In Silico Analysis for DPYD Gene and the Effect of the Mutation on Dihydropyrimidine Dehydrogenase Enzyme
Asia M. Elrashid *
Faculty of Science, Khartoum University, Sudan
Mohamed Y. Basher
Faculty of Veterinary Medicine, Khartoum University, Sudan
Ali I. A. Gharib
Faculty of Biotechnology, Omdurman Islamic University, Sudan
Mohamed A. I. Alfaki
Faculty of Computer Science, Neelain University, Sudan
Nawarz M. Mohammed
Faculty of Pharmacy, Omdurman Islamic University, Sudan
Ahmed M. Elmoselhy
Faculty of Science, Alexandria University, Egypt
Sahar G. Elbager
Faculty of Medical Laboratory Sciences, University of Medical Sciences and Technology (UMST), Sudan
Safinaz I. Khalil
Faculty of Medicine, University of Medical Sciences and Technology (UMST), Sudan
*Author to whom correspondence should be addressed.
Abstract
Aim: The aim of this study was to implement an in silico bioinformatics analysis for clinically observed missense variants in human DPYD gene to investigate the effect these variants on Dihydropyrimidine dehydrogenase enzyme 's structure and function.
Methods: The human DPYD gene was investigated in dbSNP/NCBI, 273238 SNPs were found; 99645 SNPs were Homo sapins; of which 534 were missense SNPs. Missense SNPs were selected for in silico analysis; SIFT, Polyphen2, SNPs & GO, Imutant 2.0, Mutation 3D , UCSF Chimera and HOPE were used to investigate the effect of SNPs on DPD protein's structure and function.
Results: 69 SNPs were found to be highly damaging for the protein by SIFT and Polyphen, of which 4 SNPs were observed to be associated to clinical presentations (M166V, V335L, I560S, D949V). These 69 SNPs were further analyzed by SNPs & GO, one SNP (D949V) was observed to be associated to clinical presentations. The 4 nsSNPs that observed to be associated to clinical presentations were further analyzed by I-Mutant, HOPE and chimera tools to predict their stability index and visualize wide and mutant residues in their protein 3D structure
Conclusions: We observe a range of structural and functional changes caused by single amino acid differences, including changes in protein structural, stability and binding properties associated with the 4nsSNPs (M166V, V335L, I560S, D949V). This can explain the variability in drug response and toxicity in patients who acquire these nsSNPs and treated with 5-FU.
Keywords: DPYD, 5 flurouracil, DPD, in silico analysis, SIFT, polyphen2, SNPs & GO, Imutant 2.0, Mutation 3D, UCSF Chimera, HOPE