Marine cyanobacteria are extraordinarily rich in their production of biologically-active and structurally- unique natural products. A number of these secondary metabolites or their derivatives are lead compounds n drug development programs aimed at providing new therapies to treat cancer, bacterial infections, inflammatory responses, and in crop protection to kill harmful microbial pathogens and insects. Isolation and structural analysis of marine and terrestrial cyanobacterial natural products has provided access to an unusually large number of mixed non-ribosomal peptide synthetase/polyketide synthase (NRPS/PKS) systems. The corresponding metabolic systems are comprised of an intriguing set of complex multifunctional proteins that along with allied enzymes generate structurally complex molecules via a modular multi-step process. Over the past several years the Sherman and Gerwick laboratories have developed a complementary program to clone and characterize the biosynthetic pathways of novel cyanobacterial secondary metabolites that possess significant potential for biotechnological applications. A full understanding of the molecular mechanisms, catalytic activities, kinetic properties, and substrate specificities within cyanobacterial biosynthetic pathways is just beginning to unfold. The proposed research will build upon our studies of the curacin and jamaicamide metabolic systems, two distinct yet related pathways that are genetically characterized and poised for detailed biochemical studies. This detailed genetic and biochemical understanding will facilitate the design of new biosynthetic systems that harness the growing potential of cyanobacterial secondary metabolism. Despite considerable gains over the past few years, the full promise of cyanobacterial natural products to yield new lead compounds for development as useful Pharmaceuticals, will only be realized by closing a series of key gaps in knowledge and technology. Solving these challenges will require development and optimization of genetic and biochemical methods that allow us to 1) utilize unique secondary metabolite enzymes for creation of novel small molecules, 2) manipulate cyanobacterial natural product gene clusters to produce analog structures.
The specific aims are: 1. To investigate biochemically unique aspects of the curacin (Cur), and jamaicamide (Jam) biosynthetic pathways including formation of the cyclopropane ring, cis-alkene formation, and termination in Cur, and chain initiation, vinyl chloride formation and termination in Jam. 2. Perform bioassays on new compounds resulting from Specific Aim 1 including evaluation for inhibition of tubulin polymerization and binding site specificity, biochemical assays relevant to cancer, and in house screens at U-M and SIO relevant to anti-microbial activity and neurotoxicity, respectively.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA108874-04
Application #
7619891
Study Section
Special Emphasis Panel (ZRG1-BCMB-B (02))
Program Officer
Fu, Yali
Project Start
2006-07-01
Project End
2011-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
4
Fiscal Year
2009
Total Cost
$338,896
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Skiba, Meredith A; Bivins, Marissa M; Schultz, John R et al. (2018) Structural Basis of Polyketide Synthase O-Methylation. ACS Chem Biol :
Skiba, Meredith A; Maloney, Finn P; Dan, Qingyun et al. (2018) PKS-NRPS Enzymology and Structural Biology: Considerations in Protein Production. Methods Enzymol 604:45-88
Skiba, Meredith A; Sikkema, Andrew P; Moss, Nathan A et al. (2018) Biosynthesis of t-Butyl in Apratoxin A: Functional Analysis and Architecture of a PKS Loading Module. ACS Chem Biol 13:1640-1650
Skiba, Meredith A; Sikkema, Andrew P; Moss, Nathan A et al. (2017) A Mononuclear Iron-Dependent Methyltransferase Catalyzes Initial Steps in Assembly of the Apratoxin A Polyketide Starter Unit. ACS Chem Biol 12:3039-3048
Leao, Tiago; Castelão, Guilherme; Korobeynikov, Anton et al. (2017) Comparative genomics uncovers the prolific and distinctive metabolic potential of the cyanobacterial genus Moorea. Proc Natl Acad Sci U S A 114:3198-3203
Leão, Pedro N; Nakamura, Hitomi; Costa, Margarida et al. (2016) Corrigendum: Biosynthesis-Assisted Structural Elucidation of the Bartolosides, Chlorinated Aromatic Glycolipids from Cyanobacteria. Angew Chem Int Ed Engl 55:14895
Maloney, Finn P; Gerwick, Lena; Gerwick, William H et al. (2016) Anatomy of the ?-branching enzyme of polyketide biosynthesis and its interaction with an acyl-ACP substrate. Proc Natl Acad Sci U S A 113:10316-21
Cummings, Susie L; Barbé, Debby; Leao, Tiago Ferreira et al. (2016) A novel uncultured heterotrophic bacterial associate of the cyanobacterium Moorea producens JHB. BMC Microbiol 16:198
Moss, Nathan A; Bertin, Matthew J; Kleigrewe, Karin et al. (2016) Integrating mass spectrometry and genomics for cyanobacterial metabolite discovery. J Ind Microbiol Biotechnol 43:313-24
Skiba, Meredith A; Sikkema, Andrew P; Fiers, William D et al. (2016) Domain Organization and Active Site Architecture of a Polyketide Synthase C-methyltransferase. ACS Chem Biol 11:3319-3327

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