Natural products have a proven record of providing a significant fraction, either directly or as lead compounds, of human medicines. Among these, the terpenoids (isoprenoids) stand out as being the largest class (>50,000 already known), with the diterpenoids targeted here making up a significant fraction (>11,000 known). Indeed, the extensive diversification of diterpenoids indicates that these natural products provide a rich source of biological activity, with a number of these being used as pharmaceuticals (e.g., TaxolTM and the tanshinones) and/or research tools (e.g., phorbol esters). In addition, some LRDs serve important physiological roles in the native producing organisms - e.g., in plant defense against microbial diseases. Accordingly, we propose here to continue our productive investigation of the biosynthetic enzymes required to produce bioactive diterpenoids. Specifically, we will build on our previous work in this area, which includes elucidation of novel diterpenoid metabolic networks. This proposal then advances our long-term goal of engineering enzymes and metabolic pathways for the production of targeted libraries and specific individual terpenoid 'natural' products to benefit human health. In particular, the objective of this proposal is investigation of novel diterpenoid metabolism in a variety of plants, including the important crop plant rice as well as medicinal herbs. Accordingly, our studies have important implications for providing increased access to diterpenoid natural products, whose extensive diversification suggests that these are built upon privileged scaffolds from which biological activity is readily derived.

Public Health Relevance

The diterpenoids form a very large class of natural products (>11,000 known), which includes many of realized (e.g., TaxolTM) or potential (e.g., tanshinones) pharmaceutical use. Here we propose to continue our fruitful investigations of the biosynthetic enzymes required for production of bioactive diterpenoids. This will increase our understanding of the relevant enzymes for engineering such biosynthesis to increase access to these generally scarcely available natural products.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Gerratana, Barbara
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Iowa State University
Schools of Arts and Sciences
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Nagel, Raimund; Peters, Reuben J (2018) Diverging Mechanisms: Cytochrome-P450-Catalyzed Demethylation and ?-Lactone Formation in Bacterial Gibberellin Biosynthesis. Angew Chem Int Ed Engl 57:6082-6085
Nagel, Raimund; Peters, Reuben J (2018) Probing the specificity of CYP112 in bacterial gibberellin biosynthesis. Biochem J 475:2167-2177
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