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Nature Metabolism Sep 2021Umami refers to the savoury taste that is mediated by monosodium glutamate (MSG) and enhanced by inosine monophosphate and other nucleotides. Umami foods have been...
Umami refers to the savoury taste that is mediated by monosodium glutamate (MSG) and enhanced by inosine monophosphate and other nucleotides. Umami foods have been suggested to increase the risk for obesity and metabolic syndrome but the mechanism is not understood. Here we show that MSG induces obesity, hypothalamic inflammation and central leptin resistance in male mice through the induction of AMP deaminase 2 and purine degradation. Mice lacking AMP deaminase 2 in both hepatocytes and neurons are protected from MSG-induced metabolic syndrome. This protection can be overcome by supplementation with inosine monophosphate, most probably owing to its degradation to uric acid as the effect can be blocked with allopurinol. Thus, umami foods induce obesity and metabolic syndrome by engaging the same purine nucleotide degradation pathway that is also activated by fructose and salt consumption. We suggest that the three tastes-sweet, salt and umami-developed to encourage food intake to facilitate energy storage and survival but drive obesity and diabetes in the setting of excess intake through similar mechanisms.
Topics: Animals; Energy Intake; Metabolic Syndrome; Mice; Nucleotides; Obesity; Sodium Glutamate; Taste; Uric Acid
PubMed: 34552272
DOI: 10.1038/s42255-021-00454-z -
FASEB Journal : Official Publication of... Nov 2021Inosine monophosphate (IMP) is the intracellular precursor for both adenosine monophosphate and guanosine monophosphate and thus plays a central role in intracellular...
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 A , A and A 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.
Topics: Adenosine A2 Receptor Antagonists; Adenosine A3 Receptor Antagonists; Animals; Disease Models, Animal; Endotoxemia; Inosine; Inosine Monophosphate; Interleukin-10; Male; Mice; Mice, Inbred C57BL; Pneumonia, Pneumococcal; Quinazolines; Receptor, Adenosine A2A; Receptor, Adenosine A2B; Receptor, Adenosine A3; Signal Transduction; Streptococcus pneumoniae; Triazoles; Tumor Necrosis Factor-alpha
PubMed: 34591327
DOI: 10.1096/fj.202100862R -
Cell Metabolism Sep 2018Small cell lung cancer (SCLC) is a rapidly lethal disease with few therapeutic options. We studied metabolic heterogeneity in SCLC to identify subtype-selective...
Small cell lung cancer (SCLC) is a rapidly lethal disease with few therapeutic options. We studied metabolic heterogeneity in SCLC to identify subtype-selective vulnerabilities. Metabolomics in SCLC cell lines identified two groups correlating with high or low expression of the Achaete-scute homolog-1 (ASCL1) transcription factor (ASCL1 and ASCL1), a lineage oncogene. Guanosine nucleotides were elevated in ASCL1 cells and tumors from genetically engineered mice. ASCL1 tumors abundantly express the guanosine biosynthetic enzymes inosine monophosphate dehydrogenase-1 and -2 (IMPDH1 and IMPDH2). These enzymes are transcriptional targets of MYC, which is selectively overexpressed in ASCL1 SCLC. IMPDH inhibition reduced RNA polymerase I-dependent expression of pre-ribosomal RNA and potently suppressed ASCL1 cell growth in culture, selectively reduced growth of ASCL1 xenografts, and combined with chemotherapy to improve survival in genetic mouse models of ASCL1/MYC SCLC. The data define an SCLC subtype-selective vulnerability related to dependence on de novo guanosine nucleotide synthesis.
Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Line, Tumor; Guanosine; Heterografts; Humans; IMP Dehydrogenase; Lung Neoplasms; Mice; Mice, Knockout; Small Cell Lung Carcinoma
PubMed: 30043754
DOI: 10.1016/j.cmet.2018.06.005 -
Protein Science : a Publication of the... Sep 2022Inosine 5'-monophosphate dehydrogenase (IMPDH) is an evolutionarily conserved enzyme that mediates the first committed step in de novo guanine nucleotide biosynthetic... (Review)
Review
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.
Topics: Allosteric Regulation; Enzyme Inhibitors; Guanine Nucleotides; IMP Dehydrogenase; Inosine Monophosphate
PubMed: 36040265
DOI: 10.1002/pro.4399 -
Journal of Pharmacological Sciences Oct 2015As the first discovered gaseous signaling molecule, nitric oxide (NO) affects a number of cellular processes, including those involving vascular cells. This brief review... (Review)
Review
As the first discovered gaseous signaling molecule, nitric oxide (NO) affects a number of cellular processes, including those involving vascular cells. This brief review summarizes the contribution of NO to the regulation of vascular tone and its sources in the blood vessel wall. NO regulates the degree of contraction of vascular smooth muscle cells mainly by stimulating soluble guanylyl cyclase (sGC) to produce cyclic guanosine monophosphate (cGMP), although cGMP-independent signaling [S-nitrosylation of target proteins, activation of sarco/endoplasmic reticulum calcium ATPase (SERCA) or production of cyclic inosine monophosphate (cIMP)] also can be involved. In the blood vessel wall, NO is produced mainly from l-arginine by the enzyme endothelial nitric oxide synthase (eNOS) but it can also be released non-enzymatically from S-nitrosothiols or from nitrate/nitrite. Dysfunction in the production and/or the bioavailability of NO characterizes endothelial dysfunction, which is associated with cardiovascular diseases such as hypertension and atherosclerosis.
Topics: Animals; Arginine; Cardiovascular Diseases; Cell Physiological Phenomena; Cyclic GMP; Endothelium, Vascular; Guanylate Cyclase; Humans; Muscle Contraction; Muscle Tonus; Muscle, Smooth, Vascular; Nitrates; Nitric Oxide; Nitric Oxide Synthase Type III; Nitrites; S-Nitrosothiols; Signal Transduction
PubMed: 26499181
DOI: 10.1016/j.jphs.2015.09.002 -
Cell Reports Aug 2022The relationship between nutrient starvation and mitochondrial dynamics is poorly understood. We find that cells facing amino acid starvation display clear mitochondrial...
The relationship between nutrient starvation and mitochondrial dynamics is poorly understood. We find that cells facing amino acid starvation display clear mitochondrial fusion as a means to evade mitophagy. Surprisingly, further supplementation of glutamine (Q), leucine (L), and arginine (R) did not reverse, but produced stronger mitochondrial hyperfusion. Interestingly, the hyperfusion response to Q + L + R was dependent upon mitochondrial fusion proteins Mfn1 and Opa1 but was independent of MTORC1. Metabolite profiling indicates that Q + L + R addback replenishes amino acid and nucleotide pools. Inhibition of fumarate hydratase, glutaminolysis, or inosine monophosphate dehydrogenase all block Q + L + R-dependent mitochondrial hyperfusion, which suggests critical roles for the tricarboxylic acid (TCA) cycle and purine biosynthesis in this response. Metabolic tracer analyses further support the idea that supplemented Q promotes purine biosynthesis by serving as a donor of amine groups. We thus describe a metabolic mechanism for direct sensing of cellular amino acids to control mitochondrial fusion and cell fate.
Topics: Amines; Amino Acids; Mitochondria; Mitochondrial Dynamics; Mitochondrial Proteins; Purines
PubMed: 35977476
DOI: 10.1016/j.celrep.2022.111198 -
Basic & Clinical Pharmacology &... Aug 2020Almost fifty years ago, experiments on isolated veins showed that acute hypoxia augments venoconstrictor responses in vitro and that such facilitation relied on... (Review)
Review
Almost fifty years ago, experiments on isolated veins showed that acute hypoxia augments venoconstrictor responses in vitro and that such facilitation relied on anaerobic glycolysis. Over the years, this phenomenon was extended to a number of arterial preparations of different species and revisited, from a mechanistic point of view, with the successive demonstration that it depends on calcium handling in the vascular smooth muscle cells, is endothelium-dependent and requires the production of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS) and the activation of soluble guanylyl cyclase (sGC). However, rather than the vasodilator cyclic nucleotide 3',5'-cyclic guanosine monophosphate (cGMP), its canonical product, the latter enzyme produces 3',5'-cyclic inosine monophosphate (cIMP) instead during acute hypoxia; this non-canonical cyclic nucleotide facilitates the contractile process in the vascular smooth muscle cells. This 'biased' activity of soluble guanylyl cyclase appears to involve stimulation of NAD(P)H:quinone oxidoreductase 1 (NQO-1). The exact interactions between hypoxia, anaerobic metabolism and NQO-1 leading to biased activity of soluble guanylyl cyclase remain to be established.
Topics: Animals; Calcium; Cyclic IMP; Endothelium, Vascular; Humans; Hypoxia; Muscle, Smooth, Vascular; NAD(P)H Dehydrogenase (Quinone); Nitric Oxide; Soluble Guanylyl Cyclase; Vasoconstriction; Vasodilator Agents
PubMed: 31310708
DOI: 10.1111/bcpt.13295 -
Journal of Clinical Laboratory Analysis May 2022Inosine monophosphate dehydrogenase (IMPDH) is the key enzyme in the biosynthesis of purine nucleotides. IMPDH1 and IMPDH2 are the two isoforms of IMPDH and they share...
BACKGROUND
Inosine monophosphate dehydrogenase (IMPDH) is the key enzyme in the biosynthesis of purine nucleotides. IMPDH1 and IMPDH2 are the two isoforms of IMPDH and they share 84% amino acid similarity and virtually indistinguishable catalytic activity. Although high expression of IMPDH2 has been reported in various cancers, the roles of IMPDH1 in hepatocellular carcinoma (HCC) are largely unknown.
METHODS
The expression and the clinical relevance of IMPDH1 in 154 HCC patients were detected by immunohistochemistry analysis. The stable IMPDH1 knockdown HuH7 cells were established by lentiviral RNAi approach. The single cell proliferation was detected by colony-forming unit assay. The tumor initiation and growth ability were measured by using xenograft tumor model in immunodeficient mice. The effect of IMPDH1 on cellular signaling pathways was analyzed by genome-wide transcriptomic profiling.
RESULTS
The expression of IMPDH1 is upregulated in tumor tissue compared with adjacent liver tissue, and higher expression of IMPDH1 is associated with better patient cumulative survival. In experimental models, loss of IMPDH1 in HCC cells inhibits the ability of single cell colony formation in vitro, and reduces the efficiency of tumor initiation and growth in immunodeficient mice. Consistently, loss of IMPDH1 results in distinct alterations of signaling pathways revealed by genome-wide transcriptomic profiling.
CONCLUSION
IMPDH1 sustains HCC growth and progression.
Topics: Animals; Carcinoma, Hepatocellular; Cell Line; Humans; IMP Dehydrogenase; Liver Neoplasms; Mice
PubMed: 35403278
DOI: 10.1002/jcla.24416 -
Central European Journal of Urology 2018There is a need for a new biochemical marker of aggressive prostate cancer (PCa). Inosine monophosphate dehydrogenase 2 (IMPDH2) is a candidate for such a marker - its...
INTRODUCTION
There is a need for a new biochemical marker of aggressive prostate cancer (PCa). Inosine monophosphate dehydrogenase 2 (IMPDH2) is a candidate for such a marker - its activity is increased in certain tumors and neoplastic cell lines, including PCa, and may correlate with cancer aggressiveness.
MATERIAL AND METHODS
IMPDH2 levels were measured in blood samples from 34 PCa patients. The results were analyzed and correlated with prostate-specific antigen (PSA), digital rectal examination (DRE), Gleason score, risk groups according to d'Amico and metastatic disease. Twenty healthy (non-PCa) patients served as the control group.
RESULTS
There was no significant difference in IMPDH2 level between the PCa and control group, and no significant correlation between PSA and IMPDH2. IMPDH2 levels were significantly higher in the DRE (+) patients (148.5 ±174.8 vs. 33.4 ±46.4, p <0.05), in patients with metastatic disease (100.1 ±139.0 vs. 25.3 ±25.9, p <0.05) and in the high-risk group according to d'Amico (93.4 ±129.2 vs. 18.8 ±10.4, p <0.05). There was a significant correlation between the Gleason score and IMPDH2.
CONCLUSIONS
These results suggest that IMPDH2 is a promising candidate as a biomarker for those with advanced PCa and those at high risk of progression towards advanced PCa.
PubMed: 30680233
DOI: 10.5173/ceju.2018.1696