title: Structural and functional impact of missense mutations in TPMT: An integrated computational approach.
abstract: BACKGROUND
  Thiopurine 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 level
  
  
  METHODS
  A 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.
  
  
  RESULTS
  Our 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.
  
  
  CONCLUSIONS
  In 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.
authors.affiliation: Medical Genetics Laboratory, Alzahra University Hospital, Isfahan University of Medical Sciences, Isfahan, Iran.
authors.forename: Esmat
authors.initials: E
authors.lastname: Fazel-Najafabadi
authors.affiliation: Institute of Biochemistry and Biophysics, University of Tehran, Iran.
authors.forename: Elham
authors.initials: E
authors.lastname: Vahdat Ahar
authors.affiliation: Medical Genetics Laboratory, Alzahra University Hospital, Isfahan University of Medical Sciences, Isfahan, Iran.
authors.forename: Shirin
authors.initials: S
authors.lastname: Fattahpour
authors.affiliation: Medical Genetics Laboratory, Alzahra University Hospital, Isfahan University of Medical Sciences, Isfahan, Iran; Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-communicable disease, Isfahan University of Medical Sciences, Isfahan, Iran. Electronic address: m_sedghi@azh.mui.ac.ir.
authors.forename: Maryam
authors.initials: M
authors.lastname: Sedghi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019295:Computational Biology; D006801:Humans; D008024:Ligands; D008780:Methyltransferases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense
chemical_list: D008024:Ligands; D050505:Mutant Proteins; D008780:Methyltransferases; C022745:thiopurine methyltransferase
keywords: Bioinformatic analysis; Missense mutations; Structure-function relationship; TPMT