Phosphate esters are key compounds in important biological reactions, One family of enzymes, PTPases, catalyze the dephosphorylation of tyrosine residues from other proteins by a cystein side-chain nucleophilic attack at tyrosin phosphate. Very little is known about the intrinsic reactivity of thiol nucleophiles with phosphor-us centers. To explore this important reaction, we have performed ab initio calculations on the trimethyl phosphate ester (TMP) thiolysis by (CH3S)(-). Results in the gas phase indicate that attack at TMP carbon is essentially predominant over phosphorus. Mechanisms are A(n)D(n) and exoergic for reaction at carbon and A(n) + D-n with large activation barriers and endoergic reaction for attack on phosphorus. A trigonal-bipyramid intermediate was formed upon (CH3S)(-) reaction at phosphorus and two different and competitive pathways were found for the elimination of methoxide from this intermediate. One of the elimination pathways is positioned in-line to the thiol group, as proposed in the enzymatic mechanism. If PTPases work by the same mechanism as the gas-phase reaction, these enzymes should drastically lower the activation barriers for attack at phosphorus.