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In this dissertation, a multi-leveled analysis is performed to understand the physiological functions of several key SLC/ABC transporters. First, a single transporter was studied, and then, the scope of study was extended to a set of 4 transporters; and finally 12 transporters were studied as a group. First, using the systems biology analysis and computational chemistry analysis, the function of OAT1 is individually studied in the context of cellular metabolism. This two-layered computational method not only predicts new OAT1-binding metabolites but also provides a clear picture how the function of OAT1 is involved in cellular metabolism. In addition, based on this multi-scaled computational method, the construction of an OAT1-centered metabolic network is achievable. In this network, metabolites known to or predicted to interact with OAT1 are shown along with their immediate first neighbors in metabolic reactions. Identified in this network are metabolites which are direct substrates of OAT1 and metabolites which are indirectly affected by OAT1 (through metabolic cascading effects). In addition, since metabolites within this network can be grouped according to which metabolic pathways they are part of, one can also understand how OAT1 is involved in individual metabolic pathways. In addition to OAT1, other SLC transporters known to handle organic compounds are OAT3, OCT1, and OCT2. With the tools from computational chemistry and machine learning, a systemic ligand-based approach was used to understand the substrate overlap and substrate preference between transporters, which helps us study how these transporters work in a systemic fashion. Finally, to understand how the major ABC/SLC transporters are involved in cellular metabolism, metabolic networks are constructed for the 12 ABC/SLC transporters; the resulting networks demonstrate how individual transporters are involved in various aspects of cellular metabolism and how they work, collectively, to contribute to the whole-body hemostasis. In conclusion, a wide variety of tools are used to study the transporting functions, structural differences, and physiological significance of the major ABC/SLC transporters. Using the combination of these tools provides a novel and multi-scaled way to study the transporters |
