# Engineering Dynamic Control of Natural Product Biosynthesis in Bacteria

> **NIH NIH R35** · UNIVERSITY OF GEORGIA · 2022 · $350,866

## Abstract

Project Summary
Engineering natural product biosynthesis in bacteria represents a promising strategy to produce these high-value
and pharmaceutically important compounds. However, to achieve economically viable production is quite difficult
and challenging. To address this challenge, establishing artificial logic and dynamic control functions in cells by
mimicking natural regulations in biological systems has been developed and becomes a powerful approach to
enable superior microbial production. This approach render great biological robustness to the cells and allows
them to autonomously adjust their metabolic states and activities by sensing the cellular and environmental
changes. However, compared with natural regulations that exert simultaneous and orthogonal up- and down-
regulation on various gene targets, the current dynamic control techniques mainly relies on simple gene circuits
to perform mono-function, either up- or down-regulation, on a limited set of genes, which are still rudimentary
and less sophisticated. To bridge these gaps, development of new genetic tools and their use in novel control
strategies are highly desired. Recently, the PI’s lab has achieved the biosynthesis of natural products with
defined pharmaceutical properties and therapeutic effects such as 4-hydroxycoumarin and 5-hydroxytryptophan
in E. coli through synthetic biology, metabolic engineering and protein engineering approaches and developed
antisense RNA tools for intervening cellular metabolism to enhance the biosynthesis of plant polyketides, such
as flavanone naringenin. In this MIRA proposal, we aim at exploring a new and general strategy for developing
more sophisticated dynamic control network to greatly enhance natural product biosynthesis in bacteria. The
dynamic control network is expected to have the capability of implementing autonomous and intelligent up-
regulation and down-regulation functions in response to cellular and environmental changes and maintain the
cells at optimal production states throughout all growth stages to achieve maximal production efficiency. Our
recent progress on the biosynthesis of 4-hydroxycoumarin, 5-hydroxytryptophan and the development of
antisense RNAs tools will serve as the groundwork for us to understand how to efficiently establish and
implement the dynamic control network and decision-making strategies in cells for real-world applications.
Specifically, four coherent projects with distinct research activities will be pursued, which include: 1) developing
salicylic acid, p-coumaric acid and tryptophan responsive promoters for up-regulation of gene expression; 2)
expanding antisense RNA tools for controllable down-regulation of gene expression; 3) developing and
characterizing promoter and antisense RNA based dynamic control network; 4) applying dynamic control network
to improve biosynthesis of 4-hydroxycoumarin, flavanone naringenin and 5-hydroxytryptophan in E. coli.

## Key facts

- **NIH application ID:** 10469475
- **Project number:** 5R35GM128620-05
- **Recipient organization:** UNIVERSITY OF GEORGIA
- **Principal Investigator:** Yajun Yan
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $350,866
- **Award type:** 5
- **Project period:** 2018-09-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10469475

## Citation

> US National Institutes of Health, RePORTER application 10469475, Engineering Dynamic Control of Natural Product Biosynthesis in Bacteria (5R35GM128620-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10469475. Licensed CC0.

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