# Diverse Transition-Metal and Free-Radical Chemistry Enabling 2'-Deoxyribonucleotide Production by Bacteria in Restrictive Environments

> **NIH NIH R01** · PENNSYLVANIA STATE UNIVERSITY, THE · 2021 · $377,432

## Abstract

Project Summary/Abstract
All organisms obtain the deoxynucleotide substrates for DNA synthesis and repair by the action of an enzyme
known as ribonucleotide reductase (RNR). The several known types of RNRs, which have been divided into
classes I, II, and III, differ in the transition-metal and free-radical chemistry that they use to initiate their
common, challenging reduction/dehydroxylation reaction. Recent studies have shown that many bacteria that
infect and cause disease in humans use class I RNRs that differ markedly from the human class I, subclass a
enzyme. Some of these microbial RNRs (subclasses b and d) use manganese instead of iron in what is
thought to be an adaptation to iron deprivation caused by the human immune response, and others use both
metals (subclass c). We just discovered that a new type of RNR from the causative agent of strep throat and
scarlet fever may have fully escaped the usual dependence on transition metals by using a previously
unknown type of stable amino acid radical, thus founding subclass e. This project will reveal precisely how the
members of three new subclasses of class I RNRs (including d and e) that were recently identified in
pathogenic bacteria acquire their catalytic activity and initiate nucleotide reduction. The very different initiation
chemistry used by the pathogens' enzymes offers opportunities for their selective inhibition by antibiotics. This
project will provide the conceptual underpinnings for such drug discovery efforts and will shed light on the ways
in which pathogenic microbes have adapted to cope with their hosts' hostile immune response.

## Key facts

- **NIH application ID:** 10165753
- **Project number:** 5R01GM132653-03
- **Recipient organization:** PENNSYLVANIA STATE UNIVERSITY, THE
- **Principal Investigator:** JOSEPH M BOLLINGER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $377,432
- **Award type:** 5
- **Project period:** 2019-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10165753

## Citation

> US National Institutes of Health, RePORTER application 10165753, Diverse Transition-Metal and Free-Radical Chemistry Enabling 2'-Deoxyribonucleotide Production by Bacteria in Restrictive Environments (5R01GM132653-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10165753. Licensed CC0.

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