Evidence for a Cross-Talk Between Cytosolic 5′-Nucleotidases and AMP-Activated Protein Kinase

Camici, Marcella; Garcia‐Gil, Mercedes; Allegrini, Simone; Pesi, Rossana; Tozzi, Maria Grazia

doi:10.3389/fphar.2020.609849

Cited by 7 publications

(14 citation statements)

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“…NT5C1, which has been mainly studied in skeletal muscle, and NT5C2, which is ubiquitously expressed, are the major cytosolic NT5Cs acting on intracellular nucleotides (Camici et al, 2020). Among purine nucleotides, AMP, with a K M in the millimolar range (Hunsucker et al, 2001;Tkacz-Stachowska et al, 2005) is the preferred substrate for NT5C1, while IMP and GMP are better substrates for NT5C2 (K M in the micromolar range) (Tozzi et al, 2013;Pesi et al, 2021), but this enzyme catalyzes also the hydrolysis of the phosphoester bond of AMP (with a K M in the millimolar range) (Tozzi et al, 2013).…”

Section: '-Nucleotidasesmentioning

confidence: 99%

“…In fact, at high energy charge, excess IMP, synthesized by de novo or salvage pathways, is converted to inosine and therefore directed to catabolic pathways, while at low energy charge IMP and AMP accumulate (Pesi et al, 1994;Allegrini et al, 2004;Wallden and Nordlund, 2011;Camici et al, 2018a). NT5C1 has been associated to some autoimmune diseases (Rietveld et al, 2018), while an association has been reported between NT5C2 expression and psychiatric and psychomotor disorders including schizophrenia (Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013; Duarte et al, 2016;Duarte et al, 2019) and hereditary spastic paraplegias (HSP) (Garcia-Gil et al, 2018;Camici et al, 2020). At early stages of AD, NT5C activity is reduced in membranes and cytosol in distinct cortical regions such as the frontal cortex, and only at advanced stages in cytosol in the temporal cortex (Alonso-Andres et al, 2018).…”

Section: '-Nucleotidasesmentioning

confidence: 99%

“…In fact, through complex and various signaling pathways, AMPK switches off the anabolic pathways that require ATP and switches on the catabolic pathways that produce ATP (Hardie and Hawley, 2001;Gowans et al, 2013). Increasing evidence supports a relevant role of AMPK in the physiopathology of the central nervous system (Camici et al, 2020). The roles of AMPK in brain and its cross-talk with many hormones in the hypothalamus to mediate their anorexigenic and orexigenic effects as well as thermogenic influences have been thoroughly reviewed (Huynh et al, 2016;Rosso et al, 2016;Peixoto et al, 2017;Liu et al, 2020).…”

Section: Amp-activated Protein Kinasementioning

confidence: 99%

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Metabolic Aspects of Adenosine Functions in the Brain

et al. 2021

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Adenosine, acting both through G-protein coupled adenosine receptors and intracellularly, plays a complex role in multiple physiological and pathophysiological processes by modulating neuronal plasticity, astrocytic activity, learning and memory, motor function, feeding, control of sleep and aging. Adenosine is involved in stroke, epilepsy and neurodegenerative pathologies. Extracellular concentration of adenosine in the brain is tightly regulated. Adenosine may be generated intracellularly in the central nervous system from degradation of AMP or from the hydrolysis of S-adenosyl homocysteine, and then exit via bi-directional nucleoside transporters, or extracellularly by the metabolism of released nucleotides. Inactivation of extracellular adenosine occurs by transport into neurons or neighboring cells, followed by either phosphorylation to AMP by adenosine kinase or deamination to inosine by adenosine deaminase. Modulation of the nucleoside transporters or of the enzymatic activities involved in the metabolism of adenosine, by affecting the levels of this nucleoside and the activity of adenosine receptors, could have a role in the onset or the development of central nervous system disorders, and can also be target of drugs for their treatment. In this review, we focus on the contribution of 5′-nucleotidases, adenosine kinase, adenosine deaminase, AMP deaminase, AMP-activated protein kinase and nucleoside transporters in epilepsy, cognition, and neurodegenerative diseases with a particular attention on amyotrophic lateral sclerosis and Huntington’s disease. We include several examples of the involvement of components of the adenosine metabolism in learning and of the possible use of modulators of enzymes involved in adenosine metabolism or nucleoside transporters in the amelioration of cognition deficits.

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Section: '-Nucleotidasesmentioning

confidence: 99%

Section: '-Nucleotidasesmentioning

confidence: 99%

Section: Amp-activated Protein Kinasementioning

confidence: 99%

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Metabolic Aspects of Adenosine Functions in the Brain

et al. 2021

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“…Furthermore, in a mice model, the knockout of the enzyme was associated with reduced body weight also after a high-fat diet [17]. Consistently, a single-nucleotide polymorphism in NT5C2 (the cN-II gene) was associated with a lower tendency to accumulate adipose tissue in Japanese women [18,19]. Finally, recent reports describe several effects of cN-II silencing, possibly through activation of AMPK both in skeletal muscle and in human neural progenitor cells [20,21].…”

Section: Introductionmentioning

confidence: 74%

Cytosolic 5′-Nucleotidase II Silencing in Lung Tumor Cells Regulates Metabolism through Activation of the p53/AMPK Signaling Pathway

Pesi

Allegrini

Garcia‐Gil

et al. 2021

IJMS

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Cytosolic 5′-nucleotidase II (cN-II) is an allosteric catabolic enzyme that hydrolyzes IMP, GMP, and AMP. The enzyme can assume at least two different structures, being the more active conformation stabilized by ATP and the less active by inorganic phosphate. Therefore, the variation in ATP concentration can control both structure and activity of cN-II. In this paper, using a capillary electrophoresis technique, we demonstrated that a partial silencing of cN-II in a pulmonary carcinoma cell line (NCI-H292) is accompanied by a decrease in adenylate pool, without affecting the energy charge. We also found that cN-II silencing decreased proliferation and increased oxidative metabolism, as indicated by the decreased production of lactate. These effects, as demonstrated by Western blotting, appear to be mediated by both p53 and AMP-activated protein kinase, as most of them are prevented by pifithrin-α, a known p53 inhibitor. These results are in line with our previous observations of a shift towards a more oxidative and less proliferative phenotype of tumoral cells with a low expression of cN-II, thus supporting the search for specific inhibitors of this enzyme as a therapeutic tool for the treatment of tumors.

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“…Since alterations in the nucleoside system play a very important role in modulating both physiological and pathophysiological processes in humans, the modulation of 5′-nucleotidase activity may be a promising therapeutic tool for treating various diseases (Kovács et al, 2013 ); therefore, the regulation of mammalian 5′-nucleotidase activity has been investigated in-depth (Pesi et al 1994 ; Camici et al 2020 ). Much less is known about the regulation of microbial 5′-nucleotidase activity.…”

Section: Regulation Of Microbial 5′-nucleotidase Activitymentioning

confidence: 99%

Microbial 5′-nucleotidases: their characteristics, roles in cellular metabolism, and possible practical applications

Zakataeva

2021

Appl Microbiol Biotechnol

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Abstract5′-Nucleotidases (EC 3.1.3.5) are enzymes that catalyze the hydrolytic dephosphorylation of 5′-ribonucleotides and 5′-deoxyribonucleotides to their respective nucleosides and phosphate. Most 5′-nucleotidases have broad substrate specificity and are multifunctional enzymes capable of cleaving phosphorus from not only mononucleotide phosphate molecules but also a variety of other phosphorylated metabolites. 5′-Nucleotidases are widely distributed throughout all kingdoms of life and found in different cellular locations. The well-studied vertebrate 5′-nucleotidases play an important role in cellular metabolism. These enzymes are involved in purine and pyrimidine salvage pathways, nucleic acid repair, cell-to-cell communication, signal transduction, control of the ribo- and deoxyribonucleotide pools, etc. Although the first evidence of microbial 5′-nucleotidases was obtained almost 60 years ago, active studies of genetic control and the functions of microbial 5′-nucleotidases started relatively recently. The present review summarizes the current knowledge about microbial 5′-nucleotidases with a focus on their diversity, cellular localizations, molecular structures, mechanisms of catalysis, physiological roles, and activity regulation and approaches to identify new 5′-nucleotidases. The possible applications of these enzymes in biotechnology are also discussed.Key points• Microbial 5′-nucleotidases differ in molecular structure, hydrolytic mechanism, and cellular localization.• 5′-Nucleotidases play important and multifaceted roles in microbial cells.• Microbial 5′-nucleotidases have wide range of practical applications. Graphical abstract

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Evidence for a Cross-Talk Between Cytosolic 5′-Nucleotidases and AMP-Activated Protein Kinase

Cited by 7 publications

References 43 publications

Metabolic Aspects of Adenosine Functions in the Brain

Metabolic Aspects of Adenosine Functions in the Brain

Cytosolic 5′-Nucleotidase II Silencing in Lung Tumor Cells Regulates Metabolism through Activation of the p53/AMPK Signaling Pathway

Microbial 5′-nucleotidases: their characteristics, roles in cellular metabolism, and possible practical applications

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