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Principal Investigator: Kylie Jacobs
Organization: UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
Fiscal Year: 2024
Award: $76,756
Funding agency: National Institute of General Medical Sciences
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.
Terms: <Affect><Amino Acid Channel><Amino Acid Permease><Amino Acid Transport Systems><Amino Acid Transporter><Amino Acids><Arrestins><Autoregulation><Baker's Yeast><Biologic Models><Biological Models><Blood Serum><Branched-Chain Amino Acids><Brewer's Yeast><Budding Yeast><Buffers><Cancers><Carbon><Cardiac Diseases><Cardiac Disorders><Cardiovascular Diseases><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cell membrane><Cell surface><Cells><Cellular Expansion><Cellular Function><Cellular Growth><Cellular Physiology><Cellular Process><Communities><Cysteine><Cytoplasmic Membrane><Data><Diabetes Mellitus><Disease><Disorder><Dose><Drug Targeting><Endomycetales><Essential Amino Acids><Exposure to><Gene Modified><Gene Transcription><Generalized Growth><Genetic><Genetic Screening><Genetic Transcription><Growth><Half-Cystine><Health><Heart Diseases><Hereditary Metabolic Disorder><Homeostasis><Human><Image><Impairment><Inborn Errors of Metabolism><Insulin Resistance><Intermediary Metabolism><Intracellular Communication and Signaling><Knowledge><L-Cysteine><Lysosomes><Maintenance><Malignant Neoplasms><Malignant Tumor><Mammalian Cell><Membrane Transport Proteins><Membrane Transporters><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic Processes><Metabolism><Methionine><Model System><Modern Man><Mutate><Neutral Amino Acids><Nitrogen><Nucleotides><Organelles><Organism><Pathway interactions><Patients><Phenylalanine hydroxylase deficiency><Phenylketonurias><Physiological Homeostasis><Plasma Membrane><Play><Production><Proliferating><Protein Biosynthesis><Proteins><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Recycling><Regulation><Research><Research Resources><Resources><Retinal S-Antigen><Ribosomal Peptide Biosynthesis><Ribosomal Protein Biosynthesis><Ribosomal Protein Synthesis><Role><S cerevisiae><S. cerevisiae><Saccharomyces cerevisiae><Saccharomycetales><Serum><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Source><Specificity><Starvation><Subcellular Process><System><Systems Biology><Thesaurismosis><Tissue Growth><Toxic effect><Toxicities><Transcription><Translations><Vacuole><Yeasts><aminoacid><biological signal transduction><branched amino acids><cardiovascular disorder><cell growth><deprivation><design><designing><diabetes><experiment><experimental research><experimental study><experiments><gene manipulation><gene modification><genetic manipulation><genetically manipulate><genetically modified><genetically perturb><heart disorder><imaging><inborn metabolism disorder><insight><insulin resistant><insulin tolerance><lipidomics><living system><malignancy><metabolism disorder><metabolism measurement><metabolomics><metabonomics><mutant><neoplasm/cancer><ontogeny><overexpress><overexpression><pathway><permease><phenylalaninemia><plasmalemma><protein synthesis><response><sensor><social role><transcriptome sequencing><transcriptomic sequencing><transcriptomics><translation><uptake><yeast genetics>