# Characterization of Branched Chain Amino Acid Metabolism and Its Deficiency

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $544,348

## Abstract

Disorders of the branched chain amino acid (BCAA) metabolism are the most common of the organic
acidemias identified by newborn screening. The catabolism of leucine (LEU), isoleucine (ILE), and valine (VAL)
begins through a set of common transporters and enzymes localized to the mitochondria. Thereafter, the
pathways diverge. Four disorders in these pathways share enormous unmet needs for treatment: maple syrup
urine disease (MSUD), and isovaleric (IVA), propionic (PA), and methylmalonic acidemias (MMA). This is a
renewal application for a project with a long-term goal to characterize BCAA acid metabolism and its
deficiencies. Significant progress has been made on each aim of the original project, and our results have
provided unique opportunities to study novel therapies. This new application has three specific aims. Specific
Specific Aim 1 is to continue characterization of the mitochondrial architecture of BCAA metabolism. Based
on our data, I hypothesize that the catabolic enzymes of LEU and ILE/VAL comprise two separate metabolons
within the mitochondrial matrix. Specific Aim 1a is to examine the physical interactions of BCKADH, IVDH,
and 3MCC as a putative metabolon using STED and cryo-CLEM, and cryo-ET techniques. Specific Aim 1b is
to examine the interactions of the enzymes involved in BCAA catabolism using protein cross linking and co-
immunoprecipitation studies. Specific Aim 2 is to identify novel small molecules to treat IVDH and BCKADH
deficiency, either as substrate inhibitors or chemical chaperonins to improve folding of IVDH to restore partial
flux through the leucine pathway. I hypothesize that small molecule inhibitors of BCAT will reduce
accumulation of toxic intermediates of these disorders, while inhibitors of distal enzymes in the LEU pathway
will induce accumulation of proximal substrates and stabilize mutant enzymes. Specific Aim 2a is to examine
effects of a panel of BCAA catabolism inhibitors on IVDH and BCKADH stability and function in cells from
patients with IVA and MSUD. I predict that these molecules will stabilize mutant IVDH and BCKADH proteins,
making them compelling candidates for further preclinical drug development. Specific Aim 2b is to examine
the effect of a BCAT inhibitor on flux through BCAA catabolism, and accumulation of toxic metabolites in cells
from patients with IVA and MSUD. I predict that this compound will reduce accumulation of toxic metabolites in
cells, identifying it as a potential therapy for IVA and MSUD. Specific Aim 3 is to examine mitochondrial ETC
and TCA cycle dysfunction in cells from patients with PA and MMA. I hypothesize that correction of such
defects will allow development of therapeutic agents for these disorders. Specific Aim 3a is to examine the
use of novel mitochondrial antioxidants to reverse secondary ETC dysfunction in cells from patients with MMA
and PA. Specific Aim 3b is to examine the effect of restoring TCA cycle imbalance in cells from patients with
PA and MMA on bi...

## Key facts

- **NIH application ID:** 10813165
- **Project number:** 5R01DK109907-08
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** GERARD VOCKLEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $544,348
- **Award type:** 5
- **Project period:** 2016-07-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10813165

## Citation

> US National Institutes of Health, RePORTER application 10813165, Characterization of Branched Chain Amino Acid Metabolism and Its Deficiency (5R01DK109907-08). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10813165. Licensed CC0.

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