title: First computational evidence for a catalytic bridging hydroxide ion in a phosphodiesterase active site.
abstract: Phosphodiesterases are clinical targets for a variety of biological disorders, because this superfamily of enzymes regulates the intracellular concentration of cyclic nucleotides that serve as the second messengers playing a critical role in a variety of physiological processes. Understanding the structure and mechanism of a phosphodiesterase will provide a solid basis for rational design of the more efficient therapeutics. Although a three-dimensional X-ray crystal structure of the catalytic domain of human phosphodiesterase 4B2B was recently reported, it is uncertain whether a critical bridging ligand in the active site is a water molecule or a hydroxide ion. The identity of this bridging ligand is theoretically determined by performing first-principles quantum chemical calculations on models of the active site. All the results obtained indicate that this critical bridging ligand in the active site of the reported X-ray crystal structure is a hydroxide ion, rather than a water molecule, expected to serve as the nucleophile to initialize the catalytic degradation of the intracellular second messengers.
authors.affiliation: Department of Chemistry, Central China Normal University, Wuhan 430070, P. R. China. Chang-Guo.Zhan@pnl.gov
authors.forename: C G
authors.initials: CG
authors.lastname: Zhan
authors.forename: F
authors.initials: F
authors.lastname: Zheng
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D006801:Humans; D006878:Hydroxides / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry* / Q000378:metabolism
chemical_list: D006878:Hydroxides; C031356:hydroxide ion; D010727:Phosphoric Diester Hydrolases