NT5C3

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NT5C3A
Protein NT5C3 PDB 2bdu.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases NT5C3A, NT5C3, P5'N-1, P5N-1, PN-I, POMP, PSN1, UMPH, UMPH1, cN-III, hUMP1, p36, 5'-nucleotidase, cytosolic IIIA
External IDs MGI: 1927186 HomoloGene: 9534 GeneCards: NT5C3A
EC number 3.1.3.91
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001002009
NM_001002010
NM_001166118
NM_016489

NM_001252374
NM_026004

RefSeq (protein)

NP_001002009
NP_001002010
NP_001159590
NP_057573

NP_001239303.1
NP_080280.3
NP_001239303
NP_080280

Location (UCSC) Chr 7: 33.01 – 33.06 Mb Chr 6: 56.88 – 56.92 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse

Cytosolic 5'-nucleotidase 3 (NTC53), also known as cytosolic 5'-nucleotidase 3A, pyrimidine 5’-nucleotidase (PN-I or P5'NI), and p56, is an enzyme that in humans is encoded by the NT5C3, or NT5C3A, gene on chromosome 7.[3][4][5][6]

This gene encodes a member of the 5'-nucleotidase family of enzymes that catalyze the dephosphorylation of nucleoside 5'-monophosphates. The encoded protein is the type 1 isozyme of pyrimidine 5' nucleotidase and catalyzes the dephosphorylation of pyrimidine 5' monophosphates. Mutations in this gene are a cause of hemolytic anemia due to uridine 5-prime monophosphate hydrolase deficiency. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and pseudogenes of this gene are located on the long arm of chromosomes 3 and 4. [provided by RefSeq, Mar 2012][5]

Structure[edit]

The NT5C3 gene consists of 10 exons and can be alternatively spliced at exon 2.[7] Four possible isoforms have been identified, encoding proteins with lengths of 336 residues, 297 residues, 286 residues, and 285 residues.[7][8] The 286-residue long isozyme is a monomeric protein containing 5 cysteine residues and no disulfide bridges or phosphate content.[6][7] It has a predicted mass of 32.7 kDa and a predicted globular tertiary structure consisting of approximately 30% α-helices and 26% extended strands.[7] This enzyme structurally resembles members of the haloacid dehalogenase (HAD) superfamily in regards to the shared α/β-Rossmann-like domain and a smaller 4-helix bundle domain. Three motifs in the α/β-Rossmann-like domain form the catalytic phosphate-binding site. Motif I is responsible for the 5′-nucleotidase activity: the first Asp makes a nucleophilic attack on the phosphate of the nucleoside monophosphate substrate, while the second Asp donates a proton to the leaving nucleoside. The active site is located in a cleft between the α/β-Rossmann-like domain and 4-helix bundle domain.[9]

Function[edit]

NT5C3 is a member of the 5'-nucleotidase family and one of the five cytosolic members identified in humans.[8] NTC53 catalyzes the dephosphorylation of the pyrimidine 5′ monophosphates UMP and CMP to the corresponding nucleosides.[6][7] This function contributes to RNA degradation during the erythrocyte maturation process.[4][6][8] As a result, NT5C3 regulates both the endogenous nucleoside and nucleotide pool balance, as well as that of pyrimidine analogs such as gemcitabine and AraC.[8]

NT5C3 was first discovered in red blood cells, but its expression has been observed in multiple tumors (lung, ovary, colon, bladder), fetal tissues (lung, heart, spleen, liver), adult testis, and the brain.[4][7] In particular, the 297-residue isoform of this enzyme is highly expressed in lymphoblastoid cells.[8]

Clinical Significance[edit]

The loss of NT5C3 in pyrimidine 5' nucleotidase deficiency, an autosomal recessive condition, leads to the accumulation of high concentrations of pyrimidine nucleotides within erythrocytes.[4][6][7] This deficiency is characterized by moderate hemolytic anemia, jaundice, splenomegaly, and marked basophilic stippling, and has been associated with learning difficulties.[4][7] Two homozygous mutations identified in this gene produced large deletions that could cripple the enzyme’s structure and function, and are thus causally linked to pyrimidine 5' nucleotidase deficiency and hemolytic anemia. Heterozygous mutations in pyrimidine 5' nucleotidase deficiency may contribute to the large variability in thalassemia phenotypes.[7] Pyrimidine 5' nucleotidase deficiency is also linked to the conversion of hemoglobin E disease into an unstable hemoglobinopathy-like disease.[4][7] NT5C3 is identical to p36, a previously identified alpha-interferon-induced protein involved in forming lupus inclusions.[4][6] Since NT5C3 can metabolize AraC, a nucleoside analog used in chemotherapy for acute myeloid leukemia patients, genotyping one of its polymorphisms may aid detection of patients who will respond favorably to this therapy.[10]

Interactions[edit]

NTC53 is known to interact with pyrimidine nucleoside monophosphates, specifically UMP and CMP, as well as the anineoplastic agents 5’-AZTMP and 5’-Ara-CMP.[6]

References[edit]

  1. ^ "Human PubMed Reference:". 
  2. ^ "Mouse PubMed Reference:". 
  3. ^ Zhang QH, Ye M, Wu XY, Ren SX, Zhao M, Zhao CJ, Fu G, Shen Y, Fan HY, Lu G, Zhong M, Xu XR, Han ZG, Zhang JW, Tao J, Huang QH, Zhou J, Hu GX, Gu J, Chen SJ, Chen Z (Nov 2000). "Cloning and Functional Analysis of cDNAs with Open Reading Frames for 300 Previously Undefined Genes Expressed in CD34+ Hematopoietic Stem/Progenitor Cells". Genome Res. 10 (10): 1546–60. doi:10.1101/gr.140200. PMC 310934Freely accessible. PMID 11042152. 
  4. ^ a b c d e f g Amici A, Emanuelli M, Raffaelli N, Ruggieri S, Saccucci F, Magni G (Sep 2000). "Human erythrocyte pyrimidine 5-nucleotidase, PN-I, is identical to p36, a protein associated to lupus inclusion formation in response to alpha-interferon". Blood. 96 (4): 1596–8. PMID 10942414. 
  5. ^ a b "Entrez Gene: NT5C3 5'-nucleotidase, cytosolic III". 
  6. ^ a b c d e f g Amici, A; Magni, G (15 January 2002). "Human erythrocyte pyrimidine 5'-nucleotidase, PN-I.". Archives of Biochemistry and Biophysics. 397 (2): 184–90. doi:10.1006/abbi.2001.2676. PMID 11795870. 
  7. ^ a b c d e f g h i j Marinaki, AM; Escuredo, E; Duley, JA; Simmonds, HA; Amici, A; Naponelli, V; Magni, G; Seip, M; Ben-Bassat, I; Harley, EH; Thein, SL; Rees, DC (1 June 2001). "Genetic basis of hemolytic anemia caused by pyrimidine 5' nucleotidase deficiency.". Blood. 97 (11): 3327–32. doi:10.1182/blood.v97.11.3327. PMID 11369620. 
  8. ^ a b c d e Aksoy, P; Zhu, MJ; Kalari, KR; Moon, I; Pelleymounter, LL; Eckloff, BW; Wieben, ED; Yee, VC; Weinshilboum, RM; Wang, L (August 2009). "Cytosolic 5'-nucleotidase III (NT5C3): gene sequence variation and functional genomics.". Pharmacogenetics and genomics. 19 (8): 567–76. doi:10.1097/fpc.0b013e32832c14b8. PMID 19623099. 
  9. ^ Walldén, K; Stenmark, P; Nyman, T; Flodin, S; Gräslund, S; Loppnau, P; Bianchi, V; Nordlund, P (15 June 2007). "Crystal structure of human cytosolic 5'-nucleotidase II: insights into allosteric regulation and substrate recognition.". The Journal of Biological Chemistry. 282 (24): 17828–36. doi:10.1074/jbc.m700917200. PMID 17405878. 
  10. ^ Cheong, HS; Koh, Y; Ahn, KS; Lee, C; Shin, HD; Yoon, SS (September 2014). "NT5C3 polymorphisms and outcome of first induction chemotherapy in acute myeloid leukemia.". Pharmacogenetics and genomics. 24 (9): 436–41. doi:10.1097/fpc.0000000000000072. PMID 25000516. 

Further reading[edit]