Systematic discovery of metabolic transporter functions

Project Summary Metabolism encompasses all chemical reactions within a cell. Solute carriers (SLCs), a family of 450 metabolic transporters, play a crucial role in these processes by controlling intracellular and organellar metabolite availability. Dysfunction of these transporters can lead to homeostatic disturbances, contributing to progression of various diseases. Despite extensive research, approximately 30% of SLC family members remain orphan, or lacking annotated substrates. Identifying the physiological substrates of SLCs remains challenging for various reasons that include promiscuity, structural diversity, compartmentalization, and redundancy. Addressing this problem necessitates the development of unbiased, systematic, and efficient methods. Recent Genome-Wide Association Studies (GWAS) of the human metabolome have revealed significant genetic influences underlying blood chemical composition providing an opportunity for linking the genes encoding for transporters to their substrate. This approach has previously identified SLC22A1 as an acylcarnitine carrier and SLC2A9 as a urate transporter. Earlier in my thesis, I leveraged such datasets to develop large-scale platforms that led to the discovery of FLVCR1 and SLC25A48 as plasma membrane and mitochondrial choline transporters. This proposal aims to develop advanced methods for deorphanizing metabolic transporters and uncovering their roles in cellular and organismal metabolism. Leveraging machine learning-driven analysis, Aim 1 will comprehensively investigate the function of SLC25A45 as a methylated basic amino acid transporter, emphasizing its impact on renal physiology. Aim 2 will integrate diverse multiomic databases to not only deorphanize metabolic transporters but also provide an insight into their roles in organismal metabolism, with a particular focus on kidney function. Successfully completing these studies will yield an innovative tool for data integration and serve as a valuable resource for advancing biological discoveries related to metabolism and renal physiology.