The gateway to guanine nucleotides: Allosteric regulation of IMP dehydrogenases

Protein Sci. 2022 Sep;31(9):e4399. doi: 10.1002/pro.4399.

Abstract

Inosine 5'-monophosphate dehydrogenase (IMPDH) is an evolutionarily conserved enzyme that mediates the first committed step in de novo guanine nucleotide biosynthetic pathway. It is an essential enzyme in purine nucleotide biosynthesis that modulates the metabolic flux at the branch point between adenine and guanine nucleotides. IMPDH plays key roles in cell homeostasis, proliferation, and the immune response, and is the cellular target of several drugs that are widely used for antiviral and immunosuppressive chemotherapy. IMPDH enzyme is tightly regulated at multiple levels, from transcriptional control to allosteric modulation, enzyme filamentation, and posttranslational modifications. Herein, we review recent developments in our understanding of the mechanisms of IMPDH regulation, including all layers of allosteric control that fine-tune the enzyme activity.

Keywords: IMP dehydrogenase; allosteric regulation; enzyme filamentation; protein structure and function; purine nucleotide biosynthesis.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Enzyme Inhibitors
  • Guanine Nucleotides*
  • IMP Dehydrogenase* / genetics
  • IMP Dehydrogenase* / metabolism
  • Inosine Monophosphate

Substances

  • Enzyme Inhibitors
  • Guanine Nucleotides
  • Inosine Monophosphate
  • IMP Dehydrogenase