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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM109773-03
Application #
9321865
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Fabian, Miles
Project Start
2015-08-05
Project End
2019-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Iowa State University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
005309844
City
Ames
State
IA
Country
United States
Zip Code
50011
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Nagel, Raimund; Peters, Reuben J (2018) Probing the specificity of CYP112 in bacterial gibberellin biosynthesis. Biochem J 475:2167-2177
Su, Ping; Guan, Hongyu; Zhao, Yujun et al. (2018) Identification and functional characterization of diterpene synthases for triptolide biosynthesis from Tripterygium wilfordii. Plant J 93:50-65
Nett, Ryan S; Contreras, Tiffany; Peters, Reuben J (2017) Characterization of CYP115 As a Gibberellin 3-Oxidase Indicates That Certain Rhizobia Can Produce Bioactive Gibberellin A4. ACS Chem Biol 12:912-917
Nagel, Raimund; Peters, Reuben J (2017) Investigating the Phylogenetic Range of Gibberellin Biosynthesis in Bacteria. Mol Plant Microbe Interact 30:343-349
Nett, Ryan S; Montanares, Mariana; Marcassa, Ariana et al. (2017) Elucidation of gibberellin biosynthesis in bacteria reveals convergent evolution. Nat Chem Biol 13:69-74
Xu, Meimei; Hillwig, Matthew L; Tiernan, Mollie S et al. (2017) Probing Labdane-Related Diterpenoid Biosynthesis in the Fungal Genus Aspergillus. J Nat Prod 80:328-333
Nagel, Raimund; Turrini, Paula C G; Nett, Ryan S et al. (2017) An operon for production of bioactive gibberellin A4 phytohormone with wide distribution in the bacterial rice leaf streak pathogen Xanthomonas oryzae pv. oryzicola. New Phytol 214:1260-1266
Guo, Juan; Ma, Xiaohui; Cai, Yuan et al. (2016) Cytochrome P450 promiscuity leads to a bifurcating biosynthetic pathway for tanshinones. New Phytol 210:525-34
Kitaoka, Naoki; Wu, Yisheng; Zi, Jiachen et al. (2016) Investigating inducible short-chain alcohol dehydrogenases/reductases clarifies rice oryzalexin biosynthesis. Plant J 88:271-279

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