Maria Acsm Borba1, Renato P Melo-Neto1, Glauber M Leitão1,2, Carlos Hm Castelletti1,3, José L Lima-Filho4, Danyelly Bg Martins1,4. 1. Molecular Prospection and Bioinformatics Group (ProspecMol) - Laboratory of Immunopathology Keizo Asami (LIKA), Federal University of Pernambuco (UFPE), Av. Prof. Moraes Rego 1235, 50670-901, Cidade Universitária, Recife, PE, Brazil. 2. Clinical Hospital - Federal University of Pernambuco (UFPE), Av. Prof. Moraes Rego 1235, 50670-901, Cidade Universitária, Recife, PE, Brazil. 3. Agronomic Institute of Pernambuco (IPA), Av. General San Martin 1371, 50761-000, Bongi, Recife, PE, Brazil. 4. Biochemistry Department, Federal University of Pernambuco (UFPE), Av. Prof. Moraes Rego 1235, 50670-901, Cidade Universitária, Recife, PE, Brazil.
Abstract
UNLABELLED: CYP2D6 is a high polymorphic enzyme from P450, responsible for metabolizing almost 25% of drugs. The distribution of different mutations among CYP2D6 alleles has been associated with poor, intermediate, extensive and ultra-metabolizers. AIM: To evaluate how missenses mutations in CYP2D6*7 and CYP2D6*14A poor metabolizer alleles affect CYP2D6 stability and function. MATERIALS & METHODS: CYPalleles database was used to collect polymorphisms data present in 105 alleles. We selected only poor metabolizers alleles that presented exclusively missenses mutations. They were analyzed through seven algorithms to predict the impact on CYP2D6 structure and function. RESULTS: H324P, the unique mutation in CYP2D6*7, has high impact in enzyme function due to its occurrence between two alpha-helixes involved in active site dynamics. G169R, a mutation that occurs only in CYP2D6*14A, leads to the gain of solvent accessibility and severe protein destabilization. CONCLUSION: Our in silico analysis showed that missenses mutations in CYP2D6*7 and CYP2D6*14A cause CYP2D6 dysfunction.
UNLABELLED: CYP2D6 is a high polymorphic enzyme from P450, responsible for metabolizing almost 25% of drugs. The distribution of different mutations among CYP2D6 alleles has been associated with poor, intermediate, extensive and ultra-metabolizers. AIM: To evaluate how missenses mutations in CYP2D6*7 and CYP2D6*14A poor metabolizer alleles affect CYP2D6 stability and function. MATERIALS & METHODS: CYPalleles database was used to collect polymorphisms data present in 105 alleles. We selected only poor metabolizers alleles that presented exclusively missenses mutations. They were analyzed through seven algorithms to predict the impact on CYP2D6 structure and function. RESULTS:H324P, the unique mutation in CYP2D6*7, has high impact in enzyme function due to its occurrence between two alpha-helixes involved in active site dynamics. G169R, a mutation that occurs only in CYP2D6*14A, leads to the gain of solvent accessibility and severe protein destabilization. CONCLUSION: Our in silico analysis showed that missenses mutations in CYP2D6*7 and CYP2D6*14A cause CYP2D6 dysfunction.
Authors: Maria Amélia Carlos Souto Maior Borba; Carlos Henrique Madeiros Castelletti; José Luiz de Lima Filho; Danyelly Bruneska Gondim Martins Journal: Future Sci OA Date: 2017-07-14