5′-Nucleotidases and their new roles in NAD+ and phosphate metabolism

Abstract

5 0 -Nucleotidase (EC 3.1.3.5) designates a set of enzymes, which catalyze the hydrolysis of ribonucleoside and deoxyribonucleoside monophosphates into the corresponding nucleosides plus orthophosphate. 5 0 -Nucleotidases are classified according to subcellular localization, nucleobase specificity and their ability to hydrolyze deoxynucleoside monophosphate substrates. Membrane-bound 5 0 -nucleotidases are ectoenzymes principally involved in salvage of extracellular nucleosides, and often display a preference toward adenosine monophosphate, thereby modulating signal transduction cascades involving purinergic receptors. Cytosolic 5 0 -nucleotidases are members of the haloacid dehalogenase superfamily of enzymes, which are two-domain proteins containing a modified Rossman fold as the core and a variable cap structure. Extracellular and intracellular 5 0 -nucleotidase activities participate in purine and pyrimidine salvage to support balanced synthesis of nucleotides, which is critical for maintaining high fidelity DNA replication. While the production of ribonucleosides from ribonucleotides by 5 0 -nucleotidases remains the most well studied function, it appears that the physiological functions of these activities are more broad. Indeed, Sdt1, previously termed a pyrimidine-specific 5 0 -nucleotidase, and Isn1, previously termed an inosine monophosphate (IMP)-specific 5 0 -nucleotidase, have recently been implicated in catabolic processes in nicotinamide adenine dinucleotide (NAD + ) metabolism, and are regulated by the NAD + precursor vitamin nicotinic acid, glucose and phosphate availability in the medium. In addition, Usha, Pho5, Sdt1 and Phm8 are phosphate starvation-induced 5 0 -nucleotidases with diverse substrate specificities that liberate phosphate under phosphate starvation conditions. Here we review 5 0 -nucleotidase enzyme structure, catalytic mechanism and substrate specificity and focus on new biological roles for these enzymes in nucleotide, NAD + and phosphate metabolism. 5 0 -Nucleotidases are regulators of nucleotide and nucleobase metabolism 5 0 -Nucleotidase was first reported to dephosphorylate AMP and IMP in heart and skeletal muscle. 1 Since this discovery, similar enzymes have been described in diverse species, tissues

A Systems Oncology Approach Identifies NT5E as a Key Metabolic Regulator in Tumor Cells and Modulator of Platinum Sensitivity

“…58 It is also possible that NT5E could regulate the availability of nucleotide triphosphates required for DNA synthesis and repair processes. 59 Our gene set enrichment analysis also shows correlation between NT5E expression and processes related to mRNA and DNA metabolism, processing, and replication. However, the exact mechanism that leads to the effect we observe is still to be elucidated.…”

Identification and characterization of a gene encoding for a nucleotidase from Phaseolus vulgaris

“…In this group are found enzymes such as hydrolases, phosphatases, nucleotidases and several phosphotransferases (Bogan and Brenner, 2010). All of them contain a nucleophilic aspartate in the phosphate transfer reaction.…”

“…The relative activity of phosphorylation versus dephosphorylation could be the responsible of the balance between synthesis and degradation (Bogan and Brenner, 2010). It has been postulated that 5´-nucleotidase activities are regulated according to the nucleotide-nucleoside ratio of the cells (Bogan and Brenner, 2010). Despite the recent progress in genes and enzymes involved in the synthesis of ureides, the phosphatase activity that catalyses the dephosphorilation of nucleotides in the degradation pathway of nucleotides has not been yet identified.…”

“…Nucleoside kinases catalyse the reverse reactions to 5´-nucleotidases, and these opposite reactions exist for almost all the nucleoside-nucleotide pairs (Bogan and Brenner, 2010). The relative activity of phosphorylation versus dephosphorylation could be the responsible of the balance between synthesis and degradation (Bogan and Brenner, 2010).…”

Genome Sequence of Lactobacillus fermentum Strain NCC2970 (CNCM I-5068)

“…Compared to other L. fermentum genomes, it harbors a more complete shikimate pathway with a 3-dehydroquinate dehydratase (EC 4.2.1.10; CDS0787) and a shikimate dehydrogenase (EC 1.1.1.25; CDS0788), which are, respectively, the third and the fourth enzymes of this pathway, enabling the conversion of quinic acid to shikimic acid. It harbors also a 5′-nucleotidase (EC 3.1.3.5; CDS0645), which in C. glutamicum is required for growth when nucleotides are provided as the sole source of phosphate (11), as well as a phosphopentomutase (EC 5.4.2.7; CDS0031), which has been shown in Bacillus cereus to be necessary to isomerize ribose-1P in ribose-5P, thus enabling it to enter the pentose phosphate pathway (12). …”