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Inosine monophosphate dehydrogenases are key players for functional embryo and seedling development in Arabidopsis

ABSTRACT: In plants, nucleotide de novo synthesis is required throughout development to energize biochemical reactions, provide DNA for cell division and RNAs for gene expression and translation. Inosine Monophosphate Dehydrogenases (IMPDH) are key enzymes in guanylate synthesis. We identify IMPDH2 from Arabidopsis as the major isoform, being enzymatically active in the plant cytosol and catalyzing the key enzymatic step in CTP biosynthesis. BIFC analysis suggests that IMPDH 1 nd 2 interact with thenmselves and with Cytidine Triphosphate Synthetase (CTPS) isoforms, by this connecting purone and pyrimidine metabolsim. Nucleotide quantification identifies IMPDH2 as bottleneck in guanylate biosynthesis, leading to nucleotide imbalance and limitation, causing reductions in ribosomal RNAs by reducing Target of Rapamycin (TOR) activity. Impaired photosynthesis and growth are consequences thereof. In contrast, overexpression of IMPDH supported growth and in strong lines lead to altered organ development presumably due to altered auxin metabolism during embryo development

ORGANISM(S): Arabidopsis thaliana

PROVIDER: GSE312534 | GEO | 2025/12/23

REPOSITORIES: GEO

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De Novo Purine Synthesis Mediates Circadian Control of Cell Cycle in Zebrafish (HTS)

Project description:Inosine 5'-phosphate dehydrogenase (impdh) has been well known as a key enzyme in GTP biosynthesis pathway. We found that three isoforms of impdh in zebrafish, namely impdh1a, impdh1b and impdh2, all show robust circadian expression.To examine the molecular functions of three impdh isoforms in zebrafish on the genome scale, we measured the global expression changes of impdh1a, impdh1b and impdh2 morpholino injected larvae (morphants) respectively using RNA-seq. Wild type (WT), control and three impdh morphants were collected at 32 hpf. In our RNA-seq result, we identified 468, 331 and 1166 significant genes affected by impdh1a, impdh1b and impdh2 morpholino (MO) knock-down respectively. Among them, there are limited overlaps between genes affected by different MOs and only 36 genes in common among all three MOs. This indicates that the three impdh isoforms have distinct molecular functions. To knock down the target genes, three impdh MOs and control MO were pressure-injected into 1- to 2-cell stage embryos. WT, control and three impdh morphants were raised at 28Â°C under 14h: 10h light/dark cycle from birth and sampled simultaneously at 32 hpf. Each group has at least 40 embryos.

2013-10-01 | E-GEOD-51278 | biostudies-arrayexpress

De Novo Purine Synthesis Mediates Circadian Control of Cell Cycle in Zebrafish (HTS)

2013-10-01 | GSE51278 | GEO

Inosine Monophosphate Dehydrogenase 2 (IMPDH2) Modulates Response to Therapy and Chemo-Resistance in Triple Negative Breast Cancer

Project description:Triple negative breast cancer (TNBC) is one of the deadliest subtypes of breast cancer, whose high frequency of relapse is often due to occurrence of resistance to chemotherapy. Here, we identify inosine monophosphate dehydrogenase 2 (IMPDH2) as a contributor to doxorubicin resistance in different TNBC models. Analysis of public dataset reveals elevated IMPDH2 expression to correlate with worse overall TNBC prognosis in the clinic, including lower recurrence-free survival post adjuvant/neoadjuvant therapy. Importantly, genetic depletion or pharmacological inhibition of IMPDH2 leads to reduction of pro-tumorigenic phenotypes in multiple doxorubicin-resistant TNBC models, both in vitro and in vivo. Overall, we propose IMPDH2 as a novel vulnerability that could be leveraged therapeutically to suppress and/or prevent the growth of chemoresistant lesions.

2025-01-07 | GSE264197 | GEO

A kinetic alignment of orthologous inosine-5'-monophosphate dehydrogenases.

Project description:IMP dehydrogenase (IMPDH) catalyzes two very different chemical transformations, a dehydrogenase reaction and a hydrolysis reaction. The enzyme toggles between the open conformation required for the dehydrogenase reaction and the closed conformation of the hydrolase reaction by moving a mobile flap into the NAD site. Despite these multiple functional constraints, the residues of the flap and NAD site are highly diverged, and the equilibrium between open and closed conformations ( K c ) varies widely. In order to understand how differences in the dynamic properties of the flap influence the catalytic cycle, we have delineated the kinetic mechanism of IMPDH from the pathogenic protozoan parasite Cryptosporidium parvum ( CpIMPDH), which was obtained from a bacterial source through horizontal gene transfer, and its host counterpart, human IMPDH type 2 (hIMPDH2). Interestingly, the intrinsic binding energy of NAD (+) differentially distributes across the dinucleotide binding sites of these two enzymes as well as in the previously characterized IMPDH from Tritrichomonas foetus ( TfIMPDH). Both the dehydrogenase and hydrolase reactions display significant differences in the host and parasite enzymes, in keeping with the phylogenetic and structural divergence of their active sites. Despite large differences in K c , the catalytic power of both the dehydrogenase and hydrolase conformations are similar in CpIMPDH and TfIMPDH. This observation suggests that the closure of the flap simply sets the stage for catalysis rather than plays a more active role in the chemical transformation. This work provides the essential mechanistic framework for drug discovery.

| S-EPMC2646883 | biostudies-literature

Differential effects of inosine monophosphate dehydrogenase (IMPDH/GuaB) inhibition in Acinetobacter baumannii and Escherichia coli

Project description:Inosine 5’-monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting step in the de novo guanine biosynthesis and is conserved from humans to bacteria, where it is called GuaB. We developed a series of potent inhibitors that selectively target GuaB over its human homolog. Here we show that these GuaB inhibitors are bactericidal, generate phenotypic signatures that are distinct from other antibiotics, and elicit different time-kill kinetics and regulatory responses in two important gram-negative pathogens: Acinetobacter baumannii and Escherichia coli. Specifically, the GuaB inhibitor G6 rapidly kills A. baumannii but only kills E. coli after 24 hours. After exposure to G6, the expression of genes involved in purine biosynthesis and stress responses change in opposite directions while siderophore biosynthesis is downregulated in both species. Our results suggest that different species respond to GuaB inhibition using distinct regulatory programs, and possibly explain the different bactericidal kinetics upon GuaB inhibition. The comparison highlights opportunities for developing GuaB inhibitors as novel antibiotics.

2024-08-25 | GSE275261 | GEO

Porcine epidemic diarrhea virus manipulates IMPDH-dependent nucleotide biosynthesis to facilitate replication

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2025-10-17 | MTBLS13153 | MetaboLights

A structural determinant of mycophenolic acid resistance in eukaryotic inosine 5'-monophosphate dehydrogenases.

Project description:Mycophenolic acid (MPA) is a potent natural product inhibitor of fungal and other eukaryotic inosine 5'-monophosphate dehydrogenases (IMPDHs) originally isolated from spoiled corn silage. MPA is produced by the filamentous fungi Penicillium brevicompactum, which contains two IMPDHs, PbIMPDHA and PbIMPDHB, both of which are MPA-resistant. The MPA binding sites of these enzymes are identical to MPA-sensitive IMPDHs, so the structural determinants of resistance are unknown. Here we show that a single residue, Ser267, accounts for the MPA resistance of PbIMPDHA. Substitution of Ser267 with Ala, the residue most commonly found in this position in eukaryotic IMPDHs, makes PbIMPDHA sensitive to MPA. Conversely, Aspergillus nidulans IMPDH becomes MPA-resistant when the analogous Ala residue is substituted with Ser. These substitutions have little effect on the catalytic cycles of either enzyme, suggesting the fitness costs are negligible despite the strong conservation of Ala at this position. Intriguingly, while only 1% of fungal IMPDHs contain Ser or Thr at position 267, these residues are found in the IMPDHs from several Aspergillus species that grow at the low temperatures also favored by Penicillium. Perhaps Ser/Thr267 is an evolutionary signature of MPA exposure.

| S-EPMC7021006 | biostudies-literature

Pharmacogenetics of the mycophenolic acid targets inosine monophosphate dehydrogenases IMPDH1 and IMPDH2: gene sequence variation and functional genomics.

Project description:Background and purposeInosine monophosphate dehydrogenases, encoded by IMPDH1 and IMPDH2, are targets for the important immunosuppressive drug, mycophenolic acid (MPA). Variation in MPA response may result, in part, from genetic variation in IMPDH1 and IMPDH2.Experimental approachWe resequenced IMPDH1 and IMPDH2 using DNA from 288 individuals from three ethnic groups and performed functional genomic studies of the sequence variants observed.Key resultsWe identified 73 single nucleotide polymorphisms (SNPs) in IMPDH1, 59 novel, and 25 SNPs, 24 novel, in IMPDH2. One novel IMPDH1 allozyme (Leu275) had 10.2% of the wild-type activity as a result of accelerated protein degradation. Decreased activity of the previously reported IMPDH2 Phe263 allozyme was primarily due to decreased protein quantity, also with accelerated degradation. These observations with regard to the functional implications of variant allozymes were supported by the IMPDH1 and IMPDH2 X-ray crystal structures. A novel IMPDH2 intron 1 SNP, G > C IVS1(93), was associated with decreased mRNA quantity, possibly because of altered transcription.Conclusions and implicationsThese results provide insight into the nature and extent of sequence variation in the IMPDH1 and IMPDH2 genes. They also describe the influence of gene sequence variation that alters the encoded amino acids on IMPDH function and provide a foundation for future translational studies designed to correlate sequence variation in these genes with outcomes in patients treated with MPA.

| S-EPMC3010569 | biostudies-literature

Genome-wide IMPDH profiling in Drosophila larvae and S2 cells by ChIP-chip.

Project description:Division of labor is a central feature of cellular organization. Consequently, gene regulation and intermediary metabolism are generally believed to be conducted by strictly separate classes of proteins. Here, we show that inosine monophosphate dehydrogenase (IMPDH), the central enzyme in guanine nucleotide biosynthesis, moonlights as a gene-specific transcription factor. Nuclear exclusion during S phase coordinates IMPDH’s transcriptional activities with the cell cycle. IMPDH represses target gene expression, including the histone genes. Unexpectedly, genomic IMPDH loci have the propensity to unwind. Genome-wide profiling and in vitro experiments revealed that IMPDH binds sequence-specifically to single stranded C/T-rich DNA elements. Thus, a classic biosynthetic enzyme can act as a DNA-binding transcription factor, suggestive of a more reciprocal and intimate relationship between metabolism and gene expression than commonly assumed.

2012-05-01 | GSE29202 | GEO

Inosine monophosphate and inosine differentially regulate endotoxemia and bacterial sepsis.

Project description:Inosine monophosphate (IMP) is the intracellular precursor for both adenosine monophosphate and guanosine monophosphate and thus plays a central role in intracellular purine metabolism. IMP can also serve as an extracellular signaling molecule, and can regulate diverse processes such as taste sensation, neutrophil function, and ischemia-reperfusion injury. How IMP regulates inflammation induced by bacterial products or bacteria is unknown. In this study, we demonstrate that IMP suppressed tumor necrosis factor (TNF)-α production and augmented IL-10 production in endotoxemic mice. IMP exerted its effects through metabolism to inosine, as IMP only suppressed TNF-α following its CD73-mediated degradation to inosine in lipopolysaccharide-activated macrophages. Studies with gene targeted mice and pharmacological antagonism indicated that A2A , A2B, and A3 adenosine receptors are not required for the inosine suppression of TNF-α production. The inosine suppression of TNF-α production did not require its metabolism to hypoxanthine through purine nucleoside phosphorylase or its uptake into cells through concentrative nucleoside transporters indicating a role for alternative metabolic/uptake pathways. Inosine augmented IL-β production by macrophages in which inflammasome was activated by lipopolysaccharide and ATP. In contrast to its effects in endotoxemia, IMP failed to affect the inflammatory response to abdominal sepsis and pneumonia. We conclude that extracellular IMP and inosine differentially regulate the inflammatory response.

| S-EPMC9812230 | biostudies-literature

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