Theoretical 3D model of histamine N-methyltransferase: Insights into the effects of a genetic polymorphism on enzymatic activity and thermal stability

Histamine N-methyltransferase (HNMT) catalyzes the N-methylation of histami ne in mammals. The experimentally determined HNMT three-dimensional (3D) st ructure is not available. However, there is a common genetic polymorphism f or human HNMT (Thr105Ile) that reduces enzymatic activity and is a risk fac tor for asthma. To obtain insights into mechanisms responsible for the effe cts of that polymorphism on enzymatic activity and thermal stability, we pr edicted the 3D structure of HNMT using the threading method and molecular d ynamics simulations in water. Herein, we report a theoretical 3D model of h uman HNMT which reveals that polymorphic residue Thr105Ile is located in th e turn between a beta strand and an alpha helix on the protein surface away from the active site of HNMT. Ile105 energetically destabilizes folded HNM T because of its low Chou-Fasman score for forming a turn conformation and the exposure of its hydrophobic side chain to aqueous solution. It thus pro motes the formation of misfolded proteins that are prone to the clearance b y proteasomes. This information explains, for the first time, how genetic p olymorphisms can cause enhanced protein degradation and why the thermal sta bility of allozyme Ile105 is lower than that of Thr105. It also supports th e hypothesis that the experimental observation of a significantly lower lev el of HNMT enzymatic activity for allozyme Ile105 than that with Thr105 is due to a decreased concentration of allozyme Ile105, but not an alternation of the active-site topology of HNMT caused by the difference at residue 10 5. (C) 2001 Academic Press.