The Structure and Function of Metabolic Filaments

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 DESCRIPTION (provided by applicant): Ribonucleotides are small molecules that are fundamentally important to almost all cellular processes. They are the building blocks of DNA and RNA, are important precursors and intermediates in cellular metabolism, provide energy to drive cellular processes, and play important roles in regulating cellular activity. Because of thei central importance the production of new ribonucleotides is very tightly controlled in cells. One way the cell controls both the number of ribonucleotides and the balance between different types of nucleotides is to modulate the activity of two critically important enzymes, CTPS and IMPDH. Because of their critical roles in regulating ribonucleotide abundance and balance, CTPS and IMPDH are important drug targets for both chemotherapy and anti-parasitic applications, and IMPDH is implicated in human diseases that lead to blindness. While CTPS and IMPDH have been studied in detail for decades we only very recently learned that the enzymes co-assemble into large-scale structures that are important in maintaining metabolic balance in the cell. This discovery has created new areas of research that are changing the way we think about the regulation of metabolic enzymes and has opened up new possibilities for targeted drug design. This proposal aims to understand at the molecular level how CTPS and IMPDH assemble into large-scale structures, how these structures influence the activity of the enzymes, and how the celll manipulates these structures to maintain optimal ribonucleotide levels.