Coran M H. Watanabe
Associate Professor
Ph. D., The Johns Hopkins University
Contact
Information:
Department of Chemistry
Texas A&M University
College Station, TX 77842
Phone:
(979) 458-8094
Fax: (979) 458-8095
watanabe@chem.tamu.edu
The research interests of my group span the interface of chemistry and biology including:
Nature greatly influences our research interests. Secondary metabolites, for example, are compounds that are found only in specific organisms and are an expression of the individuality of species. Investigation of secondary metabolism began with curiosity about the structures of compounds from natural sources. It is the experimental outcome of this curiosity that led to the discovery that many natural products exhibit a wide range of biological activities and include antibiotics, such as the penicillins and vancomycin (often referred as the drug of last resort), anti-cancer agents such as mitomycin C and Taxol (both on the market) and other medicinals. Indeed, at least 60% of all small molecule drugs on the market today are either natural products or have been derived from natural product leads.
The realization of the importance and impact that natural products have had on pharmaceutical industry notwithstanding, the field faces obstacles that need to be addressed. Limited supplies, low concentrations of the compounds in natural sources and complicated structures can often prevent the therapeutic use of these agents. Moreover, it is estimated that fewer than 0.1% of microorganisms collected from marine waters can be cultivated utilizing standard methods. These practical limitations are yet further compounded by the continual re-isolation of previously characterized compounds. One focus of our research program is to employ genetic and biochemical strategies to access the biosynthetic machinery from 'unculturable' marine microorganisms. The basic idea is to isolate the genetic material from these organisms and transfer them into heterologous 'culturable' organisms for natural product production. The produced metabolites are examined in a variety of biologically relevant drug screens and the structure of these compounds elucidated by standard spectroscopic methods. We are also interested in taking less traditional approaches in culturing marine microorganisms in the screening of mixed microbial cultures for natural product production. Can microbial interactions impact natural product production?
My group is also interested in investigating the mode of action and biosynthesis of azinomycin B. The azinomycins are anti-tumor antibiotics isolated from culture broths of two Streptomyces sp., Streptomyces sahachiroi and Streptomyces grieseofuscus, respectively. Their biological activity appears to reside in their ability to covalently alkylate and subsequently cross-link double stranded DNA (binding of azinomycin to DNA shown below).
Additionally, we are investigating the biological roles of a series of substituted cyclohexadienes. Our interest in this chemical scaffold stems from the protein β-lactoglobulin, the principle whey protein of milk that has been shown to induce self-condensation of β-ionylideneacetaldehyde to give a ring-fused dimer. Chemical synthesis of a library of these molecules is currently underway. Biological assays have also been established in our laboratory to investigate the effects of these molecules on developmental processes.
Bench, B. J.; Russell, W. K.; Foulke-Abel, J.; Agbo, H.; Watanabe, C. M. H. "Got Milk? The Darkside of Drinking Bovine Milk," 2009 submitted.
Sharma, V.; Kelly, G. T.; Foulke-Abel, J.; Watanabe, C. M. H. "Aminoacetone as the Penultimate Precursor to the Anti-Tumor Agent Azinomycin A," Org. Lett. 2009, in press.
Sharma, V.; Kelly, G. T.; Watanabe, C. M. H. "Exploration of the Molecular Origin of the Azinomycin Epoxide: Timing of the Biosynthesis Revealed", Org. Lett. 2008, 10, 4815-4818. Bench, B. J.; Tichy, S. E.; Perez, L. M.; Benson, J.; Watanabe, C. M. H. "Synthesis and Cellular Effects of Cycloterpinals: Cyclohexadienal-Based Activators of Neurite Outgrowth," Bioorg. Med. Chem. 2008, 16, 7573-7581.
Bench, B. J.; Suarez, V. H.; Watanabe, C. M. H. "An Efficient One-Pot Synthesis of Tethered Cyclohexadiene Enaminonitriles from Methyl-Ketones: An Effective Route to Quinozolines," Bioorg. Med. Chem. Lett. 2008, (Special Issue: Symposium in Print, Wilfred van der Donk), 18, 3126-3130 (Epub 2007, Oct. 18). Kim, E. J.; Angell, S.; Janes, J.; Watanabe, C. M. H. "Estimating P-Coverage of Biosynthetic Pathways in DNA Libraries and Screening by Genetic Selection: Biotin Biosynthesis in the Marine Microorganism Chromohalobacter," 2008 (Special Issue: Emerging Investigators, invited submission), 4, 606-613 (Epub 2007, Nov 22).
Kelly, G. T.; Sharma, V.; Watanabe, C. M. H. "An Improved Method for Culturing Streptomyces sahachiroi: Biosynthetic Origin of the Enol Fragment of Azinomycin B Firmly Established," Bioorg. Chem. 2008 (Special Issue: Ian Scott Dedication) 36, 4-15 (Epub 2007, Sept 27). Liu, C.; Kelly, G. T.; Watanabe, C. M. H. "In vitro Biosynthesis of the Antitumor Agent Azinomycin B," Org. Lett. 2006, 8, 1065-1068. Kelly, G. T.; Liu, C., Smith III, R.; Coleman, R. S.; Watanabe, C. M. H. "Cellular Effects Induced by the Anti-tumor Agent Azinomycin B," Chem. & Biol. 2006, 13, 485-492. Angell, S.; Bench, B. J.; Watanabe, C. M. H. "Pyocyanin Isolated from a Marine Microbial Population: Synergistic Production Between Two Distinct Bacterial Species and Mode of Action," 2006, Chem. Biol. 2006, 13, 1349-1359. Bench, B. J.; Liu, C.; Evett, C. R.; Watanabe, C. M. H. "Proline Promoted Synthesis of Ring-Fused Homodimers: Self-Condensation of α, β-Unsaturated Aldehydes," J. Org. Chem. 2006, 71, 9458-9463 (article) Williams, B.; Watanabe; C. M. H.; Schultz, P. G.; Krucker, T. "Age-dependent effects of Ginkgo biloba extract (EGb 761) on synaptic transmission and plasticity in mouse CA1 hippocampus," Neurobiol. Aging 2004, 25, 955-962.
Watanabe, C. M. H.; Supekova, L.; Schultz, P. G. "Transcriptional Effects to the Potent Enediyne Anti-Cancer Agent Calicheamicin Gamma γ1I," Chem. Biol. 2002, 9, 245-251.
Watanabe, C. M. H.; Townsend, C. A. "Initial Characterization of a Type I Fatty Acid Synthase and Polyketide Synthase Multienzyme Complex NorS in the Biosynthesis of Aflatoxin B1," Chem. Biol. 2002, 9, 245-251. Watanabe, C. M. H.; Wolffram, S.; Ader, P.; Rimbach, G.; Packer, L.; Maguire, J. J.; Schultz, P. G.; Gohil, K. "The In vivo Neuromodulatory Effects of the Herbal Medicine Ginkgo Biloba," Proc. Nat. Acad. Sci. USA 2001, 98, 6577-6580.
