Marine invertebrates, such as sponges, tunicates, and gorgonians, produce a stunning diversity of secondary metabolites, many of which show promise as pharmaceutical agents. However, supplying marine natural products for clinical development has been a major hurdle, since the organisms are often rare or difficult to collect. Recombinant DNA technology offers a possible strategy to circumvent the supply problem by expression of biosynthetic genes in bacterial culture, but there are many problems that have prevented the widespread use of this approach. The large bacterial diversity found within marine invertebrates and the difficulty of whole pathway expression greatly hinder the usefulness of the approach. In addition, it is often difficult to engineer pathways to produce new natural products. We recently reported the first example of rational whole-pathway identification and heterologous expression for a marine natural product from an animal-bacterium symbiosis. A pathway encoding formation of patellamides A and C was identified in Prochloron, the obligate symbiont of an ascidian, and expressed in Escherichia coli. In this project, we will capitalize on this early success by cloning and engineering biomedically important natural product pathways from a variety of symbiotic associations in the marine environment. By further exploring this model symbiotic system, we will establish and validate methodology for the general cloning of symbiotic products, develop a supply of drugs that are currently in clinical or preclinical trials, and discover new drugs via rational pathway engineering. This study will thus provide practical solutions to problems in drug discovery and development with marine natural products.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM071425-03
Application #
7354108
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Jones, Warren
Project Start
2006-01-06
Project End
2010-12-31
Budget Start
2008-01-01
Budget End
2008-12-31
Support Year
3
Fiscal Year
2008
Total Cost
$284,580
Indirect Cost
Name
University of Utah
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Ruffner, Duane E; Schmidt, Eric W; Heemstra, John R (2015) Assessing the combinatorial potential of the RiPP cyanobactin tru pathway. ACS Synth Biol 4:482-92
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Agarwal, Vinayak; Pierce, Elizabeth; McIntosh, John et al. (2012) Structures of cyanobactin maturation enzymes define a family of transamidating proteases. Chem Biol 19:1411-22
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Donia, Mohamed S; Fricke, W Florian; Partensky, Frederic et al. (2011) Complex microbiome underlying secondary and primary metabolism in the tunicate-Prochloron symbiosis. Proc Natl Acad Sci U S A 108:E1423-32
Donia, Mohamed S; Schmidt, Eric W (2011) Linking chemistry and genetics in the growing cyanobactin natural products family. Chem Biol 18:508-19
Donia, Mohamed S; Fricke, W Florian; Ravel, Jacques et al. (2011) Variation in tropical reef symbiont metagenomes defined by secondary metabolism. PLoS One 6:e17897
McIntosh, John A; Donia, Mohamed S; Nair, Satish K et al. (2011) Enzymatic basis of ribosomal peptide prenylation in cyanobacteria. J Am Chem Soc 133:13698-705
Donia, Mohamed S; Ruffner, Duane E; Cao, Sheng et al. (2011) Accessing the hidden majority of marine natural products through metagenomics. Chembiochem 12:1230-6

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