# Engineering Yeast towards High Titer Production of Monoterpene Indole Alkaloid Natural Products

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $224,328

## Abstract

ABSTRACT
Reconstruction of plant natural product pathways in genetically well-characterized microbial organisms such as
Saccharomyces cerevisiae is a sustainable and scalable method of producing high value pharmaceutical
compounds. Strictosidine is the universal precursor to thousands of monoterpene indole alkaloids (MIAs) such
as vinblastine and camptothecin. MIAs are indispensable pharmaceutical ingredients, but are also expensive
due to difficulties in production and isolation from plant producers. In this proposal, we will use strictosidine
biosynthesis as a model system to explore the use of newly developed yeast-based technologies at UCLA and
Stanford Genome Technology Center (SGTC) for high-titer production of strictosidine in yeast. Our labs and
others have shown that critical parts of this biosynthetic pathway are subject to considerable crosstalk with the
endogenous yeast redox active enzymes, resulting in significant loss of flux toward irrecoverable shunt products.
Our preliminary efforts have led to increase in product titer of the intermediate nepetalactol, and suggest a more
global approach aimed at the different intermediates in the pathway will lead to significant improvements. This
collaborative proposal will leverage the Tang labs expertise in natural product biosynthesis with the new synthetic
biological tools developed for yeast by SGTC. This will pave the way for complete reconstitution of important
MIAs in yeast, as well as elucidation of hitherto unknown MIA biosynthetic pathways involving strictosidine.
Together we will address four aims: 1) Use high-throughput pathway construction to achieve improved baseline
production of strictosidine; 2) establish metabolite-responsive growth screenings for strictosidine and other key
biosynthetic pathway intermediates; 3) employ new genome-engineered tools to rapidly create, screen and
genotype yeast strains that can achieve high level of strictosidine production starting from the improved baseline
strain; and 4) heterologous production and downstream pathway exploration of complex MIAs, such as
vinblastine and camptothecin, starting from strictosidine.

## Key facts

- **NIH application ID:** 10120163
- **Project number:** 3R01AT010001-03S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Yi Tang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $224,328
- **Award type:** 3
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10120163

## Citation

> US National Institutes of Health, RePORTER application 10120163, Engineering Yeast towards High Titer Production of Monoterpene Indole Alkaloid Natural Products (3R01AT010001-03S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10120163. Licensed CC0.

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