Document Detail


Cytosolic 5'-nucleotidase III (NT5C3): gene sequence variation and functional genomics.
MedLine Citation:
PMID:  19623099     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: 5'-Nucleotidases play a critical role in nucleotide pool balance and in the metabolism of nucleoside analogs such as gemcitabine and cytosine arabinoside (AraC). We previously performed an expression array association study with gemcitabine and AraC cytotoxicity using 197 human lymphoblastoid cell lines. One gene that was significantly associated with gemcitabine cytotoxicity was a nucleotidase family member, NT5C3. Very little is known with regard to the pharmacogenomics of this family of enzymes.
METHODS: We set out to identify common genetic variation in NT5C3 by resequencing the gene and to determine the effect of that variation on NT5C3 protein function and potential effect on response to cytidine analogs. We identified 61 NT5C3 polymorphisms, 48 of which were novel, by resequencing 240 ethnically defined DNA samples. Functional studies were performed with one nonsynonymous (G847C, Asp283His) and four synonymous cSNPs (T9C, C276T, T306C, and G759A),as well as three combined variants (T276/His283, T276/C306, T276/C9).
RESULTS: The His283 and T276/His283 constructs showed decreased levels of enzyme activity and protein. Substrate kinetic analysis showed no significant differences in Km values between wild type and His283 when cytidine monophosphate, AraCMP, and GemMP were used as substrates. An association study between single nucleotide polymorphisms (SNPs) and NT5C3 expression in the 240 cell lines from which DNA was extracted to resequence NT5C3 identified four SNPs that were significantly associated with NT5C3 expression. Electrophoretic mobility shift assays showed that two of those SNPs, I4(-114) and I6(9), altered DNA-protein binding patterns. These findings suggest that genetic variation in NT5C3 might affect protein function and potentially influence drug response.
Authors:
Pinar Aksoy; Min Jia Zhu; Krishna R Kalari; Irene Moon; Linda L Pelleymounter; Bruce W Eckloff; Eric D Wieben; Vivien C Yee; Richard M Weinshilboum; Liewei Wang
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Pharmacogenetics and genomics     Volume:  19     ISSN:  1744-6872     ISO Abbreviation:  Pharmacogenet. Genomics     Publication Date:  2009 Aug 
Date Detail:
Created Date:  2009-07-30     Completed Date:  2009-09-11     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  101231005     Medline TA:  Pharmacogenet Genomics     Country:  United States    
Other Details:
Languages:  eng     Pagination:  567-76     Citation Subset:  IM    
Affiliation:
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA.
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MeSH Terms
Descriptor/Qualifier:
5'-Nucleotidase / genetics*
Animals
Antimetabolites, Antineoplastic / pharmacology
COS Cells
Cell Line, Tumor
Cercopithecus aethiops
Cytarabine / pharmacology
DNA / chemistry
Deoxycytidine / analogs & derivatives,  pharmacology
Genetic Variation*
Glycoproteins / genetics*
Haplotypes
Humans
Kinetics
Models, Genetic
Pharmacogenetics / methods
Grant Support
ID/Acronym/Agency:
K22 CA130828/CA/NCI NIH HHS; K22 CA130828-01A1/CA/NCI NIH HHS; K22 CA130828-02/CA/NCI NIH HHS; R01 CA132780/CA/NCI NIH HHS; R01 CA132780-01/CA/NCI NIH HHS; R01 CA132780-02/CA/NCI NIH HHS; R01 CA138461/CA/NCI NIH HHS; R01 CA138461-01/CA/NCI NIH HHS; R01 GM028157-28/GM/NIGMS NIH HHS; R01 GM028157-29/GM/NIGMS NIH HHS; R01 GM035720-20/GM/NIGMS NIH HHS; R01 GM035720-21/GM/NIGMS NIH HHS; R01 GM28157/GM/NIGMS NIH HHS; R01 GM35720/GM/NIGMS NIH HHS; U01 GM061388-09/GM/NIGMS NIH HHS; U01 GM61388/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Antimetabolites, Antineoplastic; 0/Glycoproteins; 147-94-4/Cytarabine; 9007-49-2/DNA; 951-77-9/Deoxycytidine; B76N6SBZ8R/gemcitabine; EC 3.1.3.5/5'-Nucleotidase; EC 3.1.3.5/NT5C3 protein, human
Comments/Corrections

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