NT5M

NT5M
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1MH9, 1Q91, 1Q92, 1Z4I, 1Z4J, 1Z4K, 1Z4L, 1Z4M, 1Z4P, 1Z4Q, 2JAU, 2JAW, 4L6A, 4L6C, 4MUM, 4MWO, 4NFL, 4YIK
Identifiers
Aliases	NT5M , dNT-2, dNT2, mdN, 5',3'-nucleotidase, mitochondrial
External IDs	OMIM: 605292 MGI: 1917127 HomoloGene: 10622 GeneCards: NT5M
Gene location (Human) Chr. Chromosome 17 (human) [1] Band 17p11.2 Start 17,303,335 bp [1] End 17,347,663 bp [1]
Gene location (Mouse) Chr. Chromosome 11 (mouse) [2] Band 11|11 B1.3 Start 59,730,273 bp [2] End 59,771,794 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in monocyte gastrocnemius muscle prefrontal cortex Brodmann area 9 left ventricle amygdala nucleus accumbens caudate nucleus putamen anterior pituitary Top expressed in spermatocyte interventricular septum seminiferous tubule spermatid facial motor nucleus visual cortex lateral geniculate nucleus cerebellar cortex superior frontal gyrus medial dorsal nucleus More reference expression data BioGPS n/a
Gene ontology Molecular function nucleotide binding nucleotidase activity 5'-nucleotidase activity hydrolase activity metal ion binding Cellular component mitochondrial matrix mitochondrion Biological process pyrimidine deoxyribonucleotide catabolic process DNA replication dUMP catabolic process deoxyribonucleotide catabolic process nucleotide metabolic process pyrimidine nucleoside catabolic process dephosphorylation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 56953 103850 Ensembl ENSG00000205309 ENSMUSG00000032615 UniProt Q9NPB1 Q8VCE6 RefSeq (mRNA) NM_020201 NM_134029 RefSeq (protein) NP_064586 NP_598790 Location (UCSC) Chr 17: 17.3 – 17.35 Mb Chr 11: 59.73 – 59.77 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. ^{[5] [6]}

Structure

The cDNA of mdN encodes a 25.9-kDa polypeptide, and the crystal structure of this enzymes reveals a 196-long amino acid sequence in the mature protein. ^{[7] [8]} The first 32 amino acids, which contain the mitochondrial targeting sequence, are removed during the processing of the premature protein for its import into the mitochondrial matrix. The enzyme is likely a dimer protein formed by the interaction of alpha and beta loops between the cores of the two monomers. Each monomer is composed of a large and small domain connected by two loops. The large domain forms an alpha/beta Rossmann fold as well as 2 helix loops in the fold, whereas the small domain forms a truncated four-helix bundle which is inserted between a beta strand and alpha-helix in the large domain. The active site is found in a cleft between the two domains and binds a magnesium ion that is coordinated by three exogenous ligands, a phosphate ion, and two water molecules in an octahedral shape. ^[8]

mdN 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 cytosolic counterpart of mdN, cdN, is the most closely related to mdN. Their genes, NT5M and NT5C, share the same exon/intron organization, and their amino acid sequences are 52% identical. ^{[7] [8]} In addition, mdN structurally resembles members of the HAD family despite no significant sequence similarity. ^[8]

Function

This enzyme functions in dephosphorylating nucleoside triphosphates, especially the 5′- and 2′(3′)-phosphates of uracil and thymine deoxyribonucleotides (dUMPs and dTMPs). ^{[7] [8] [10]} Due to this function, mdN regulates the size of pyrimidine deoxyribonucleotide pools within mitochondria, in conjunction with the mitochondrial thymidine kinase, as part of the thymidine (dTTP)/dTMP substrate cycle. Since excess dTTP leads to aberrant mitochondrial DNA replication, the regulatory role of mdN serves to maintain dTTP levels to ensure proper mitochondrial DNA replication. ^{[9] [10]}

Similar to other mitochondrial enzymes, mdN mRNA is found in heart, brain, and muscle, and to a lesser degree in kidney and pancreas, while it is absent from placenta, liver, and lung. ^[7] Though the enzyme is ubiquitous, mdN activity has only been detected in brain and heart tissue. ^{[7] [8]}

Clinical significance

Since the NT5M gene is located in the Smith–Magenis syndrome region of chromosome 17, mutations in this gene could contribute to the disease. Moreover, its location may indicate that the disease involves a mitochondrial component. ^[7] The protein mdN is essential to counteract dTTP accumulation, as excess dTTP has been linked to mitochondrial genetic disease. ^[10] In addition, this enzyme's dephosphorylation function could be applied to anticancer and antiviral treatments which use nucleoside analogs. ^{[8] [9]} 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. ^[9] mdN can be used to maintain the concentrations of nucleoside analogs at low levels to avoid mitochondrial toxicity. Thus, only analogs whose 5' phosphates are rapidly and specifically degraded by mdN should be used. ^{[8] [9]}

Interactions

mdN binds and dephosphorylates uracil and thymine deoxyribonucleotides. ^{[7] [8]}

See also

• NT5C

References

1. GRCh38: Ensembl release 89: ENSG00000205309 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000032615 - 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. "UniProtKB: Q9NPB1 (NT5M_HUMAN)".
6. "Entrez Gene: NT5M 5',3'-nucleotidase, mitochondrial".
7. Rampazzo C, Gallinaro L, Milanesi E, Frigimelica E, Reichard P, Bianchi V (Jul 2000). "A deoxyribonucleotidase in mitochondria: involvement in regulation of dNTP pools and possible link to genetic disease". Proceedings of the National Academy of Sciences of the United States of America. 97 (15): 8239–44. Bibcode:2000PNAS...97.8239R. doi: 10.1073/pnas.97.15.8239 . PMC   26931 . PMID   10899995.
8. Rinaldo-Matthis A, Rampazzo C, Reichard P, Bianchi V, Nordlund P (Oct 2002). "Crystal structure of a human mitochondrial deoxyribonucleotidase". Nature Structural Biology. 9 (10): 779–87. doi:10.1038/nsb846. PMID   12352955. S2CID   29533643.
9. Walldén K, Ruzzenente B, Rinaldo-Matthis A, Bianchi V, Nordlund P (Jul 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.
10. Gallinaro L, Crovatto K, Rampazzo C, Pontarin G, Ferraro P, Milanesi E, Reichard P, Bianchi V (Sep 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.