# Changes in coenzyme A levels are a key mechanism regulating metabolic pathways

> **NIH NIH R35** · WEST VIRGINIA UNIVERSITY · 2020 · $375,000

## Abstract

PROJECT SUMMARY/ABSTRACT
Coenzyme A (CoA) is an essential cofactor that is emerging as a key regulator of energy metabolism and
glucose homeostasis. CoA levels are tightly controlled and dynamically adjusted to support the changes in
nutrient utilization that occur between the fed and fasted states. The importance of such a tight control over
the concentration of this cofactor is underscored by the fact that loss of regulation and abnormally high CoA
levels in the liver of diabetic mice significantly contribute to the excessive glucose production and
hyperglycemia of these animals. Conversely, genetic manipulations that reduce the concentration of hepatic
CoA decrease glucose synthesis and blood glucose. These findings underscore the potential of modulating
CoA levels in selected organs to correct deranged metabolism and hyperglycemia. Nudix hydrolase 7 and 19,
Nudt7 and Nudt19, are two recently identified CoA-degrading enzymes whose expression is limited to the liver
and kidneys, respectively. This expression pattern and their ability to degrade CoA specifically make Nudt7
and Nudt19 ideal targets to manipulate CoA levels and energy metabolism in organs that play a key role in the
maintenance of glucose homeostasis. Indeed, our preliminary results support the conclusion that these
peroxisomal enzymes actively contribute to the regulation of tissue CoA, glucose and fatty acid metabolism in
vivo; however, critical mechanistic details are currently missing. Our goal is to characterize the mechanisms
through which Nudt7 and Nudt19 regulate lipid and carbohydrate metabolism in liver and kidney and to
develop approaches to modulate the activity of these enzymes. To achieve this, we will characterize 1) the
biochemical and structural properties of Nudt7 and Nudt19, 2) the signaling pathways that regulate Nudt7 gene
expression in the liver, 3) the role of Nudt7-mediated degradation in carbohydrate and lipid metabolism in the
liver and 4) the role of Nudt19-mediated degradation in carbohydrate and lipid metabolism in the kidneys. This
research program will advance our understanding of the mechanisms that control a key metabolic regulator like
CoA and define the so far under-appreciated role of peroxisomal pathways in the regulation of glucose
metabolism. Additionally, these studies on Nudt7 and Nudt19 will aid the development of pharmacological
and/or nutritional strategies to manipulate CoA levels and reverse dysregulated metabolism.

## Key facts

- **NIH application ID:** 9932442
- **Project number:** 5R35GM119528-05
- **Recipient organization:** WEST VIRGINIA UNIVERSITY
- **Principal Investigator:** Roberta Leonardi
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $375,000
- **Award type:** 5
- **Project period:** 2016-07-15 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932442

## Citation

> US National Institutes of Health, RePORTER application 9932442, Changes in coenzyme A levels are a key mechanism regulating metabolic pathways (5R35GM119528-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9932442. Licensed CC0.

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