IMPDH dysregulation in disease: a mini review

Abstract

Inosine-5′-monophosphate dehydrogenase (IMPDH) is a highly conserved enzyme in purine metabolism that is tightly regulated on multiple levels. IMPDH has a critical role in purine biosynthesis, where it regulates flux at the branch point between adenine and guanine nucleotide synthesis, but it also has a role in transcription regulation and other moonlighting functions have been described. Vertebrates have two isoforms, IMPDH1 and IMPDH2, and point mutations in each are linked to human disease. Mutations in IMPDH2 in humans are associated with neurodevelopmental disease, but the effects of mutations at the enzyme level have not yet been characterized. Mutations in IMPDH1 lead to retinal degeneration in humans, and recent studies have characterized how they cause functional defects in regulation. IMPDH1 is expressed as two unique splice variants in the retina, a tissue with very high and specific demands for purine nucleotides. Recent studies have revealed functional differences among splice variants, demonstrating that retinal variants up-regulate guanine nucleotide synthesis by reducing sensitivity to feedback inhibition by downstream products. A better understanding of the role of IMPDH1 in the retina and the characterization of an animal disease model will be critical for determining the molecular mechanism of IMPDH1-associated blindness.

Discovery of host-directed modulators of virus infection by probing the SARS-CoV-2-host protein-protein interaction network

“…IMPDH2 regulates NF-κB signalling, and SARS-CoV-2 infection leads to NF-κB activation and induction of proinflammatory cytokines (40). IMPDH2 also plays a role in purine biosynthesis, which is needed for viral RNA replication (41). While RAB7A (Ras-related protein 7A) had high expression in lung macrophages and in respiratory epithelial cells of the bronchus (Figure 4A) , it was de-prioritised because of its key role in the maturation of late endosomes, which are not the primary sites through which SARS-CoV-2 enters human lung cells; most SARS-CoV-2s enter lung cells through fusion at the plasma membrane (42), while for the Omicron variants of concern (VOC), the virus appears to also use the endosomal route (43,44).…”

“…IMPDH2 regulates NF-κB signalling, and SARS-CoV-2 infection leads to NF-κB activation and induction of proinflammatory cytokines (40). IMPDH2 also plays a role in purine biosynthesis, which is needed for viral RNA replication (41). While RAB7A…”

COVID‐19 metabolism: Mechanisms and therapeutic targets

“…Inosine monophosphate dehydrogenase 2 (IMPDH2) and thymidine kinase 1 (TK1) are rate‐limiting enzymes that control guanine and thymidine nucleotide biosynthesis, respectively. 145 , 146 Viral proteins may boost nucleotide biosynthesis by activating these enzymes (Figure 4G ). Noteworthy, folate metabolism provides one‐carbon units to maintain nucleotide synthesis.…”

The gateway to guanine nucleotides: Allosteric regulation of IMP dehydrogenases

“… 43 Twelve missense mutations in IMPDH1 associated with retinopathies have been identified, although none of them have significant effects on the catalytic activity of IMPDH1 in vitro. 22 , 29 , 74 Six of these mutations map around the second canonical and the third non‐canonical allosteric sites in the Bateman domain, while the rest are scattered in the catalytic domain, but distal from the IMP binding site, the flap region, or the finger domain 8 , 39 (Figure 13 ). As expected, the six mutations that map into the allosteric sites interfere with nucleotide binding and confer resistance to GTP allosteric inhibition.…”