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{{Infobox_gene}}
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'''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.<ref name="pmid11042152">{{cite journal |vauthors=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 | title = Cloning and Functional Analysis of cDNAs with Open Reading Frames for 300 Previously Undefined Genes Expressed in CD34+ Hematopoietic Stem/Progenitor Cells | journal = Genome Res | volume = 10 | issue = 10 | pages = 1546–60 |date=Nov 2000 | pmid = 11042152 | pmc = 310934 | doi =10.1101/gr.140200  }}</ref><ref name="pmid10942414">{{cite journal |vauthors=Amici A, Emanuelli M, Raffaelli N, Ruggieri S, Saccucci F, Magni G | title = Human erythrocyte pyrimidine 5-nucleotidase, PN-I, is identical to p36, a protein associated to lupus inclusion formation in response to alpha-interferon | journal = Blood | volume = 96 | issue = 4 | pages = 1596–8 |date=Sep 2000 | pmid = 10942414 | pmc =  | doi =  }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: NT5C3 5'-nucleotidase, cytosolic III| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=51251| accessdate = }}</ref><ref name=pmid11795870>{{cite journal|last1=Amici|first1=A|last2=Magni|first2=G|title=Human erythrocyte pyrimidine 5'-nucleotidase, PN-I.|journal=Archives of Biochemistry and Biophysics|date=15 January 2002|volume=397|issue=2|pages=184–90|pmid=11795870|doi=10.1006/abbi.2001.2676}}</ref>
{{GNF_Protein_box
  | image = PBB_Protein_NT5C3_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 2bdu.
| PDB = {{PDB2|2bdu}}, {{PDB2|2cn1}}, {{PDB2|2g06}}, {{PDB2|2g07}}, {{PDB2|2g08}}, {{PDB2|2g09}}, {{PDB2|2g0a}}, {{PDB2|2jga}}
| Name = 5'-nucleotidase, cytosolic III
| HGNCid = 17820
| Symbol = NT5C3
| AltSymbols =; PN-I; MGC27337; MGC87109; MGC87828; P5'N-1; PSN1; UMPH; UMPH1; cN-III
| OMIM = 606224
| ECnumber =
| Homologene = 9534
| MGIid = 1927186
| Function = {{GNF_GO|id=GO:0000166 |text = nucleotide binding}} {{GNF_GO|id=GO:0000287 |text = magnesium ion binding}} {{GNF_GO|id=GO:0008253 |text = 5'-nucleotidase activity}} {{GNF_GO|id=GO:0008665 |text = 2'-phosphotransferase activity}} {{GNF_GO|id=GO:0016787 |text = hydrolase activity}}
| Component = {{GNF_GO|id=GO:0005737 |text = cytoplasm}} {{GNF_GO|id=GO:0005783 |text = endoplasmic reticulum}}
  | Process = {{GNF_GO|id=GO:0006213 |text = pyrimidine nucleoside metabolic process}} {{GNF_GO|id=GO:0009117 |text = nucleotide metabolic process}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 51251
    | Hs_Ensembl = ENSG00000122643
    | Hs_RefseqProtein = NP_001002009
    | Hs_RefseqmRNA = NM_001002009
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 7
    | Hs_GenLoc_start = 33020267
    | Hs_GenLoc_end = 33068934
    | Hs_Uniprot = Q9H0P0
    | Mm_EntrezGene = 107569
    | Mm_Ensembl = ENSMUSG00000029780
    | Mm_RefseqmRNA = NM_026004
    | Mm_RefseqProtein = NP_080280
    | Mm_GenLoc_db =   
    | Mm_GenLoc_chr = 6
    | Mm_GenLoc_start = 56811982
    | Mm_GenLoc_end = 56853407
    | Mm_Uniprot = Q9D020
  }}
}}
'''5'-nucleotidase, cytosolic III''', also known as '''NT5C3''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: NT5C3 5'-nucleotidase, cytosolic III| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=51251| accessdate = }}</ref>


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{{PBB_Summary
{{PBB Summary
| section_title =  
| section_title =  
| summary_text = Pyrimidine 5-prime-nucleotidase (P5N; EC 3.1.3.5), also called uridine 5-prime monophosphate hydrolase (UMPH), catalyzes the dephosphorylation of the pyrimidine 5-prime monophosphates UMP and CMP to the corresponding nucleosides. There are 2 isozymes of pyrimidine 5-prime nucleotidase in red blood cells, referred to as type I (UMPH1) and type II (UMPH2; MIM 191720). The 2 enzymes are not separable by electrophoresis in humans but have distinct kinetic properties, and the proteins show no homology.[supplied by OMIM]<ref name="entrez">{{cite web | title = Entrez Gene: NT5C3 5'-nucleotidase, cytosolic III| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=51251| accessdate = }}</ref>
| summary_text = This gene encodes a member of the 5'-[[nucleotidase]] family of enzymes that [[catalyze]] the de[[phosphorylation]] 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 [[isoform]]s have been observed for this gene, and [[pseudogene]]s of this gene are located on the long arm of chromosomes 3 and 4. [provided by RefSeq, Mar 2012]<ref name="entrez" />
}}
}}
==Structure==
The ''NT5C3'' gene consists of 10 [[exon]]s and can be alternatively spliced at exon 2.<ref name=pmid11369620>{{cite journal|last1=Marinaki|first1=AM|last2=Escuredo|first2=E|last3=Duley|first3=JA|last4=Simmonds|first4=HA|last5=Amici|first5=A|last6=Naponelli|first6=V|last7=Magni|first7=G|last8=Seip|first8=M|last9=Ben-Bassat|first9=I|last10=Harley|first10=EH|last11=Thein|first11=SL|last12=Rees|first12=DC|title=Genetic basis of hemolytic anemia caused by pyrimidine 5' nucleotidase deficiency.|journal=Blood|date=1 June 2001|volume=97|issue=11|pages=3327–32|pmid=11369620|doi=10.1182/blood.v97.11.3327}}</ref> Four possible isoforms have been identified, encoding proteins with lengths of 336 [[amino acid|residues]], 297 residues, 286 residues, and 285 residues.<ref name=pmid11369620/><ref name=pmid19623099>{{cite journal|last1=Aksoy|first1=P|last2=Zhu|first2=MJ|last3=Kalari|first3=KR|last4=Moon|first4=I|last5=Pelleymounter|first5=LL|last6=Eckloff|first6=BW|last7=Wieben|first7=ED|last8=Yee|first8=VC|last9=Weinshilboum|first9=RM|last10=Wang|first10=L|title=Cytosolic 5'-nucleotidase III (NT5C3): gene sequence variation and functional genomics.|journal=Pharmacogenetics and genomics|date=August 2009|volume=19|issue=8|pages=567–76|pmid=19623099|doi=10.1097/fpc.0b013e32832c14b8|pmc=2763634}}</ref> The 286-residue long isozyme is a [[monomeric]] protein containing 5 [[cysteine]] residues and no [[disulfide bridge]]s or phosphate content.<ref name=pmid11795870/><ref name=pmid11369620/> 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.<ref name=pmid11369620/> This enzyme structurally resembles members of the haloacid [[dehalogenase]] (HAD) superfamily in regards to the shared α/β-[[Rossman fold|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 [[Aspartic acid|Asp]] makes a [[nucleophilic attack]] on the phosphate of the nucleoside monophosphate [[substrate (biochemistry)|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.<ref name=pmid17405878>{{cite journal|last1=Walldén|first1=K|last2=Stenmark|first2=P|last3=Nyman|first3=T|last4=Flodin|first4=S|last5=Gräslund|first5=S|last6=Loppnau|first6=P|last7=Bianchi|first7=V|last8=Nordlund|first8=P|title=Crystal structure of human cytosolic 5'-nucleotidase II: insights into allosteric regulation and substrate recognition.|journal=The Journal of Biological Chemistry|date=15 June 2007|volume=282|issue=24|pages=17828–36|pmid=17405878|doi=10.1074/jbc.m700917200}}</ref>
==Function==
NT5C3 is a member of the 5'-nucleotidase family and one of the five cytosolic members identified in humans.<ref name=pmid19623099/> NTC53 catalyzes the dephosphorylation of the pyrimidine 5′ monophosphates [[Uridine monophosphate|UMP]] and [[Cytidine monophosphate|CMP]] to the corresponding nucleosides.<ref name=pmid11795870/><ref name=pmid11369620/> This function contributes to [[RNA]] degradation during the [[erythrocyte]] maturation process.<ref name=pmid10942414/><ref name=pmid11795870/><ref name=pmid19623099/> As a result, NT5C3 regulates both the [[endogenous]] nucleoside and nucleotide pool balance, as well as that of pyrimidine analogs such as [[gemcitabine]] and [[Cytarabine|AraC]].<ref name=pmid19623099/>
NT5C3 was first discovered in [[red blood cell]]s, but its expression has been observed in multiple tumors ([[lung]], [[ovary]], [[Large intestine|colon]], [[bladder]]), [[fetal]] tissues (lung, [[heart]], [[spleen]], [[liver]]), adult [[testis]], and the [[brain]].<ref name=pmid10942414/><ref name=pmid11369620/> In particular, the 297-residue isoform of this enzyme is highly expressed in lymphoblastoid cells.<ref name=pmid19623099/>
==Clinical Significance==
The loss of NT5C3 in pyrimidine 5' nucleotidase deficiency, an [[autosomal]] [[recessive]] condition, leads to the accumulation of high concentrations of pyrimidine nucleotides within [[erythrocyte]]s.<ref name=pmid10942414/><ref name=pmid11795870/><ref name=pmid11369620/> This deficiency is characterized by moderate hemolytic anemia, [[jaundice]], [[splenomegaly]], and marked [[basophilic stippling]], and has been associated with learning difficulties.<ref name=pmid10942414/><ref name=pmid11369620/> Two [[homozygous]] mutations identified in this gene produced large deletions that could cripple the enzyme’s structure and function, and are thus [[causal]]ly 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.<ref name=pmid11369620/> Pyrimidine 5' nucleotidase deficiency is also linked to the conversion of hemoglobin E disease into an unstable hemoglobinopathy-like disease.<ref name=pmid10942414/><ref name=pmid11369620/> NT5C3 is identical to p36, a previously identified alpha-interferon-induced protein involved in forming [[lupus]] [[inclusion bodies|inclusions]].<ref name=pmid10942414/><ref name=pmid11795870/> 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.<ref name=pmid25000516>{{cite journal|last1=Cheong|first1=HS|last2=Koh|first2=Y|last3=Ahn|first3=KS|last4=Lee|first4=C|last5=Shin|first5=HD|last6=Yoon|first6=SS|title=NT5C3 polymorphisms and outcome of first induction chemotherapy in acute myeloid leukemia.|journal=Pharmacogenetics and genomics|date=September 2014|volume=24|issue=9|pages=436–41|pmid=25000516|doi=10.1097/fpc.0000000000000072}}</ref>
==Interactions==
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.<ref name=pmid11795870/>


==References==
==References==
{{reflist|2}}
{{reflist}}
 
==Further reading==
==Further reading==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading  
{{PBB_Further_reading  
| citations =  
| citations =  
*{{cite journal | author=Amici A, Emanuelli M, Ferretti E, ''et al.'' |title=Homogeneous pyrimidine nucleotidase from human erythrocytes: enzymic and molecular properties. |journal=Biochem. J. |volume=304 ( Pt 3) |issue=  |pages= 987-92 |year= 1995 |pmid= 7818506 |doi=  }}
*{{cite journal   |vauthors=Amici A, Emanuelli M, Ferretti E, etal |title=Homogeneous pyrimidine nucleotidase from human erythrocytes: enzymic and molecular properties |journal=Biochem. J. |volume=304 |issue=  Pt 3|pages= 987–92 |year= 1995 |pmid= 7818506 |doi= 10.1042/bj3040987| pmc=1137429 }}
*{{cite journal  | author=Rich SA, Bose M, Tempst P, Rudofsky UH |title=Purification, microsequencing, and immunolocalization of p36, a new interferon-alpha-induced protein that is associated with human lupus inclusions. |journal=J. Biol. Chem. |volume=271 |issue= 2 |pages= 1118-26 |year= 1996 |pmid= 8557639 |doi=  }}
*{{cite journal  |vauthors=Rich SA, Bose M, Tempst P, Rudofsky UH |title=Purification, microsequencing, and immunolocalization of p36, a new interferon-alpha-induced protein that is associated with human lupus inclusions |journal=J. Biol. Chem. |volume=271 |issue= 2 |pages= 1118–26 |year= 1996 |pmid= 8557639 |doi=10.1074/jbc.271.2.1118 }}
*{{cite journal | author=Hillier LD, Lennon G, Becker M, ''et al.'' |title=Generation and analysis of 280,000 human expressed sequence tags. |journal=Genome Res. |volume=6 |issue= 9 |pages= 807-28 |year= 1997 |pmid= 8889549 |doi=  }}
*{{cite journal   |vauthors=Hillier LD, Lennon G, Becker M, etal |title=Generation and analysis of 280,000 human expressed sequence tags |journal=Genome Res. |volume=6 |issue= 9 |pages= 807–28 |year= 1997 |pmid= 8889549 |doi=10.1101/gr.6.9.807 }}
*{{cite journal | author=Amici A, Emanuelli M, Magni G, ''et al.'' |title=Pyrimidine nucleotidases from human erythrocyte possess phosphotransferase activities specific for pyrimidine nucleotides. |journal=FEBS Lett. |volume=419 |issue= 2-3 |pages= 263-7 |year= 1998 |pmid= 9428647 |doi= }}
*{{cite journal   |vauthors=Amici A, Emanuelli M, Magni G, etal |title=Pyrimidine nucleotidases from human erythrocyte possess phosphotransferase activities specific for pyrimidine nucleotides |journal=FEBS Lett. |volume=419 |issue= 2–3 |pages= 263–7 |year= 1998 |pmid= 9428647 |doi=10.1016/S0014-5793(97)01464-6 }}
*{{cite journal  | author=Amici A, Emanuelli M, Raffaelli N, ''et al.'' |title=Human erythrocyte pyrimidine 5-nucleotidase, PN-I, is identical to p36, a protein associated to lupus inclusion formation in response to alpha-interferon. |journal=Blood |volume=96 |issue= 4 |pages= 1596-8 |year= 2000 |pmid= 10942414 |doi=  }}
*{{cite journal  |vauthors=Hartley JL, Temple GF, Brasch MA |title=DNA Cloning Using In Vitro Site-Specific Recombination |journal=Genome Res. |volume=10 |issue= 11 |pages= 1788–95 |year= 2001 |pmid= 11076863 |doi=10.1101/gr.143000  | pmc=310948 }}
*{{cite journal  | author=Zhang QH, Ye M, Wu XY, ''et al.'' |title=Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells. |journal=Genome Res. |volume=10 |issue= 10 |pages= 1546-60 |year= 2001 |pmid= 11042152 |doi= }}
*{{cite journal   |vauthors=Wiemann S, Weil B, Wellenreuther R, etal |title=Toward a Catalog of Human Genes and Proteins: Sequencing and Analysis of 500 Novel Complete Protein Coding Human cDNAs |journal=Genome Res. |volume=11 |issue= 3 |pages= 422–35 |year= 2001 |pmid= 11230166 |doi= 10.1101/gr.GR1547R  | pmc=311072 }}
*{{cite journal  | author=Hartley JL, Temple GF, Brasch MA |title=DNA cloning using in vitro site-specific recombination. |journal=Genome Res. |volume=10 |issue= 11 |pages= 1788-95 |year= 2001 |pmid= 11076863 |doi=  }}
*{{cite journal   |vauthors=Marinaki AM, Escuredo E, Duley JA, etal |title=Genetic basis of hemolytic anemia caused by pyrimidine 5' nucleotidase deficiency |journal=Blood |volume=97 |issue= 11 |pages= 3327–32 |year= 2001 |pmid= 11369620 |doi=10.1182/blood.V97.11.3327 }}
*{{cite journal | author=Wiemann S, Weil B, Wellenreuther R, ''et al.'' |title=Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs. |journal=Genome Res. |volume=11 |issue= 3 |pages= 422-35 |year= 2001 |pmid= 11230166 |doi= 10.1101/gr.154701 }}
*{{cite journal  |vauthors=Amici A, Magni G |title=Human erythrocyte pyrimidine 5'-nucleotidase, PN-I |journal=Arch. Biochem. Biophys. |volume=397 |issue= 2 |pages= 184–90 |year= 2002 |pmid= 11795870 |doi= 10.1006/abbi.2001.2676 }}
*{{cite journal | author=Marinaki AM, Escuredo E, Duley JA, ''et al.'' |title=Genetic basis of hemolytic anemia caused by pyrimidine 5' nucleotidase deficiency. |journal=Blood |volume=97 |issue= 11 |pages= 3327-32 |year= 2001 |pmid= 11369620 |doi=  }}
*{{cite journal   |vauthors=Amici A, Emanuelli M, Ruggieri S, etal |title=Kinetic evidence for covalent phosphoryl-enzyme intermediate in phosphotransferase activity of human red cell pyrimidine nucleotidases |journal=Meth. Enzymol. |volume=354 |issue=  |pages= 149–59 |year= 2003 |pmid= 12418222 |doi=10.1016/S0076-6879(02)54011-8  | series=Methods in Enzymology  | isbn=978-0-12-182257-6 }}
*{{cite journal  | author=Amici A, Magni G |title=Human erythrocyte pyrimidine 5'-nucleotidase, PN-I. |journal=Arch. Biochem. Biophys. |volume=397 |issue= 2 |pages= 184-90 |year= 2002 |pmid= 11795870 |doi= 10.1006/abbi.2001.2676 }}
*{{cite journal   |vauthors=Strausberg RL, Feingold EA, Grouse LH, etal |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 | pmc=139241 }}
*{{cite journal | author=Amici A, Emanuelli M, Ruggieri S, ''et al.'' |title=Kinetic evidence for covalent phosphoryl-enzyme intermediate in phosphotransferase activity of human red cell pyrimidine nucleotidases. |journal=Meth. Enzymol. |volume=354 |issue=  |pages= 149-59 |year= 2003 |pmid= 12418222 |doi=  }}
*{{cite journal   |vauthors=Balta G, Gumruk F, Akarsu N, etal |title=Molecular characterization of Turkish patients with pyrimidine 5' nucleotidase-I deficiency |journal=Blood |volume=102 |issue= 5 |pages= 1900–3 |year= 2003 |pmid= 12714505 |doi= 10.1182/blood-2003-02-0628 }}
*{{cite journal | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
*{{cite journal   |vauthors=Bianchi P, Fermo E, Alfinito F, etal |title=Molecular characterization of six unrelated Italian patients affected by pyrimidine 5'-nucleotidase deficiency |journal=Br. J. Haematol. |volume=122 |issue= 5 |pages= 847–51 |year= 2003 |pmid= 12930399 |doi=10.1046/j.1365-2141.2003.04532.x }}
*{{cite journal | author=Balta G, Gumruk F, Akarsu N, ''et al.'' |title=Molecular characterization of Turkish patients with pyrimidine 5' nucleotidase-I deficiency. |journal=Blood |volume=102 |issue= 5 |pages= 1900-3 |year= 2003 |pmid= 12714505 |doi= 10.1182/blood-2003-02-0628 }}
*{{cite journal  |vauthors=Kanno H, Takizawa T, Miwa S, Fujii H |title=Molecular basis of Japanese variants of pyrimidine 5'-nucleotidase deficiency |journal=Br. J. Haematol. |volume=126 |issue= 2 |pages= 265–71 |year= 2004 |pmid= 15238149 |doi= 10.1111/j.1365-2141.2004.05029.x }}
*{{cite journal | author=Bianchi P, Fermo E, Alfinito F, ''et al.'' |title=Molecular characterization of six unrelated Italian patients affected by pyrimidine 5'-nucleotidase deficiency. |journal=Br. J. Haematol. |volume=122 |issue= 5 |pages= 847-51 |year= 2003 |pmid= 12930399 |doi=  }}
*{{cite journal   |vauthors=Gerhard DS, Wagner L, Feingold EA, etal |title=The Status, Quality, and Expansion of the NIH Full-Length cDNA Project: The Mammalian Gene Collection (MGC) |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121–7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 | pmc=528928 }}
*{{cite journal  | author=Kanno H, Takizawa T, Miwa S, Fujii H |title=Molecular basis of Japanese variants of pyrimidine 5'-nucleotidase deficiency. |journal=Br. J. Haematol. |volume=126 |issue= 2 |pages= 265-71 |year= 2004 |pmid= 15238149 |doi= 10.1111/j.1365-2141.2004.05029.x }}
*{{cite journal   |vauthors=Wiemann S, Arlt D, Huber W, etal |title=From ORFeome to Biology: A Functional Genomics Pipeline |journal=Genome Res. |volume=14 |issue= 10B |pages= 2136–44 |year= 2004 |pmid= 15489336 |doi= 10.1101/gr.2576704 | pmc=528930 }}
*{{cite journal | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121-7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
*{{cite journal   |vauthors=Chiarelli LR, Bianchi P, Fermo E, etal |title=Functional analysis of pyrimidine 5'-nucleotidase mutants causing nonspherocytic hemolytic anemia |journal=Blood |volume=105 |issue= 8 |pages= 3340–5 |year= 2005 |pmid= 15604219 |doi= 10.1182/blood-2004-10-3895 }}
*{{cite journal | author=Wiemann S, Arlt D, Huber W, ''et al.'' |title=From ORFeome to biology: a functional genomics pipeline. |journal=Genome Res. |volume=14 |issue= 10B |pages= 2136-44 |year= 2004 |pmid= 15489336 |doi= 10.1101/gr.2576704 }}
*{{cite journal   |vauthors=Mehrle A, Rosenfelder H, Schupp I, etal |title=The LIFEdb database in 2006 |journal=Nucleic Acids Res. |volume=34 |issue= Database issue |pages= D415–8 |year= 2006 |pmid= 16381901 |doi= 10.1093/nar/gkj139 | pmc=1347501 }}
*{{cite journal | author=Chiarelli LR, Bianchi P, Fermo E, ''et al.'' |title=Functional analysis of pyrimidine 5'-nucleotidase mutants causing nonspherocytic hemolytic anemia. |journal=Blood |volume=105 |issue= 8 |pages= 3340-5 |year= 2005 |pmid= 15604219 |doi= 10.1182/blood-2004-10-3895 }}
*{{cite journal | author=Mehrle A, Rosenfelder H, Schupp I, ''et al.'' |title=The LIFEdb database in 2006. |journal=Nucleic Acids Res. |volume=34 |issue= Database issue |pages= D415-8 |year= 2006 |pmid= 16381901 |doi= 10.1093/nar/gkj139 }}
}}
}}
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{{refend}}
{{PDB Gallery|geneid=51251}}


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Latest revision as of 13:17, 5 September 2017

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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Location (UCSC)n/an/a
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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.[1][2][3][4]

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][3]

Structure

The NT5C3 gene consists of 10 exons and can be alternatively spliced at exon 2.[5] Four possible isoforms have been identified, encoding proteins with lengths of 336 residues, 297 residues, 286 residues, and 285 residues.[5][6] The 286-residue long isozyme is a monomeric protein containing 5 cysteine residues and no disulfide bridges or phosphate content.[4][5] 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.[5] 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.[7]

Function

NT5C3 is a member of the 5'-nucleotidase family and one of the five cytosolic members identified in humans.[6] NTC53 catalyzes the dephosphorylation of the pyrimidine 5′ monophosphates UMP and CMP to the corresponding nucleosides.[4][5] This function contributes to RNA degradation during the erythrocyte maturation process.[2][4][6] 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.[6]

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.[2][5] In particular, the 297-residue isoform of this enzyme is highly expressed in lymphoblastoid cells.[6]

Clinical Significance

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.[2][4][5] This deficiency is characterized by moderate hemolytic anemia, jaundice, splenomegaly, and marked basophilic stippling, and has been associated with learning difficulties.[2][5] 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.[5] Pyrimidine 5' nucleotidase deficiency is also linked to the conversion of hemoglobin E disease into an unstable hemoglobinopathy-like disease.[2][5] NT5C3 is identical to p36, a previously identified alpha-interferon-induced protein involved in forming lupus inclusions.[2][4] 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.[8]

Interactions

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.[4]

References

  1. ↑ 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 310934. PMID 11042152.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 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.
  3. ↑ 3.0 3.1 "Entrez Gene: NT5C3 5'-nucleotidase, cytosolic III".
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 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.
  5. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 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.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 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. PMC 2763634. PMID 19623099.
  7. ↑ 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.
  8. ↑ 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


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