# A Chemoenzymatic Approach to Accessing Novel Isoprenoid Scaffolds

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA · 2022 · $140,635

## Abstract

Summary of the funded parent award (1R01GM138800-01A1). Isoprenoids represent a diverse class of
compounds with a broad range of applications in medicine and industry. Their extraction from natural sources is
both challenging and potentially harmful to the environment, while the enormous structural complexity of many
isoprenoids makes traditional chemical synthesis nontrivial. Modern metabolic engineering and synthetic biology
approaches have overcome some of these difficulties, but issues related to metabolic flux and the limited
availability of the universal isoprenoid precursors complicate their widespread implementation. The artificial
pathways developed thus far have been solely focused on synthesizing dimethylallyl and isopentenyl diphosphates
and require additional enzymes for the generation of polyprenyl-diphosphates (polyprenyl-PPs). Thus, the
primary objective of this proposal is to develop an efficient strategy for the synthesis of both natural and unnatural
(poly)prenyl-PPs for downstream applications. This will be achieved using two complementary methods: i)
employing undecaprenol kinases and isopentenyl phosphate kinases; and ii) employing hydroxyethylthiazole
kinase, isopentenyl phosphate kinases, and farnesyl diphosphate synthase. Additionally, the two methods will
work in conjunction with isoprenoid methylatransferases to incorporate additional diversity into the polyprenyl-
PPs. The proposed studies include: i) structural and functional assessment of selected enzymes, ii) catalyst
engineering, and iii) optimization of coupled in vitro and in vivo platforms for the generation of diversified
libraries of select natural products. We expect these studies to generate: i) rules and concepts to advance
knowledge on structure-activity relationships in selected classes of enzymes; ii) an optimized, enzyme-coupled
platform to generate diversified substrates and isoprenoids; and iii) novel isoprenoid analogs with potential
therapeutic applications. Thus, the proposed work will offer unprecedented access to uniquely bioactive
isoprenoid libraries not readily accessible via traditional methods, and it stands to deepen our fundamental
understanding of four enzyme classes while also developing them into useful biocatalysts.

## Key facts

- **NIH application ID:** 10582364
- **Project number:** 3R01GM138800-01A1S1
- **Recipient organization:** UNIVERSITY OF OKLAHOMA
- **Principal Investigator:** Shanteri Singh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $140,635
- **Award type:** 3
- **Project period:** 2022-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10582364

## Citation

> US National Institutes of Health, RePORTER application 10582364, A Chemoenzymatic Approach to Accessing Novel Isoprenoid Scaffolds (3R01GM138800-01A1S1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10582364. Licensed CC0.

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