Enzyme Assemblies in Nucleotide Metabolism: Structure, Regulation, and Disease Implications

Nucleotide biosynthesis is essential for cell growth and relies on the coordination of both salvage and de novo pathways to satisfy intracellular needs. While traditionally, the regulation of these pathways has been attributed to factors like substrate availability, genetic rewiring, and metabolite-driven feedback inhibition, recent findings have unveiled a new, more complex layer of regulation. Enzymes within these pathways assemble into dynamic supramolecular protein assemblies, such as metabolons and filaments, which findings suggest might influence enzymatic activity and regulate nucleotide flux. Advances in fluorescence microscopy and cryo-electron microscopy have enhanced our ability to characterize the spatial and temporal dynamics, as well as the biophysical properties, of these assemblies. In this chapter, we explore the diverse higher-order purine and pyrimidine metabolic enzyme assemblies, highlight how state-of-the-art microscopy has transformed our understanding of their structures and regulatory roles in nucleotide biosynthesis, and discuss their implications in human disease.