Computational study of human phosphomannose isomerase: Insights from homology modeling and molecular dynamics simulation of enzyme bound substrate.
Phosphomannose isomerase is a zinc metalloenzyme that catalyzes the reversible isomerization of mannose-6-phosphate and fructose-6-phosphate, and the three-dimensional (3D) structure of human phosphomannose isomerase has not been reported. In order to understand the catalytic mechanism, the 3D structure of the protein is built by using homology modeling based on the known crystal structure of mannose-6-phosphate isomerase from (PDB code 1PMI). The model structure is further refined by energy minimization and molecular dynamics methods. The mannose-6-phosphate-enzyme complex is developed by molecular docking and the key residues involved in the ligand binding are determined, which will facilitate the understanding of the action mode of the ligands and guide further genetic studies. Our results suggest a hydride transfer mechanism of alpha-hydrogen between the C1 and C2 positions but do not support the cis-enediol mechanism. The detailed mechanism involves, on one side, Zn2+ mediating the movement of a proton between O1 and O2, and, on the other side, the hydrophobic environment formed in part by Tyr278 promoting transfer of a hydride ion.
Xiao
Jingfa
J
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Guo
Zongru
Z
Guo
Yanshen
Y
Chu
Fengming
F
Sun
Piaoyang
P
D000595:Amino Acid Sequence; D001665:Binding Sites; D002384:Catalysis; D003198:Computer Simulation; D005636:Fructosephosphates / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007536:Isomerism; D008359:Mannose-6-Phosphate Isomerase / Q000737:chemistry* / Q000378:metabolism; D008360:Mannosephosphates / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D005636:Fructosephosphates; D008360:Mannosephosphates; C027693:mannose-6-phosphate; C027618:fructose-6-phosphate; D008359:Mannose-6-Phosphate Isomerase