# Mechanisms of Biosynthetic Formation of Deoxy Sugars

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2020 · $387,847

## Abstract

ABSTRACT
Carbohydrates play a critical role in the activity of many important biological agents and pharmaceuticals, and
small alterations in their structures can have a significant impact on their efficacy. Hence, it is not necessarily
unexpected that naturally occurring glycans and sugar appendages are so structurally diverse. What is
surprising, however, is that most of these unusual carbohydrates are biosynthesized from a relatively small pool
of common sugars via a series of reactions that often include new and unusual chemical transformations. By
exploiting the machinery of these pathways, it is possible to enhance or vary the biological activities of the
glycosylated compounds and apply the principles learned to new systems. However, in order to fully realize the
potential of such an approach, the biosynthetic pathways must be characterized and the underlying chemistry
thoroughly understood. In this spirit, we have identified several systems to be investigated in the next funding
period. The first specific aim is the mechanistic study of the five- to four-membered ring contraction at the heart
of oxetanocin A and albucidin biosynthesis. The enzymes involved in these reactions are members of the B12-
dependent radical SAM family that has only recently been discovered and remains very poorly understood. The
ultimate goal of the work proposed is to determine the mechanism of the highly unusual ring contraction as well
as the roles played by the B12 cofactor and the radical SAM machinery. The second specific aim is focused on
understanding the mechanism by which glycosidic linkages are oxidatively cyclized to form the characteristic
spirocyclic ortho-δ-lactones of the orthosomycin class of antibiotics and in particular hygromycin B. This is an
unprecedented transformation in carbohydrate biochemistry that is likely to involve radical intermediates and be
of value to the discovery of new orthosomycin antibiotics. The third specific aim seeks to complete the description
of gentamicin biosynthesis. The final uncharacterized process in this pathway is a unique α,β-dideoxygenation
that stands in contrast to all previously characterized monodeoxygenation reactions involving carbohydrates.
While there is little information about how this dideoxygenation might be accomplished, genetic analyses suggest
the involvement of exciting radical chemistry. Through the collective application of our expertise in deoxysugar
biosynthesis, chemical synthesis and enzymology, we aim to investigate the uncharacterized enzymes in the
pathway to resolve this question. These research aims have been selected on the basis of their novelty,
implications for the fields of mechanistic enzymology and natural product biosynthesis as well as potential utility
in biomedical and biotechnological research at the basic and translational levels.

## Key facts

- **NIH application ID:** 9927627
- **Project number:** 5R01GM035906-36
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** HUNG-WEN LIU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,847
- **Award type:** 5
- **Project period:** 1986-01-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9927627

## Citation

> US National Institutes of Health, RePORTER application 9927627, Mechanisms of Biosynthetic Formation of Deoxy Sugars (5R01GM035906-36). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9927627. Licensed CC0.

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