The 5′-nucleotidases as regulators of nucleotide and drug metabolism

Hunsucker, Sally A.; Mitchell, Beverly S.; Spychała, Józef

doi:10.1016/j.pharmthera.2005.01.003

Cited by 243 publications

(293 citation statements)

References 224 publications

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“…Reported K m values for AMP range between 1 and 50 μM (ref. in [201,202]). The enzyme has a broad tissue distribution, and it is expressed by subpopulations of human T and B lymphocytes and also by a considerable variety of tumor cells [203].…”

Section: Ecto-5′-nucleotidasementioning

confidence: 99%

“…General molecular properties EN was first cloned from rat [237], human placenta [238], and the electric ray Torpedo electric organ [239], followed by identification of the cDNA sequence of a considerable variety of mammalian species [202,240]. The human cDNA encodes a precursor of 574 residues that is converted to the mature form of 523 residues after cleavage of the signal peptide and the hydrophobic domain at the C-terminus, which is replaced with the GPI anchor, similar to the enzymes cloned from rat [237] and mouse [204].…”

Section: Ecto-5′-nucleotidase Versus Soluble 5′-nucleotidasesmentioning

confidence: 99%

“…In mammals, these include in addition to eN the Ser/Thr protein phosphatases and tartrateresistant acid phosphatase [289,290]. Molecular cloning revealed phylogenetic relationships between vertebrate eN and functionally related enzymes in invertebrates, yeasts/ fungi, eubacteria, and archaea but seem to be lacking in plants [201,202,240]. The bacterial enzymes reveal a broader spectrum of substrate specificity.…”

Section: Phylogenetic Relationshipmentioning

confidence: 99%

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Cellular function and molecular structure of ecto-nucleotidases

Zimmermann

Zebisch

Sträter

2012

Purinergic Signalling

876

922

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Ecto-nucleotidases play a pivotal role in purinergic signal transmission. They hydrolyze extracellular nucleotides and thus can control their availability at purinergic P2 receptors. They generate extracellular nucleosides for cellular reuptake and salvage via nucleoside transporters of the plasma membrane. The extracellular adenosine formed acts as an agonist of purinergic P1 receptors. They also can produce and hydrolyze extracellular inorganic pyrophosphate that is of major relevance in the control of bone mineralization. This review discusses and compares four major groups of ectonucleotidases: the ecto-nucleoside triphosphate diphosphohydrolases, ecto-5′-nucleotidase, ecto-nucleotide pyrophosphatase/phosphodiesterases, and alkaline phosphatases. Only recently and based on crystal structures, detailed information regarding the spatial structures and catalytic mechanisms has become available for members of these four ecto-nucleotidase families. This permits detailed predictions of their catalytic mechanisms and a comparison between the individual enzyme groups. The review focuses on the principal biochemical, cell biological, catalytic, and structural properties of the enzymes and provides brief reference to tissue distribution, and physiological and pathophysiological functions.

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Section: Ecto-5′-nucleotidasementioning

confidence: 99%

Section: Ecto-5′-nucleotidase Versus Soluble 5′-nucleotidasesmentioning

confidence: 99%

Section: Phylogenetic Relationshipmentioning

confidence: 99%

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Cellular function and molecular structure of ecto-nucleotidases

Zimmermann

Zebisch

Sträter

2012

Purinergic Signalling

876

922

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“…This family of enzymes is critical for the physiological control of energy balance, metabolic regulation, and cell replication (14). Of the seven identified human 5Ј-nucleotidases, five (NT5C1A, NT5C1B, NT5C2, NT5C3, and NT5C3L) are localized in the cytoplasm, one (eN) is bound to the extracellular part of the plasma membrane, and one is present in the mitochondrial matrix (mdN) (15,16). 5Ј-Nucleotidases have broad substrate specificity and are involved in maintaining cellular nucleotide and nucleoside levels by catalyzing the hydrolysis of either AMP to adenosine and phosphate or IMP to inosine and phosphate (15).…”

mentioning

confidence: 99%

Suppression of 5′-Nucleotidase Enzymes Promotes AMP-activated Protein Kinase (AMPK) Phosphorylation and Metabolism in Human and Mouse Skeletal Muscle

Kulkarni

Karlsson

Szekeres

et al. 2011

Journal of Biological Chemistry

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Background: The 5Ј-nucleotidase (NT5) family of enzymes dephosphorylates non-cyclic nucleoside monophosphates to produce nucleosides and inorganic phosphates. Results: NT5 silencing increases the intracellular availability of AMP/ATP and invokes AMP-activated protein kinase (AMPK) activation, glucose uptake, and lipid oxidation. Conclusion: NT5C enzymes inhibit basal lipid oxidation and glucose transport in skeletal muscle. Significance: Suppression of cytosolic NT5C expression or activity may bypass metabolic inflexibility in type 2 diabetes.

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“…Its activity is not only found in the cytosolic membrane-bound form but also in the extracelullar membrane-bound form. While soluble 5'-nucleotidase controls intracellular levels of nucleoside 5'-monophosphate,the extracellular surface-located 5'-nucleotidase plays a part in the cascade that hydrolyzes ATP to adenosine [65]. Ecto 5'-nucleotidase (CD 73) is a glycosilphosphatidylinositol (GPI)-linked, which is found on the outside of a variety of cell types and hydrolyzes extracellular nucleoside monophosphates to nucleoside intermediates [71].…”

Section: '-Nucleotidase: General Characteristicsmentioning

confidence: 99%

NTPDase and 5'‐nucleotidase activities in physiological and disease conditions: New perspectives for human health

et al. 2007

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Abstract. Extracellular nucleotides and nucleosides act as signaling molecules involved in a wide spectrum of biological effects. Their levels are controlled by a complex cell surface-located group of enzymes called ectonucleotidases. There are four major families of ectonucleotidases, nucleoside triphosphate diphosphohydrolases (NTPDases/CD39), ectonucleotide pyrophosphatase/phosphodiesterases (E-NPPs), alkaline phosphatases and ecto-5'-nucleotidase. In the last few years, substantial progress has been made toward the molecular identification of members of the ectonucleotidase families and their enzyme structures and functions. In this review, there is an emphasis on the involvement of NTPDase and 5'-nucleotidase activities in disease processes in several tissues and cell types. Brief background information is given about the general characteristics of these enzymes, followed by a discussion of their roles in thromboregulatory events in diabetes, hypertension, hypercholesterolemia and cancer, as well as in pathological conditions where platelets are less responsive, such as in chronic renal failure. In addition, immunomodulation and cell-cell interactions involving these enzymes are considered, as well as ATP and ADP hydrolysis under different clinical conditions related with alterations in the immune system, such as acute lymphoblastic leukemia (ALL), Bchronic lymphocytic leukemia (B-CLL) and infections associated with human immunodeficiency virus (HIV). Finally, changes in ATP, ADP and AMP hydrolysis induced by inborn errors of metabolism, seizures and epilepsy are discussed in order to highlight the importance of these enzymes in the control of neuronal activity in pathological conditions. Despite advances made toward understanding the molecular structure of ectonucleotidases, much more investigation will be necessary to entirely grasp their role in physiological and pathological conditions.

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The 5′-nucleotidases as regulators of nucleotide and drug metabolism

Cited by 243 publications

References 224 publications

Cellular function and molecular structure of ecto-nucleotidases

Cellular function and molecular structure of ecto-nucleotidases

Suppression of 5′-Nucleotidase Enzymes Promotes AMP-activated Protein Kinase (AMPK) Phosphorylation and Metabolism in Human and Mouse Skeletal Muscle

NTPDase and 5'‐nucleotidase activities in physiological and disease conditions: New perspectives for human health

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