Sequence analysis of NAT2 gene in Brazilians: identification of undescribed single nucleotide polymorphisms and molecular modeling of the N-acetyltransferase 2 protein structure

dc.creatorTeixeira, Raquel L. F.
dc.creatorSilva, Floriano P.
dc.creatorSilveira, Aline R.
dc.creatorCabello, Pedro H.
dc.creatorLima, Leila Mendonça
dc.creatorRabahi, Marcelo F.
dc.creatorKritski, Afrânio L.
dc.creatorMello, Fernanda C. Q.
dc.creatorSuffys, Philip N.
dc.creatorMiranda, Antonio B. de
dc.creatorSantos, Adalberto R.
dc.date2017-08-24T16:24:08Z
dc.date2017-08-24T16:24:08Z
dc.date2010
dc.date.accessioned2023-09-26T22:23:11Z
dc.date.available2023-09-26T22:23:11Z
dc.identifierTEIXEIRA, Raquel L. F. et al. Sequence analysis of NAT2 gene in Brazilians: Identification of undescribed single nucleotide polymorphisms and molecular modeling of the N-acetyltransferase 2 protein structure. Mutation Research, v. 683, p. 43-49, 2010.
dc.identifier0027-5107
dc.identifierhttps://www.arca.fiocruz.br/handle/icict/20742
dc.identifier10.1016/j.mrfmmm.2009.10.009
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8878573
dc.descriptionN-Acetyltransferase 2 (NAT2) metabolizes a variety of xenobiotics that includes many drugs, chemicals and carcinogens. This enzyme is genetically variable in human populations and polymorphisms in the NAT2 gene have been associated with drug toxicity and efficacy as well as cancer susceptibility. Here, we have focused on the identification of NAT2 variants in Brazilian individuals from two different regions, Rio de Janeiro and Goiás, by direct sequencing, and on the characterization of new haplotypes after cloning and re-sequencing. Upon analysis of DNA samples from 404 individuals, six new SNPs (c.29T>C, c.152G>T, c.203G>A, c.228C>T, c.458C>T and c.600A>G) and seven new NAT2 alleles were identified with different frequencies in Rio de Janeiro and Goiás. All new SNPs were found as singletons (observed only once in 808 genes) and were confirmed by three independent technical replicates. Molecular modeling and structural analysis suggested that p.Gly51Val variant may have an important effect on substrate recognition by NAT2. We also observed that amino acid change p.Cys68Tyr would affect acetylating activity due to the resulting geometric restrictions and incompatibility of the functional group in the Tyr side chain with the admitted chemical mechanism for catalysis by NATs. Moreover, other variants, such like p.Thr153Ile, p.Thr193Met, p.Pro228Leu and p.Val280Met, may lead to the presence of hydrophobic residues on NAT2 surface involved in protein aggregation and/or targeted degradation. Finally, the new alleles NAT2*6H and NAT2*5N, which showed the highest frequency in the Brazilian populations considered in this study, may code for a slow activity. Functional studies are needed to clarify the mechanisms by which new SNPs interfere with acetylation.
dc.description2030-01-01
dc.formatapplication/pdf
dc.languageeng
dc.publisherElsevier
dc.rightsrestricted access
dc.subjectModelagem molecular
dc.subjectPolimorfismo
dc.subjectPopulação brasileira
dc.subjectN-Acetiltransferase
dc.subjectHuman NAT2
dc.subjectPolymorphism
dc.subjectMolecular modeling
dc.subjectN-Acetylation
dc.subjectStructure/function
dc.subjectBrazilian population
dc.titleSequence analysis of NAT2 gene in Brazilians: identification of undescribed single nucleotide polymorphisms and molecular modeling of the N-acetyltransferase 2 protein structure
dc.typeArticle


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