Digestive lipases: inactivation by phosphonates.

Phosphonates mimicking the transition state which occurs during carboxyester hydrolysis were synthesized and investigated as potential inactivators of human pancreatic (HPL) and gastric (HGL) lipases. Their efficiency as inactivators was studied on the basis of the alkyl chain length, the nature of the leaving group and the influence of the ester substituent. In each case, HGL was found to be more sensitive than HPL towards these phosphonates. The released p-nitrophenol to enzyme ratio indicates that a 1:1 complex was formed. In the absence of substrate, the most powerful inactivator was O-methyl O-(p-nitrophenyl) n-pentylphosphonate (4A), which has a short alkyl chain, a small methoxy substituent and a good leaving group.