# A systems biology approach to elucidating mechanisms underlying amino acid toxicities

> **NIH NIH F32** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $76,756

## Abstract

PROJECT SUMMARY
Amino acids are an intrinsic part of protein biosynthesis, nucleotide production, and provide sources of carbon
and nitrogen for the cell. The cell keeps amino acid (AA) levels balanced by increasing AA transporters on the
cell surface, catabolizing AAs to form essential metabolites, protein translation, and storage of surplus AAs in
the lysosome. An autophagic response is initiated when the cell is starved of AAs. Exposure to high
concentrations of AAs is also problematic, but the mechanisms underlying that toxicity are not yet fully
understood. AA levels are tightly regulated and when this regulation is disrupted, toxic intermediates can buildup
and diseases such as phenylketonuria and cancer can occur. Previous research in our lab has studied amino
acid toxicity through vacuole impairment, which is imprecise and cannot always provide a detailed understanding
of the effects of single amino acids. To circumvent these issues, I have designed a yeast strain that
overexpresses a mutated copy of Gap1, a high-capacity, low-specificity amino acid permease. Because of the
two mutated Gap1 residues, this permease remains on the plasma membrane instead of being recycled to the
vacuole in high AA conditions. This causes the tight AA regulation to be broken and initiate continuous AA uptake,
which will allow us to study the effects of specific AAs on cellular processes. The aim of this project is to elucidate
the role each AA plays in toxicity and cellular function using Saccharomyces cerevisiae as a model system. Aim
1 will identify transcriptional, metabolic, and organellar changes resulting from AA toxicity. Aim 2 aims to
understand the cell’s capacity to buffer excess amino acids and adapt to their toxicity. Finally, the Aim 3 will
characterize the mammalian plasma membrane transporter, L-type amino acid transporter (LAT1). LAT1 and its
regulation are poorly characterized, and this aim will begin to fill this knowledge gap. Together, these proposed
aims will help to uncover how AAs affect cellular function using the power of yeast genetics and it will begin to
elucidate amino acid transporter regulation in mammalian cells.

## Key facts

- **NIH application ID:** 10994054
- **Project number:** 5F32GM150259-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Kylie Jacobs
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $76,756
- **Award type:** 5
- **Project period:** 2023-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10994054

## Citation

> US National Institutes of Health, RePORTER application 10994054, A systems biology approach to elucidating mechanisms underlying amino acid toxicities (5F32GM150259-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10994054. Licensed CC0.

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