# Diversity Supplement for Engineering an unnatural redox cofactor (uRedox) system for efficient biosynthesis of medicines

> **NIH NIH DP2** · UNIVERSITY OF CALIFORNIA-IRVINE · 2022 · $148,388

## Abstract

There is an unmet need to obtain natural product-derived medicines in a scalable and reliable manner.
Natural products are small molecules produced by biological systems, but often in low quantities. Metabolic
engineering promises to move the biosynthetic pathways of these medicinal small molecules from their native
producers into heterologous hosts such as bacteria and yeast, which can be cultured in large-scale, low-cost,
industrial processes. The long-term goal of this proposal is to address the grand challenge in metabolic
engineering, namely the extraordinary complexity of metabolism in the cells, by insulating virtually any desired
pharmaceutical biosynthetic pathway from the rest of cell metabolism, so that the former can be studied and
optimized effectively. The central hypothesis is that this goal can be achieved by establishing an unnatural
redox cofactor system (uRedox) in vivo to power the desired biosynthetic pathways. This design is inspired by
Nature: Catabolism and anabolism, two opposing metabolic systems responsible for breaking down and
building up cell components, respectively, are insulated from each other because they each have a designated
redox cofactor, NAD and NADP, respectively. The scientific premise of this hypothesis has been demonstrated:
when using nicotinamide mononucleotide (NMN) as an unnatural redox cofactor in vivo, only the engineered,
productive reaction for a pharmaceutical was active, while all other interfering reactions in the host's complex
metabolic network remained silent. To develop this prototype of uRedox into a truly universal technology, the
following specific aims are proposed: (1) Develop a facile, high-throughput selection platform for obtaining
NMN-dependent enzymes on demand and en masse. Specifically, Escherichia coli will be engineered so that
only cells harboring active NMN-dependent enzymes can survive. In combination with the computational
protein design pipeline that we established, this growth-based selection platform will allow rapid customization
of uRedox to produce different pharmaceuticals; (2) Develop E. coli and Saccharomyces cerevisiae, two most
important industrial model hosts, with a built-in NMN pool. Some other organisms can accumulate NMN inside
the cells, and their NMN biosynthetic pathways will be transplanted into E. coli and S. cerevisiae. The two
engineered hosts will serve as chassis for implementing uRedox; (3) Apply uRedox to address a major need in
metabolic engineering: preserving aldehydes. Many medicinal compounds or their biosynthetic intermediates
are aldehydes, which cannot stably exist in cells because they are modified by the cells' numerous redox
enzymes. As a proof-of-concept, uRedox will be used to render these aldehyde-modifying enzymes inactive all
at once and thereby preserve a key aldehyde intermediate in the biosynthesis of benzylisoquinoline alkaloids
(BIAs), a family of ~2,500 natural products including important antibacterial, antitussive, and ...

## Key facts

- **NIH application ID:** 10487941
- **Project number:** 3DP2GM137427-01S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Han Li
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $148,388
- **Award type:** 3
- **Project period:** 2019-09-30 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10487941

## Citation

> US National Institutes of Health, RePORTER application 10487941, Diversity Supplement for Engineering an unnatural redox cofactor (uRedox) system for efficient biosynthesis of medicines (3DP2GM137427-01S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10487941. Licensed CC0.

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