Regulation of nucleotidase activities in animal tissues

Fritzson, Per

doi:10.1016/0065-2571(78)90066-3

Cited by 44 publications

(17 citation statements)

References 29 publications

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“…Such enzymes could be cytosolic 5'-nucleotidase and the deoxyribonucleoside-activated nucleotidase, with pH optima 6.3 and 6.0 respectively, which may both exert some activity also at pH 8.1 (Fritzson, 1969;Fritzson & Smith, 1971). Contribution of these enzymes to the supernatant-fraction activity could explain a slightly smaller decrease in UMP and IMP dephosphorylation in regenerating liver compared with AMP dephosphorylation, since both enzymes show increased activity in regenerating liver (Fritzson, 1978;Tjernshaugen & Fritzson, 1984) and exhibit very low activity towards AMP at the substrate concentrations used. It may be concluded that our assay for alkaline 5'-nucleotidase in the crude supernatant fraction is about 85 or 100% specific, depending on the use of UMP or AMP as substrate respectively.…”

Section: Discussionmentioning

confidence: 99%

The presence and activity in normal and regenerating rat liver postmicrosomal supernatant fraction of an enzyme with properties similar to those of membrane-bound 5′-nucleotidase

Fritzson¹,

Haugen²,

Tjernshaugen³

1986

Biochemical Journal

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An alkaline 5′-nucleotidase with properties similar to those of membrane-bound 5′-nucleotidase was recovered in soluble form in the postmicrosomal supernatant fraction (cytosol) of rat liver. The enzyme seems to constitute a quantitatively distinct fraction, since the activity in postmicrosomal supernatants was increased by a further 10% by additional homogenization of livers. Lysosomal acid phosphatase activity increased similarly, whereas other membrane-bound marker enzymes alkaline phosphatase, phosphodiesterase I and glucose-6-phosphatase showed no increase when homogenization of liver tissue was continued. Gel-permeation chromatography and pH-dependence studies indicated that enzyme activity in the supernatant fraction with 0.3 mM-UMP or -AMP as substrate at pH 8.1 was about 85 or 100% specific respectively. In regenerating liver the enzyme recovered in soluble form showed decreased specific activity, in contrast with alkaline phosphatase measured for comparison. The nucleotidase activity per mg of cytosolic protein was 2.1 nmol/min with AMP as substrate. The total activity measured in the postmicrosomal supernatant was 1.5% of the homogenate activity measured in the presence of detergent.

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Section: Discussionmentioning

confidence: 99%

The presence and activity in normal and regenerating rat liver postmicrosomal supernatant fraction of an enzyme with properties similar to those of membrane-bound 5′-nucleotidase

Fritzson¹,

Haugen²,

Tjernshaugen³

1986

Biochemical Journal

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“…The deoxynucleotidase postulated as part of this cycle (2, 3) has a high Km for dCMP (8) and is therefore sensitive to changes in deoxynucleotide concentration. Deoxycytidine kinase, the other enzyme of the cycle, is allosterically inhibited by dCTP (10).…”

Section: Discussionmentioning

confidence: 99%

Regulation of pyrimidine deoxyribonucleotide metabolism by substrate cycles in dCMP deaminase-deficient V79 hamster cells.

Bianchi¹,

Pontis²,

Reichard³

1987

Mol. Cell. Biol.

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A mutant V79 hamster fibroblast cell line lacking the enzyme dCMP deaminase was used to study the regulation of deoxynucleoside triphosphate pools by substrate cycles between pyrimidine deoxyribosides and their 5'-phosphates. Such cycles were suggested earlier to set the rates of cellular import and export of deoxyribosides, thereby influencing pool sizes (V. Bianchi, E. Pontis, and P. Reichard, Proc. Natl. Acad. Sci. USA 83:986-990, 1986). While normal V79 cells derived more than 80% of their dTTP from CDP reduction via deamination of dCMP, the mutant cells had to rely completely on UDP reduction for de novo synthesis of dTTP, which became limiting for DNA synthesis. Because of the allosteric properties of ribonucleotide reductase, CDP reduction was not diminished, leading to a large expansion of the dCTP pool. The increase of this pool was kept in check by a shift in the balance of the deoxycytidine/dCMP cycle towards the deoxynucleoside, leading to massive excretion of deoxycytidine. In contrast, the balance of the deoxyuridine/dUMP cycle was shifted towards the nucleotide, facilitating import of extracellular deoxynucleosides.A network of biosynthetic and catabolic reactions regulates the size of deoxyribonucleoside triphosphate (dNTP) pools in mammalian cells so that the production of DNA precursors is adjusted to their utilization during DNA replication and repair. It has been appreciated for some time that the enzyme ribonucleotide reductase plays a pivotal role in this connection. It not only directs the total flow of metabolites into DNA, but also, via an exquisite allosteric control mechanism, divides the flow into four separate channels so that proper amounts of each dNTP are available for DNA synthesis (14, 18a, 21). More recently it has become apparent that catabolic reactions also control the size of dNTP pools. This first became apparent in connection with two inborn errors of metabolism arising from the lack of adenosine deaminase or purine nucleoside phosphorylase, enzymes catabolizing purine nucleosides (16). In both instances purine dNTPs accumulate and, via disturbances of the allosteric control of ribonucleotide reductase, interfere with the synthesis of DNA of lymphocytes, resulting in immunodeficiency syndromes.Catabolic reactions also contribute to the regulation of pyrimidine dNTP pools (2,3,18). Mouse 3T6 fibroblasts in tissue culture normally catabolize a fraction of pyrimidine dNTPs synthesized de novo to deoxynucleosides that are excreted into the medium. However, cells also use deoxynucleosides present in the medium for the synthesis of dNTPs. We proposed that the balance between import and export is set by the intracellular concentration of deoxynucleosides, which is regulated by substrate cycles. Such cycles operate via phosphorylation of deoxynucleosides by kinases and dephosphorylation of their 5'-phosphates by nucleotidases. The relative rates of these opposing reactions are influenced by both the rate of de novo synthesis of dNTPs and the rate of DNA synthesis. Inhibition of d...

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“…Both PMcH-U ((±)-1-trans-(2-phosphonomethoxycyclohexyl)uracil) and PMcP-U ((±)-1-trans-(2-phosphonomethoxycyclopentyl) uracil) inhibit cdN activity [92,153]. The physiological function of cdN may be involved in the regulation of pyrimidine (deoxy)nucleotide levels [148,154] as well as nucleotide recycling in dying cells [81,155].…”

Section: General Properties and Functions Of 5'ntsmentioning

confidence: 99%

5'-Nucleotidases, Nucleosides and their Distribution in the Brain: Pathological and Therapeutic Implications

Kovács

Dobolyi

Kékesi

et al. 2013

CMC

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Elements of the nucleoside system (nucleoside levels, 5'-nucleotidases (5'NTs) and other nucleoside metabolic enzymes, nucleoside transporters and nucleoside receptors) are unevenly distributed in the brain, suggesting that nucleosides have region-specific functions in the human brain. Indeed, adenosine (Ado) and non-Ado nucleosides, such as guanosine (Guo), inosine (Ino) and uridine (Urd), modulate both physiological and pathophysiological processes in the brain, such as sleep, pain, memory, depression, schizophrenia, epilepsy, Huntington's disease, Alzheimer's disease and Parkinson's disease. Interactions have been demonstrated in the nucleoside system between nucleoside levels and the activities of nucleoside metabolic enzymes, nucleoside transporters and Ado receptors in the human brain. Alterations in the nucleoside system may induce pathological changes, resulting in central nervous system (CNS) diseases. Moreover, several CNS diseases such as epilepsy may be treated by modulation of the nucleoside system, which is best achieved by modulating 5'NTs, as 5'NTs exhibit numerous functions in the CNS, including intracellular and extracellular formation of nucleosides, termination of nucleoside triphosphate signaling, cell adhesion, synaptogenesis and cell proliferation. Thus, modulation of 5'NT activity may be a promising new therapeutic tool for treating several CNS diseases. The present article describes the regionally different activities of the nucleoside system, demonstrates the associations between these activities and 5'NT activity and discusses the therapeutic implications of these associations.

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Regulation of nucleotidase activities in animal tissues

Cited by 44 publications

References 29 publications

The presence and activity in normal and regenerating rat liver postmicrosomal supernatant fraction of an enzyme with properties similar to those of membrane-bound 5′-nucleotidase

The presence and activity in normal and regenerating rat liver postmicrosomal supernatant fraction of an enzyme with properties similar to those of membrane-bound 5′-nucleotidase

Regulation of pyrimidine deoxyribonucleotide metabolism by substrate cycles in dCMP deaminase-deficient V79 hamster cells.

5'-Nucleotidases, Nucleosides and their Distribution in the Brain: Pathological and Therapeutic Implications

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Regulation of nucleotidase activities in animal tissues

Cited by 44 publications

References 29 publications

The presence and activity in normal and regenerating rat liver postmicrosomal supernatant fraction of an enzyme with properties similar to those of membrane-bound 5′-nucleotidase

The presence and activity in normal and regenerating rat liver postmicrosomal supernatant fraction of an enzyme with properties similar to those of membrane-bound 5′-nucleotidase

Regulation of pyrimidine deoxyribonucleotide metabolism by substrate cycles in dCMP deaminase-deficient V79 hamster cells.

5&#39;-Nucleotidases, Nucleosides and their Distribution in the Brain: Pathological and Therapeutic Implications

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5'-Nucleotidases, Nucleosides and their Distribution in the Brain: Pathological and Therapeutic Implications