title: Catalytic mechanism of angiotensin-converting enzyme and effects of the chloride ion.
abstract: The angiotensin-converting enzyme (ACE) exhibits critical functions in the conversion of angiotensin I to angiotensin II and the degradation of bradykinin and other vasoactive peptides. As a result, the ACE inhibition has become a promising approach in the treatment of hypertension, heart failure, and diabetic nephropathy. Extending our recent molecular dynamics simulation of the testis ACE in complex with a bona fide substrate molecule, hippuryl-histidyl-leucine, we presented here a detailed investigation of the hydrolytic process and possible influences of the chloride ion on the reaction using a combined quantum mechanical and molecule mechanical method. Similar to carboxypeptidase A and thermolysin, the promoted water mechanism is established for the catalysis of ACE. The E384 residue was found to have the dual function of a general base for activating the water nucleophile and a general acid for facilitating the cleavage of amide C-N bond. Consistent with experimental observations, the chloride ion at the second binding position is found to accelerate the reaction rate presumably due to the long-range electrostatic interactions but has little influence on the overall substrate binding characteristics.
authors.affiliation: Analytical&Testing Center, College of Chemistry, Sichuan University, Chengdu, Sichuan, 610064, PR China.
authors.forename: Chunchun
authors.initials: C
authors.lastname: Zhang
authors.forename: Shanshan
authors.initials: S
authors.lastname: Wu
authors.forename: Dingguo
authors.initials: D
authors.lastname: Xu
mesh_terms: D055162:Biocatalysis; D002712:Chlorides / Q000737:chemistry*; D006868:Hydrolysis; D007477:Ions / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000737:chemistry / Q000378:metabolism*; D011522:Protons; D011789:Quantum Theory; D013379:Substrate Specificity; D014867:Water / Q000737:chemistry / Q000378:metabolism
chemical_list: D002712:Chlorides; D007477:Ions; D009842:Oligopeptides; D011522:Protons; D014867:Water; C010980:hippuryl-histidyl-leucine; D007703:Peptidyl-Dipeptidase A