# Biosynthesis of unusual bio-orthogonal functionalities in natural products

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2022 · $78,960

## Abstract

SUMMARY
Natural products are important small molecules for studying, treating, and even causing human diseases, and
they typically have unique functional groups that are critical for their biological activities. By exploiting the
biosynthetic machinery by which these functionalities are synthesized, it is possible to enhance, vary or diminish
the biological activities of parent compounds and apply the biosynthetic machinery to new systems for functional
group installation. Toward this goal, the chemical logic and enzymatic machinery underlying natural product
biosynthesis need to be fully characterized and understood. This project will focus on functional characterization
and mechanistical interrogation of enzymes responsible for biosynthesis of unusual pharmacophores of natural
products, including terminal alkyne, isonitrile and N-hydroxytriazene. Unique metalloenzymes have been
identified important for their biosynthesis, including the membrane-bound di-iron dependent bifunctional
desaturase/acetylenase for alkyne generation, the non-heme iron and α-ketoglutarate dependent
oxidase/decarboxylase for isonitrile synthesis, and a didomain enzyme consisting of a C-terminal methionyl-
tRNA synthetase-like domain and an N-terminal cupin domain for N-hydroxytriazene formation. The biochemical
and mechanistic understanding of these newly discovered enzymes remain poor, warranting an in-depth study
in this project. In addition to serving as the warheads of bioactive natural products, these functionalities have
distinct chemical and physical properties and are utilized in bio-orthogonal chemical transformations for various
chemical biology applications. We will thus further explore the application of their biosynthetic machinery to install
these “clickable” functionalities on various biomolecules on demand. The research strategy is innovative in terms
of the choice of novel functionalities and their unique but poorly understood biosynthetic machinery, the
multidisciplinary research tools, and the goal-oriented approaches to directly target health-related applications.
In particular, we go beyond the enzyme and pathway characterization in the approach design, pursuing
applications of these unique enzymes in terms of flexibility to have a positive impact on human well-being. The
proposed research is thus significant due to both implications for the field of natural product enzymology and
utilities in biomedical and biotechnological research at the basic and translational levels.

## Key facts

- **NIH application ID:** 10600347
- **Project number:** 3R01GM136758-03S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Wenjun Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $78,960
- **Award type:** 3
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10600347

## Citation

> US National Institutes of Health, RePORTER application 10600347, Biosynthesis of unusual bio-orthogonal functionalities in natural products (3R01GM136758-03S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10600347. Licensed CC0.

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