Plants are a rich source of unique chemicals, including 25% of natural product-derived drugs. However, the vast majority of plant biosynthetic pathways remain undiscovered, and most of the known plant pathways have been discovered one or two enzymes at a time over a period of decades. While the explosion of plant genome and transcriptome sequence information is beginning to accelerate the discovery process, there is still no systematic way of efficiently decoding plant genome sequence to extract complete pathways. The goal of the proposed project is to develop a systematic, broadly applicable, and high- throughput pipeline that will drastically change the way natural products and associated pathways are discovered in plants. The pipeline capitalizes on the recent and exciting discovery in plant biology that the genes for a number of specialized metabolic pathways are organized in clusters in the genomes of diverse plant species. Recent bioinformatic analyses indicate that there are thousands of uncharacterized plant metabolic gene clusters with the potential to lead to new natural products. One of the most exciting aspects of our gene-cluster based discovery approach in plants is that it allows for discovery of both novel metabolites and new metabolic enzymes at a pace that will match that of microbes. The goal of the project will be achieved through three specific aims focused on developing and applying: new bioinformatic tools for identifying and prioritizing gene clusters encoding natural product pathways in plant genomes (SA1); new synthetic biology tools for designing and building reconstructed clusters amenable to high- throughput screening and functional validation (SA2); and analytical chemistry validation for a streamlined chemical characterization and identification platform (SA3). The project will develop a number of broadly-applicable synthetic biology tools that will accelerate discovery of natural products regardless of the source organism. By changing the paradigm by which the research community approaches plant natural product discovery, this center will have an exponential impact beyond its immediate activities and greatly accelerate drug development. The unique and complementary expertise of the project investigators in plant natural products chemistry, plant specialized metabolism, synthetic biology, and bioinformatics will be key to the successful execution of the proposed tasks and establishment of the discovery pipeline. This team will leverage their established strengths to propose best practices for standards in data, software, and resource sharing and organize forums to engage diverse communities within the broader initiative to ensure success and maximal impact.

Public Health Relevance

The broad goal of this research is to develop a transformative pipeline for plant natural products discovery that integrates recent advances in synthetic biology, bioinformatics, and genomics. Plant natural products, their derivatives, and analogs currently comprise a substantial fraction of approved drugs. Therefore, an accelerated discovery pipeline for new natural products and biosynthetic pathways from plants will transform the current drug discovery process. The integration of synthetic biology throughout the project will support the future development of scalable drug manufacturing platforms, ultimately advancing drug discovery, development, and production.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01GM110699-04
Application #
9478201
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Sledjeski, Darren D
Project Start
2015-08-15
Project End
2020-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Stanford University
Department
Biomedical Engineering
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
Medema, Marnix H (2018) Computational Genomics of Specialized Metabolism: from Natural Product Discovery to Microbiome Ecology. mSystems 3:
Chavali, Arvind K; Rhee, Seung Y (2018) Bioinformatics tools for the identification of gene clusters that biosynthesize specialized metabolites. Brief Bioinform 19:1022-1034
Huang, Ancheng C; Hong, Young J; Bond, Andrew D et al. (2018) Diverged Plant Terpene Synthases Reroute the Carbocation Cyclization Path towards the Formation of Unprecedented 6/11/5 and 6/6/7/5 Sesterterpene Scaffolds. Angew Chem Int Ed Engl 57:1291-1295
Reed, James; Osbourn, Anne (2018) Engineering terpenoid production through transient expression in Nicotiana benthamiana. Plant Cell Rep 37:1431-1441
Owen, Charlie; Patron, Nicola J; Huang, Ancheng et al. (2017) Harnessing plant metabolic diversity. Curr Opin Chem Biol 40:24-30
Huang, Ancheng C; Kautsar, Satria A; Hong, Young J et al. (2017) Unearthing a sesterterpene biosynthetic repertoire in the Brassicaceae through genome mining reveals convergent evolution. Proc Natl Acad Sci U S A 114:E6005-E6014
Schl├Ąpfer, Pascal; Zhang, Peifen; Wang, Chuan et al. (2017) Genome-Wide Prediction of Metabolic Enzymes, Pathways, and Gene Clusters in Plants. Plant Physiol 173:2041-2059
Reed, James; Stephenson, Michael J; Miettinen, Karel et al. (2017) A translational synthetic biology platform for rapid access to gram-scale quantities of novel drug-like molecules. Metab Eng 42:185-193
Kautsar, Satria A; Suarez Duran, Hernando G; Blin, Kai et al. (2017) plantiSMASH: automated identification, annotation and expression analysis of plant biosynthetic gene clusters. Nucleic Acids Res 45:W55-W63
Medema, Marnix H; Osbourn, Anne (2016) Computational genomic identification and functional reconstitution of plant natural product biosynthetic pathways. Nat Prod Rep 33:951-62

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