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Structural and functional impact of missense mutations in TPMT: An integrated computational approach

Paper ID Volume ID Publish Year Pages File Format Full-Text
14971 1365 2015 8 PDF Available
Title
Structural and functional impact of missense mutations in TPMT: An integrated computational approach
Abstract

•Pathogenecity of TPMT mutations could be predicted by an integrative approach.•Most of the mutations resulting in no enzyme activity are in conserved positions.•Missense mutations have different effects on TPMT structure and function.•Residue interaction network of approximately 85% of the alleles are different from wild type.•Cytoscape is a robust program for visualization of residue interaction network in TPMT.

BackgroundThiopurine S-methyltransferase (TPMT) detoxifies thiopurine drugs which are used for treatment of various diseases including inflammatory bowel disease (IBD), and hematological malignancies. Individual variation in TPMT activity results from mutations in TPMT gene. In this study, the effects of all the known missense mutations in TPMT enzyme were studied at the sequence and structural levelMethodsA broad set of bioinformatic tools was used to assess all the known missense mutations affecting enzyme activity. The effects of these mutations on protein stability, aggregation propensity, and residue interaction network were analyzed.ResultsOur results indicate that the missense mutations have diverse effects on TPMT structure and function. Stability and aggregation propensities are affected by various mutations. Several mutations also affect residues in ligand binding site.ConclusionsIn vitro study of missense mutation is laborious and time-consuming. However, computational methods can be used to obtain information about effects of missense mutations on protein structure. In this study, the effects of most of the mutations on enzyme activity could be explained by computational methods. Thus, the present approach can be used for understanding the protein structure-function relationships.

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Keywords
Bioinformatic analysis; TPMT; Missense mutations; Structure-function relationship
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Structural and functional impact of missense mutations in TPMT: An integrated computational approach
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Publisher
Database: Elsevier - ScienceDirect
Journal: Computational Biology and Chemistry - Volume 59, Part A, December 2015, Pages 48–55
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us