title: Theoretical 3D model of histamine N-methyltransferase: insights into the effects of a genetic polymorphism on enzymatic activity and thermal stability.
abstract: Histamine N-methyltransferase (HNMT) catalyzes the N-methylation of histamine in mammals. The experimentally determined HNMT three-dimensional (3D) structure is not available. However, there is a common genetic polymorphism for human HNMT (Thr105Ile) that reduces enzymatic activity and is a risk factor for asthma. To obtain insights into mechanisms responsible for the effects of that polymorphism on enzymatic activity and thermal stability, we predicted the 3D structure of HNMT using the threading method and molecular dynamics simulations in water. Herein, we report a theoretical 3D model of human HNMT which reveals that polymorphic residue Thr105Ile is located in the turn between a beta strand and an alpha helix on the protein surface away from the active site of HNMT. Ile105 energetically destabilizes folded HNMT 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 promotes the formation of misfolded proteins that are prone to the clearance by proteasomes. This information explains, for the first time, how genetic polymorphisms can cause enhanced protein degradation and why the thermal stability of allozyme Ile105 is lower than that of Thr105. It also supports the hypothesis that the experimental observation of a significantly lower level 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 105.
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Foundation for Medical Education and Research, 200 First Street SW, Rochester, MN 55905, USA. pang@mayo.edu
authors.forename: Y P
authors.initials: YP
authors.lastname: Pang
authors.forename: X E
authors.initials: XE
authors.lastname: Zheng
authors.forename: R M
authors.initials: RM
authors.lastname: Weinshilboum
mesh_terms: D003198:Computer Simulation; D004795:Enzyme Stability; D017353:Gene Deletion; D006637:Histamine N-Methyltransferase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008962:Models, Theoretical; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D013696:Temperature
chemical_list: D006637:Histamine N-Methyltransferase