NT5C

Last updated

NT5C
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases NT5C , DNT, DNT1, HEL74, P5N2, PN-I, PN-II, UMPH2, cdN, dNT-1, 5', 3'-nucleotidase, cytosolic
External IDs OMIM: 191720; MGI: 1354954; HomoloGene: 8745; GeneCards: NT5C; OMA:NT5C - orthologs
Orthologs
SpeciesHumanMouse
Entrez

30833

50773

Ensembl

ENSG00000125458

ENSMUSG00000020736

UniProt

Q8TCD5

Q9JM14

RefSeq (mRNA)

NM_001252377
NM_014595

NM_015807

RefSeq (protein)

NP_001239306
NP_055410

NP_056622

Location (UCSC) Chr 17: 75.13 – 75.13 Mb Chr 11: 115.38 – 115.38 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

5', 3'-nucleotidase, cytosolic, also known as 5'(3')-deoxyribonucleotidase, cytosolic type (cdN) or deoxy-5'-nucleotidase 1 (dNT-1), is an enzyme that in humans is encoded by the NT5C gene on chromosome 17. [5] [6] [7]

Contents

This gene encodes a nucleotidase that catalyzes the dephosphorylation of the 5' deoxyribonucleotides (dNTP) and 2'(3')-dNTP and ribonucleotides, but not 5' ribonucleotides. Of the different forms of nucleotidases characterized, this enzyme is unique in its preference for 5'-dNTP. It may be one of the enzymes involved in regulating the size of dNTP pools in cells. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Nov 2011] [6]

Structure

cdN is one of seven 5' nucleotidases identified in humans, all of which differ in tissue specificity, subcellular location, primary structure and substrate specificity. [8] [9] Of the seven, the mitochondrial counterpart of cdN, mdN, is the most closely related to cdN. Their genes, NT5M and NT5C, share the same exon/intron organization, and their amino acid sequences are 52% identical. [5] [8] [9] Both cdN and mdN share nearly identical catalytic phosphate binding sites with most members of the haloacid dehalogenase (HAD) superfamily. [9]

This enzyme forms a 45-kDa homodimer of two 22-kDa subunits composed of a core domain and cap domain. [9] [10] The core domain is an α/β Rossmann-like fold containing six antiparallel β-strands surrounded by α-helixes, and it spans residues 1-17 and 77-201 of the amino acid sequence. The cap domain is a 4-helix bundle spanning residues 18-76. The cleft formed by the core and cap domains acts as the enzyme's active site, where three conserved motifs in the core domain plus the cofactor Mg2+ serve as the substrate binding site. Meanwhile, the residues Phe18, Phe44, Leu45, and Tyr65 in the cap domain form an aromatic, hydrophobic pocket that coordinates with the base of the nucleotide substrate and, thus, influences the enzyme's substrate specificity. Its two main chain amides form hydrogen bonds with the 4-carbonyl group of dUMP and dTMP and with the 6-carbonyl group of dGMP and dIMP, while repelling the 4-amino group of dCMP and dAMP. The residue Asp43 is responsible for donating a proton to O5' of the nucleotide during catalysis. [9]

Function

This enzyme functions in dephosphorylating nucleoside triphosphates, especially the 5′- and 2′(3′)-phosphates of uracil and thymine, as well as inosine and guanine, dNTPs (dUMPs, dTMPs, dIMPs, and dGMPs, respectively). [5] [8] [9] [11] Due to this function, cdN regulates the size of dNTP pools in cells, in conjunction with the cytosolic thymidine kinases, as part of the dNTP substrate cycle. [9] [10] [11] [12]

The enzyme is ubiquitously expressed, though lymphoid cells display particularly high cdN activity. [12]

Clinical Significance

The protein cdN is essential to counteract accumulation of cellular dNTPs, as excess dNTPs have been linked to genetic disease. [10] In addition, this enzyme's dephosphorylation function could be applied to anticancer and antiviral treatments which use nucleoside analogs. These treatments rely on the kinase activation of the analogs, which then are incorporated into the DNA of the tumor cell or virus to act as DNA chain terminators. [12] [13] cdN can be used to maintain the concentrations of nucleoside analogs at low levels to avoid cytotoxicity. [12]

Moreover, cdN may affect the sensitivity of acute myeloid leukemia (AML) patients to treatment with ara-C. as low cdN mRNA levels in leukemic blasts have been correlated with a worse clinical outcome. [14]

Interactions

cdN binds and dephosphorylates deoxyribonucleotides such as uracil, thymine, inosine, and guanine. [9]

See also

Related Research Articles

<span class="mw-page-title-main">Phosphatase</span> Enzyme which catalyzes the removal of a phosphate group from a molecule

In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid monoester into a phosphate ion and an alcohol. Because a phosphatase enzyme catalyzes the hydrolysis of its substrate, it is a subcategory of hydrolases. Phosphatase enzymes are essential to many biological functions, because phosphorylation and dephosphorylation serve diverse roles in cellular regulation and signaling. Whereas phosphatases remove phosphate groups from molecules, kinases catalyze the transfer of phosphate groups to molecules from ATP. Together, kinases and phosphatases direct a form of post-translational modification that is essential to the cell's regulatory network.

A nucleoside triphosphate is a nucleoside containing a nitrogenous base bound to a 5-carbon sugar, with three phosphate groups bound to the sugar. They are the molecular precursors of both DNA and RNA, which are chains of nucleotides made through the processes of DNA replication and transcription. Nucleoside triphosphates also serve as a source of energy for cellular reactions and are involved in signalling pathways.

<span class="mw-page-title-main">Ribonucleotide reductase</span> Class of enzymes

Ribonucleotide reductase (RNR), also known as ribonucleoside diphosphate reductase, is an enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides. It catalyzes this formation by removing the 2'-hydroxyl group of the ribose ring of nucleoside diphosphates. This reduction produces deoxyribonucleotides. Deoxyribonucleotides in turn are used in the synthesis of DNA. The reaction catalyzed by RNR is strictly conserved in all living organisms. Furthermore, RNR plays a critical role in regulating the total rate of DNA synthesis so that DNA to cell mass is maintained at a constant ratio during cell division and DNA repair. A somewhat unusual feature of the RNR enzyme is that it catalyzes a reaction that proceeds via a free radical mechanism of action. The substrates for RNR are ADP, GDP, CDP and UDP. dTDP is synthesized by another enzyme from dTMP.

Glutathione <i>S</i>-transferase Family of enzymes

Glutathione S-transferases (GSTs), previously known as ligandins, are a family of eukaryotic and prokaryotic phase II metabolic isozymes best known for their ability to catalyze the conjugation of the reduced form of glutathione (GSH) to xenobiotic substrates for the purpose of detoxification. The GST family consists of three superfamilies: the cytosolic, mitochondrial, and microsomal—also known as MAPEG—proteins. Members of the GST superfamily are extremely diverse in amino acid sequence, and a large fraction of the sequences deposited in public databases are of unknown function. The Enzyme Function Initiative (EFI) is using GSTs as a model superfamily to identify new GST functions.

<span class="mw-page-title-main">5'-nucleotidase</span> InterPro Family

5′-Nucleotidase is an enzyme which catalyzes the phosphorylytic cleavage of 5′-nucleotides. Although originally found in snake venom, the activity of 5'nucleotidase has been described for bacteria and plant cells, and is widely distributed in vertebrate tissue. In mammalian cells the enzyme is predominantly located in the plasma membrane and its primary role is in the conversion of extracellular nucleotides, which are generally impermeable, to the corresponding nucleoside which can readily enter most cells. Consequently, the enzyme plays a key role in the metabolism of nucleotides.

A nucleotidase is a hydrolytic enzyme that catalyzes the hydrolysis of a nucleotide into a nucleoside and a phosphate.

<span class="mw-page-title-main">Dihydroorotate dehydrogenase</span> Class of enzymes

Dihydroorotate dehydrogenase (DHODH) is an enzyme that in humans is encoded by the DHODH gene on chromosome 16. The protein encoded by this gene catalyzes the fourth enzymatic step, the ubiquinone-mediated oxidation of dihydroorotate to orotate, in de novo pyrimidine biosynthesis. This protein is a mitochondrial protein located on the outer surface of the inner mitochondrial membrane (IMM). Inhibitors of this enzyme are used to treat autoimmune diseases such as rheumatoid arthritis.

<span class="mw-page-title-main">TYMP (gene)</span> Protein-coding gene in the species Homo sapiens

TYMP is a gene that encodes for the enzyme thymidine phosphorylase. The TYMP gene is also known as ECGF1 and MNGIE due to its role in MNGIE syndrome.

<span class="mw-page-title-main">HAGH</span> Protein-coding gene in the species Homo sapiens

Hydroxyacylglutathione hydrolase, mitochondrial is an enzyme that in humans is encoded by the HAGH gene.

<span class="mw-page-title-main">PCK1</span> Protein-coding gene in the species Homo sapiens

Phosphoenolpyruvate carboxykinase 1 (soluble), also known as PCK1, is an enzyme which in humans is encoded by the PCK1 gene.

<span class="mw-page-title-main">ME2 (gene)</span> Protein-coding gene in the species Homo sapiens

NAD-dependent malic enzyme, mitochondrial is a protein that in humans is encoded by the ME2 gene. This gene encodes a mitochondrial NAD-dependent malic enzyme, a homotetrameric protein, that catalyzes the oxidative decarboxylation of malate to pyruvate. It had previously been weakly linked to a syndrome known as Friedreich ataxia that has since been shown to be the result of mutation in a completely different gene.

<span class="mw-page-title-main">DGUOK</span> Protein-coding gene in the species Homo sapiens

Deoxyguanosine kinase, mitochondrial is an enzyme that in humans is encoded by the DGUOK gene.

<span class="mw-page-title-main">ME1 (gene)</span> Protein-coding gene in the species Homo sapiens

NADP-dependent malic enzyme is a protein that in humans is encoded by the ME1 gene.

<span class="mw-page-title-main">NT5C3</span> Protein-coding gene in the species Homo sapiens

Cytosolic 5'-nucleotidase 3 (NTC53), also known as cytosolic 5'-nucleotidase 3A, pyrimidine 5’-nucleotidase, and p56, is an enzyme that in humans is encoded by the NT5C3, or NT5C3A, gene on chromosome 7.

<span class="mw-page-title-main">FIS1</span> Protein-coding gene in the species Homo sapiens

Mitochondrial fission 1 protein (FIS1) is a protein that in humans is encoded by the FIS1 gene on chromosome 7. This protein is a component of a mitochondrial complex, the ARCosome, that promotes mitochondrial fission. Its role in mitochondrial fission thus implicates it in the regulation of mitochondrial morphology, the cell cycle, and apoptosis. By extension, the protein is involved in associated diseases, including neurodegenerative diseases and cancers.

<span class="mw-page-title-main">Folylpolyglutamate synthase</span> Mammalian protein found in Homo sapiens

Folylpolyglutamate synthase, mitochondrial is an enzyme that in humans is encoded by the FPGS gene.

<span class="mw-page-title-main">SUCLA2</span> Protein-coding gene in the species Homo sapiens

Succinyl-CoA ligase [ADP-forming] subunit beta, mitochondrial (SUCLA2), also known as ADP-forming succinyl-CoA synthetase (SCS-A), is an enzyme that in humans is encoded by the SUCLA2 gene on chromosome 13.

<span class="mw-page-title-main">MRPS22</span> Protein-coding gene in the species Homo sapiens

28S ribosomal protein S22, mitochondrial is a protein that in humans is encoded by the MRPS22 gene.

<span class="mw-page-title-main">Mitochondrial ribosomal protein L22</span> Protein-coding gene in the species Homo sapiens

39S ribosomal protein L22, mitochondrial is a protein that in humans is encoded by the MRPL22 gene.

<span class="mw-page-title-main">NT5M</span> Protein-coding gene in the species Homo sapiens

5',3'-nucleotidase, mitochondrial, also known as 5'(3')-deoxyribonucleotidase, mitochondrial (mdN) or deoxy-5'-nucleotidase 2 (dNT-2), is an enzyme that in humans is encoded by the NT5M gene. This gene encodes a 5' nucleotidase that localizes to the mitochondrial matrix. This enzyme dephosphorylates the 5'- and 2'(3')-phosphates of uracil and thymine deoxyribonucleotides. The gene is located within the Smith–Magenis syndrome region on chromosome 17.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000125458 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000020736 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 3 Rampazzo C, Gallinaro L, Milanesi E, Frigimelica E, Reichard P, Bianchi V (Aug 2000). "A deoxyribonucleotidase in mitochondria: involvement in regulation of dNTP pools and possible link to genetic disease". Proc Natl Acad Sci U S A. 97 (15): 8239–44. Bibcode:2000PNAS...97.8239R. doi: 10.1073/pnas.97.15.8239 . PMC   26931 . PMID   10899995.
  6. 1 2 "Entrez Gene: NT5C 5', 3'-nucleotidase, cytosolic".
  7. ↑ "UniProtKB: Q8TCD5 (NT5C_HUMAN)".
  8. 1 2 3 Rinaldo-Matthis A, Rampazzo C, Reichard P, Bianchi V, Nordlund P (October 2002). "Crystal structure of a human mitochondrial deoxyribonucleotidase". Nature Structural Biology. 9 (10): 779–87. doi:10.1038/nsb846. PMID   12352955. S2CID   29533643.
  9. 1 2 3 4 5 6 7 8 Walldén K, Rinaldo-Matthis A, Ruzzenente B, Rampazzo C, Bianchi V, Nordlund P (4 December 2007). "Crystal structures of human and murine deoxyribonucleotidases: insights into recognition of substrates and nucleotide analogues". Biochemistry. 46 (48): 13809–18. doi:10.1021/bi7014794. PMID   17985935.
  10. 1 2 3 Höglund L, Reichard P (25 April 1990). "Cytoplasmic 5'(3')-nucleotidase from human placenta". The Journal of Biological Chemistry. 265 (12): 6589–95. doi: 10.1016/S0021-9258(19)39188-4 . PMID   2157703.
  11. 1 2 Gallinaro L, Crovatto K, Rampazzo C, Pontarin G, Ferraro P, Milanesi E, Reichard P, Bianchi V (20 September 2002). "Human mitochondrial 5'-deoxyribonucleotidase. Overproduction in cultured cells and functional aspects". The Journal of Biological Chemistry. 277 (38): 35080–7. doi: 10.1074/jbc.m203755200 . PMID   12124385.
  12. 1 2 3 4 Rampazzo C, Johansson M, Gallinaro L, Ferraro P, Hellman U, Karlsson A, Reichard P, Bianchi V (25 February 2000). "Mammalian 5'(3')-deoxyribonucleotidase, cDNA cloning, and overexpression of the enzyme in Escherichia coli and mammalian cells". The Journal of Biological Chemistry. 275 (8): 5409–15. doi: 10.1074/jbc.275.8.5409 . PMID   10681516.
  13. ↑ Walldén K, Ruzzenente B, Rinaldo-Matthis A, Bianchi V, Nordlund P (July 2005). "Structural basis for substrate specificity of the human mitochondrial deoxyribonucleotidase". Structure. 13 (7): 1081–8. doi: 10.1016/j.str.2005.04.023 . PMID   16004879.
  14. ↑ Galmarini CM, Cros E, Graham K, Thomas X, Mackey JR, Dumontet C (May 2004). "5'-(3')-nucleotidase mRNA levels in blast cells are a prognostic factor in acute myeloid leukemia patients treated with cytarabine". Haematologica. 89 (5): 617–9. PMID   15136231.

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