NT5C
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesNT5C, DNT, DNT1, HEL74, P5N2, PN-I, PN-II, UMPH2, cdN, dNT-1, 5', 3'-nucleotidase, cytosolic
External IDsOMIM: 191720 MGI: 1354954 HomoloGene: 8745 GeneCards: NT5C
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 MbChr 11: 115.38 – 115.38 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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]

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

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.

Further reading

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