Faculty


David H. Sherman

Hans W. Vahlteich Professor of Medicinal Chemistry; Associate Dean for Research and Graduate Education, College of Pharmacy;
Research Professor, Life Sciences Institute;
Professor of Chemistry and Microbiology & Immunology

Ph.D., Columbia University
Postdoctoral Fellow, Yale University and MIT

Research Focus: Bioorganic Chemistry, Molecular Genetics and Biochemistry

Phone: 734.615.9907
Email: davidhs@umich.edu
Fax: 734.615.3641

The Sherman laboratory works at the interface of bioorganic chemistry, enzymology and molecular microbiology through the investigation of secondary metabolic systems involved in natural product biosynthesis. Several projects are being pursued in the group including genomic and bioinformatic analysis of antibiotic biosynthesis in Streptomyces spp., investigation of the molecular genetics and biochemistry of cyanobacterial secondary metabolic systems, synthetic chemistry of complex natural product substrates to investigate the specificity and mechanisms of natural product biosynthetic enzymes, and development of culture methods for isolation of novel marine bacteria rich in bioactive metabolite production.

A growing effort is underway to investigate a series of fascinating cyanobacterial derived metabolic pathways including the anticancer compounds cryptophycin and curacin. In this program, we are combining the isolation and analysis of specific metabolic pathway genes and enzymes coupled with synthetic chemistry to analyze the specificity and mechanism of chain elongation, processing and cyclization leading to new bioactive molecules. This program is providing novel tools for chemoenzymatic construction of complex molecules that are difficult to access using synthetic methods alone.

Within the past several years we have developed a program to isolate and investigate new types of marine bacteria from biodiverse tropical reef habitats. This project has already resulted in thousands of new bacterial isolates within the actinomycetes group of Gram-positive bacteria known to produce diverse natural product structures. Extracts from these cultures are being analyzed in our laboratory and those of our collaborators (including two pharmaceutical companies) to discover novel anti-cancer and anti-infective agents. As new high interest compounds are defined, we embark on molecular genetic characterization of the biosynthetic gene cluster and pursue biochemical studies on enzymes involved in natural product structural assembly, cellular resistance, regulation and transport mechanisms.

Finally, we are using high throughput genome and symbiont metagenomic sequence analysis and proteomics of diverse bacteria and fungi to investigate the network of pathways involved in production of secondary metabolites. This project also involves engineering of select mutations into the genome that perturb two-component regulatory systems and precursor/co-factor flux for production of high value metabolites such as the ketolide pikromycin and the b-lactamase inhibitor clavulanic acid. The ultimate goal is to understand the web of signals involved in bioactive metabolite production to pursue synthetic biological solutions to engineer new pathways and molecules.

Sherman Research Group

 

Awards

2015-2017 ASM Distinguished Lecturer
2009 Charles Thom Award. Society of Industrial Microbiology
2009
American Chemical Society Arthur C. Cope Scholar Award in Organic Chemistry
2008 AAAS Fellow
2007-present Hans W. Vahlteich Professorship
2003-2007 John Gideon Searle Professorship
1992-1995
Procter & Gamble University Exploratory Research Program
1990-1992 Eli Lilly Life Sciences Award
1984-1986 Myron A. Bantrell Postdoctoral Research Fellowship in Molecular Biology
1982-1984 National Institutes of Health Postdoctoral Fellowship
1981 Pegram Award for Excellence in Graduate Research, Columbia University
1978 American Chemical Society Award for Excellence in Undergraduate Research
1978
University of California, Santa Cruz, Honors in the Major (Chemistry)

 

Representative Publications

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

 

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