Fazel-Najafabadi Esmat, Vahdat Ahar Elham, Fattahpour Shirin, Sedghi Maryam
Medical Genetics Laboratory, Alzahra University Hospital, Isfahan University of Medical Sciences, Isfahan, Iran.
Institute of Biochemistry and Biophysics, University of Tehran, Iran.
Comput Biol Chem. 2015 Dec;59 Pt A:48-55. doi: 10.1016/j.compbiolchem.2015.09.004. Epub 2015 Sep 9.
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
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.
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.
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.
硫嘌呤甲基转移酶（TPMT）可使硫嘌呤类药物解毒，这类药物用于治疗包括炎症性肠病（IBD）和血液系统恶性肿瘤在内的多种疾病。TPMT活性的个体差异源于TPMT基因突变。在本研究中，我们在序列和结构水平上研究了TPMT酶中所有已知错义突变的影响。
使用一系列广泛的生物信息学工具来评估所有已知的影响酶活性的错义突变。分析了这些突变对蛋白质稳定性、聚集倾向和残基相互作用网络的影响。
我们的结果表明，错义突变对TPMT的结构和功能有多种影响。稳定性和聚集倾向受各种突变影响。一些突变还影响配体结合位点的残基。
错义突变的体外研究既费力又耗时。然而，计算方法可用于获取有关错义突变对蛋白质结构影响的信息。在本研究中，大多数突变对酶活性的影响可以通过计算方法来解释。因此，目前的方法可用于理解蛋白质结构-功能关系。
