Insight into TPMT23 mutation mis-folding using molecular dynamics simulation and protein structure analysis

• Published in: Journal of biomolecular structure & dynamics Vol. 31; no. 9-10; pp. 1066 - 1076
• Main Authors: Larif, S, Salem, C B, Soua, Z, Hmouda, H, Bouraoui, K
• Format: Journal Article
• Language: English
• Published: 01.10.2013
• ISSN: 0739-1102
• DOI: 10.1080/07391102.2012.721495

Thiopurine S-methyltransferase (TPMT) is an important enzyme that metabolizes thiopurine drugs. This enzyme exhibits a large number of interindividual polymorphism. TPMT*23 polymorphism has been reported in a few cases in the world in co-dominance with TPMT*3A. The phenotype has been reported to affect enzyme activity in vivo and in vitro. Its underlying structural basis is not clarified yet. In our study, the wild type (WT) protein structure was analyzed and the amino acids bordering water channels in thiopurine sites were identified. Molecular dynamics of both the WT and TPMT*23 mutation was carried out. In addition, the effects of this mutation, especially on the thiopurine site which is closed with a pincer like mechanism, were investigated. We focused on explaining how a locally occurred A167G substitution propagated through hydrogen bonds alteration to induce structural modification which affects both thiopurine and S-adenosylmethionine receptors. Finally, a genetic prediction of mutation functional consequences has been conducted confirming altered activity.