# Defining the biological roles of PRPS isozymes in normal and diseased settings

> **NIH NIH R35** · UNIVERSITY OF CINCINNATI · 2020 · $401,250

## Abstract

PROJECT SUMMARY
The phosphoribosyl pyrophosphate synthetase (PRPS) enzymes are critical regulators of nucleotide
production in all life, from bacteria to man. These enzymes generate a critical precursor necessary for
producing all nucleotide species and function as a `molecular throttle' capable of increasing or decreasing the
rate at which these genetic building blocks are made. While targeting this metabolic enzyme represents a
powerful approach to stymie nucleotide production, the redundancy afforded by the existence of two distinct
forms of the same enzyme (PRPS1 and PRPS2) also presents a phenomenal opportunity for selectively
treating certain diseases such as cancer. In order to realize this goal, however, we must first have a better
understanding of their overlapping and distinct biological roles and the mechanistic basis for these similarities
and differences. This proposal seeks to unravel the molecular basis for this selectivity through use of novel
mouse models and elegant structure/function studies, thus pinpointing a putative mechanism of action and
developing a rational basis for future drug development. We will focus our efforts on elucidating the distinct
modes of regulation that control expression of the two separate isoforms as well as how the different
biochemical properties of the individual isozymes regulate nucleotide production and metabolic homeostasis.
To make our work clinically-relevant and applicable to human disease, we will also develop and characterize
novel disease-specific mouse models of PRPS1 superactivity and loss of function that seek to recapitulate the
mutations and phenotypes observed in human inborn errors of metabolism. Our research program ultimately
strives to understand the complicated role of nucleotides in cellular metabolism and how their aberrant
production, breakdown, transport, or utilization contributes to disease. For example, specifically within this
proposal, we will elucidate the economics of nucleotide metabolism by determining how disrupting nucleotide
supply affects the overall biochemistry of the cell. Collectively, the proposed studies and our research program
in general will be transformative in our understanding of the roles of these key molecules in the normal and
disease setting, and provide a new foundation for the development of the next generation of safer, more
targeted therapies and rational approaches for ameliorating diseases associated with perturbed nucleotide
homeostasis.

## Key facts

- **NIH application ID:** 9967049
- **Project number:** 5R35GM133561-02
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** Tom Cunningham
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $401,250
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9967049

## Citation

> US National Institutes of Health, RePORTER application 9967049, Defining the biological roles of PRPS isozymes in normal and diseased settings (5R35GM133561-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9967049. Licensed CC0.

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