Faculty

The Sherman laboratory works at the interface of bioorganic chemistry 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 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 of bioactive metabolite production.

We are using microarray analysis of the Streptomyces coelicolor genome to investigate the network of regulators involved in production of secondary metabolites. This project involves engineering of select mutations into the genome focused on two-component regulatory systems and analysis their phenotypic impact relating to production of actinorhodin, undecylprodigiosin and calcium dependent antibiotic. The ultimate goal is to understand the web of signals involve in physiological development (e.g. bioactive metabolite production) in Streptomyces.
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 or transport mechanisms.

Awards

Hans W. Vahlteich Professorship, 2007-present
John Gideon Searle Professorship, 2003-2006
Procter & Gamble University Exploratory Research Program, 1992-1995
Eli Lilly Life Sciences Award, 1990-1992
Myron A. Bantrell Postdoctoral Research Fellowship in Molecular Biology, 1984-1986
National Institutes of Health Postdoctoral Fellowship, 1982-1984
Pegram Award for Excellence in Graduate Research, Columbia University, 1981
American Chemical Society Award for Excellence in Undergraduate Research, 1978
University of California, Santa Cruz, Honors in the Major (Chemistry), 1978

Representative Publications

1. Lian, W., Jayapal, K.P., Charaniya, S., Mehra, S., Glod, F., Kyung, Y.S., Sherman, D.H., Hu, W.S., "Genome-wide transcriptome analysis reveals that a pleiotropic antibiotic regulator, AfsS, modulates nutritinoal stress resonse in Streptomyces coelicolor A3(2)", BMC Genomics, 2008, 9, 56.

2. Ding, Y., Seufert, W., Beck, Z.Q., Sherman, D.H., "Analysis of the cryptophycin P450 epoxidase reveals substrate tolerance and cooperataivity", J. Am. Chem. Soc. (ASAP).

3. Miller, K.A., Welch, T.R., Greshock, T.J., Ding, Y., Sherman, D.H., Williams, R.M., "Biomimetic total synthesis of malbrancheamide and malbranceamide", B. J. Org. Chem. (ASAP).

4. Buchholz, T.J., Kittendorf, J.D. and Sherman, D.H., "Polyketide biosynthesis, modular polyketide synthases", Wiley Encyclopedia of Chem. Biol., 2007, (in press).

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

6. Geders, T.W., Gu, L.C., Mowers, J.C., Liu, H., Gerwick, W.H., Hakansson, K., Sherman, D.H. and Smith, J.L., "Crystal structure of the ECH₂ catalytic domain of CurF from Lyngbya Majuscula: Insights into a decarbozylase involved in polyketide chain β-branching", J. Biol. Chem., 2007, 282, 35954, (online).

7. Li, S., Podust, L.M. and Sherman, D.H., "Engineeering and analysis of a self-sufficient biosynthetic cytochrome P450 PikC fused to the RhFRED reductase domain", J. ACS., 2007, 129, 12940.