# Covalent regulation of branched chain amino acid metabolism

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $461,782

## Abstract

PROJECT SUMMARY/ABSTRACT
Type 2 diabetes is associated with derangements in a variety of pathways of intermediary metabolism. In
addition to the widely-known effects on glucose metabolism, diabetes is also associated with abnormalities in
lipid and amino acid metabolism including elevations in branched chain amino acids (BCAA). BCAAs are
increased in people with obesity and insulin resistance and high plasma BCAA concentrations are predictive of
future development of diabetes. Dietary restriction of BCAAs in rats improves insulin sensitivity and genome-
wide association studies in humans have demonstrated that genetic variations in enzymes controlling BCAA
metabolism are associated with increased BCAA concentrations and are also linked to the development of
insulin resistance. These data suggest that high BCAA concentrations play a causative role in the development
of insulin resistance and that strategies that correct accumulation of these bioactive amino acids may have
value as therapeutic avenues for treating diabetes. Circulating BCAA concentrations are regulated by dietary
intake, rates of protein synthesis and proteolysis, and BCAA catabolism. To be oxidized, BCAAs are first
reversibly converted to branched chain keto acids (BCKA) by branched chain aminotransferases. Next, BCKA
undergo oxidation that is catalyzed by the BCKA dehydrogenase (BCKDH) enzyme complex in the
mitochondrial matrix. BCKDH is regulated by inhibitory phosphorylation and is activated by a protein
phosphatase (PPM1K) that removes this covalent modification. Genetic or pharmacologic approaches to
reduce BCKDH phosphorylation lead to enhanced BCKA catabolism and improved insulin sensitivity in rodent
models of obesity. This application is designed to test the novel hypothesis that PPM1K phosphorylation at a
conserved serine residue suppresses the activity of this phosphatase leading to increased BCKDH
phosphorylation. Our studies are designed to identify mechanisms by which this phosphorylation is regulated,
define the effects of this covalent modification on intrinsic PPM1K activity, and determine the effects of PPM1K
phosphorylation on BCAA metabolism in liver of diabetic rodents.

## Key facts

- **NIH application ID:** 10882361
- **Project number:** 1R01DK136749-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Brian N Finck
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $461,782
- **Award type:** 1
- **Project period:** 2024-04-15 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882361

## Citation

> US National Institutes of Health, RePORTER application 10882361, Covalent regulation of branched chain amino acid metabolism (1R01DK136749-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10882361. Licensed CC0.

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