LC-MS Metabolomics Reveals the Role of SLC45A4 in GABA de novo Synthesis
Affiliations: 1Departments of Medicine, Division of Endocrinology, Robert Wood Johnson Medical School, Rutgers University; 2Metabolomics Shared Resource, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA
Solute carrier (SLC) proteins are membrane transporters that govern the cross-membrane exchanges of glucose, amino acids, inorganic ions, and other small molecule metabolites. Many SLC genes have been shown to be causes of Mendelian diseases in humans, and a number of SLC transporters are important drug targets. However, due to myriad technical difficulties, a large fraction of SLC family members are still orphan transporters without known substrates, which represents both a significant knowledge gap and a huge opportunity for new drug development. In order to systematically deorphanize SLC transporters, we developed a workflow for transcriptomic-metabolomic association analysis. Using this approach, we identified an uncharacterized gene, SLC45A4, that is the single greatest determinant of y-aminobutyric acid (GABA) levels in human cancer cells. GABA, which is mostly known as an inhibitory neurotransmitter in the mammalian central nervous system, functions in peripheral tissues to regulate cell proliferation, differentiation, and migration. Using mass spectrometry and stable isotope tracing, we found that SLC45A4 increases cellular GABA levels not by promoting GABA uptake but by facilitating GABA de novo synthesis, suggesting an entirely new regulatory mechanism of GABA synthesis.
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