# Synthetic biology tools for scalable production of medicinal plant terpenes

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $714,501

## Abstract

PROJECT SUMMARY/ABSTRACT
Plant terpenes are a critical source of clinically approved drugs and clinical candidates, yet very few complete
biosynthetic pathways have been characterized. Due to the lack of efficient chemical synthesis routes, many
complex plant natural product scaffolds including terpenes are currently still isolated from the producing plant
or plant cell culture and then converted to a clinically-used drug by semisynthetic routes (e.g. digoxin and taxol
on the 2015 WHO list of essential medicines). Lack of information regarding terpene biosynthetic pathways
severely limits the use of promising new approaches to produce plant molecules in heterologous hosts (e.g.
yeast strains that make artemisinin), as well as the intriguing possibility of engineering the biosynthetic
pathways to access analogs and non-natural derivatives with greater efficacy. Given the critical role of
medicinal plant terpenes in human health and utility of biosynthetic genes, we propose here systematic
discovery of key medicinal plant terpene biosynthesis pathways, taxol and cyclopamine, and the
engineering of yeast strains for scalable production. Classically, the discovery of plant pathways has been
slower and more painstaking than bacterial pathways; however, our team has demonstrated two approaches
that greatly accelerates identification of complete biosynthetic routes: (1) rapid combinatorial testing of
enzymes in a N. benthamiana heterologous host, and (2) transcriptional profiling and co-expression analysis to
identify pathway genes. This approach enabled the discovery of six enzymes that complete the pathway to the
etoposide aglycone from the unsequenced medicinal plant Podophyllum in a matter of months and has also led
to the discovery of numerous plant terpene pathways including a novel class of sesterterpenes. In this
proposal, we have prioritized pathways for valuable medicinal plant terpenes that are notoriously difficult to
access: the clinically used anticancer agent taxol and the clinical candidate cyclopamine. These compounds
are representative medicinal plant terpenes that will be used to demonstrate the broad utility of our discovery
and yeast engineering approach that can be applied for accessing many of the other >100,000 different plant
terpenes in nature. In addition to yeast strains that produce these highly valuable plant terpenes, a major
outcome of this work will be broadly applicable yeast synthetic biology tools for efficient production of multiple
cytochromes P450s in series which represents a major bottleneck for efficient transfer of plant pathways to
yeast heterologous hosts.

## Key facts

- **NIH application ID:** 10017156
- **Project number:** 5R01AT010593-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** JAY D KEASLING
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $714,501
- **Award type:** 5
- **Project period:** 2019-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10017156

## Citation

> US National Institutes of Health, RePORTER application 10017156, Synthetic biology tools for scalable production of medicinal plant terpenes (5R01AT010593-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10017156. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*