Ligand and active-site dependent P-O versus C-O bond cleavage in organophosphorus adducts of serine hydrolases

The stereoselectivity of phosphonylation of serine hydrolases by the ROR'P( O)X group of compounds is governed by the electronic properties of X and th e size of RO. The electronic properties of ligands attached to P are decisi ve in whether C-O or P-O bond cleavage occurs in phosphonate diesters of se rine hydrolases. Phenolate ions leave readily with P-O cleavage from chymot rypsin and the cholinesterases. The architecture and electrostatic characte r of the active site governs the fate of a covalently attached phosphonyl f ragment. Strong negative electrostatic and hydrophobic forces in the cholin esterases preferentially promote C-O bond cleavage with occasional methyl m igration whereas this route of dealkylation is nearly absent in phosphonate esters of serine proteases.