Enzyme polymerization in nucleotide biosynthesis

Abstract

Polymerization of metabolic enzymes into micron‐scale assemblies is an emerging phenomenon. However the role assembly plays in regulating metabolic flux differs between enzymes and in many cases is unknown. Furthermore, the signaling pathways that regulate assembly are often not well understood. Our work focuses on enzymes mediating pyrimidine and purine biosynthetic pathways that undergo regulated assembly. To address the biological function of these assemblies we have developed point mutants of CTP synthase and inosine monophosphate dehydrogenase (IMPDH), that prevent their assembly without eliminating their catalytic activity. We will present new data using these novel tools in mice and Drosophila to elucidate the role of polymerization of these enzymes in native contexts in which they assemble. Our findings demonstrate a critical role for assembly of CTPS and IMPDH in supporting the growth and proliferation of cells with elevated nucleotide demands. Thus, we propose that assembly of these nucleotide biosynthetic enzymes has been harnessed in metazoans as a homeostatic mechanism to ensure that metabolic biosynthetic flux meets demand. Support or Funding Information NIH GM083025

Point mutations in IMPDH2 which cause early-onset neurodevelopmental disorders disrupt enzyme regulation and filament structure

“…Both isoforms assemble filaments, but for IMPDH2 only, incorporation into filaments reduces sensitivity of the enzyme to GTP inhibition by preventing complete compression of the octamer (13,14). Assembly of enzymes into filaments is a commonly observed mechanism that cells leverage to regulate metabolic processes (29)(30)(31).…”

Neurodevelopmental disorder mutations in the purine biosynthetic enzyme IMPDH2 disrupt its allosteric regulation

“…Assembly of enzymes into filaments is a commonly observed mechanism that cells leverage to regulate metabolic processes ( 29 , 30 , 31 , 32 ). In general, filament assembly tunes allosteric regulation and can serve to directly increase or decrease activity or alter sensitivity to allosteric regulators.…”