| Author | Teixeira, Raquel L. F. | |
| Author | Silva, Floriano P. | |
| Author | Silveira, Aline R. | |
| Author | Cabello, Pedro H. | |
| Author | Lima, Leila Mendonça | |
| Author | Rabahi, Marcelo F. | |
| Author | Kritski, Afrânio L. | |
| Author | Mello, Fernanda C. Q. | |
| Author | Suffys, Philip N. | |
| Author | Miranda, Antonio B. de | |
| Author | Santos, Adalberto R. | |
| Access date | 2017-08-24T16:24:08Z | |
| Available date | 2017-08-24T16:24:08Z | |
| Document date | 2010 | |
| Citation | TEIXEIRA, 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. | pt_BR |
| ISSN | 0027-5107 | pt_BR |
| URI | https://www.arca.fiocruz.br/handle/icict/20742 | |
| Language | eng | pt_BR |
| Publisher | Elsevier | pt_BR |
| Rights | restricted access | |
| Subject in Portuguese | Modelagem molecular | pt_BR |
| Subject in Portuguese | Polimorfismo | pt_BR |
| Subject in Portuguese | População brasileira | pt_BR |
| Subject in Portuguese | N-Acetiltransferase | pt_BR |
| Title | Sequence analysis of NAT2 gene in Brazilians: identification of undescribed single nucleotide polymorphisms and molecular modeling of the N-acetyltransferase 2 protein structure | pt_BR |
| Type | Article | |
| DOI | 10.1016/j.mrfmmm.2009.10.009 | |
| Abstract | N-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. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Genética Humana. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Proteínas e Peptídeos. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Proteínas e Peptídeos. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Genética Humana. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Genômica Funcional e Bioinformática. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Secretaria de Estado de Saúde de Goiás. Hospital de Refetrência em Doenças Infecciosas Anuar Auad. Goiânia, GO, Brasil. | pt_BR |
| Affilliation | Universidade Federal do Rio de Janeiro. Escola de Medicina. Complexo Hospitalar HUCFF-IDT. Programa Acadêmico de Tuberculose. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Universidade Federal do Rio de Janeiro. Escola de Medicina. Complexo Hospitalar HUCFF-IDT. Programa Acadêmico de Tuberculose. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular Aplicada em Micobactérias. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Genômica Funcional e Bioinformática. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular Aplicada em Micobactérias. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Subject | Human NAT2 | pt_BR |
| Subject | Polymorphism | pt_BR |
| Subject | Molecular modeling | pt_BR |
| Subject | N-Acetylation | pt_BR |
| Subject | Structure/function | pt_BR |
| Subject | Brazilian population | pt_BR |
| Embargo date | 2030-01-01 | |
