007. Engineering and analysis of a self-sufficient biosynthetic cytochrome P450 PikC fused to the RhFRED reductase domain. J. Amer. Chem. Soc. 129: 12940-12941.

   Geders, T. W., Gu, L. C., Mowers, J. C., Liu, H., Gerwick, W. H., Håkansson, K., Sherman, D. H., Smith, J. L. 2007. Crystal structure of the ECH2 catalytic domain of CurF from Lyngbya majuscula: Insights into a decarboxylase involved in polyketide chain b-branching. J. Biol. Chem. (published on line, October 10, 2007)

   Gu, L. C., Geders, T. W., Wang, B., Gerwick, W. H., Håkansson, K., Smith, J. L., Sherman, D. H. 2007. GNAT-like strategy for polyketide chain initiation. Science 318: 970-974.

   Buchholz, T. J., Kittendorf, J. D., and Sherman, D. H. 2007. Polyketide biosynthesis, modular polyketide synthases. Wiley Encyclopedia of Chemical Biology (in press).