DIGESTIVE LIPASES - INACTIVATION BY PHOSPHONATES

Phosphonates mimicking the transition state which occurs during carbox yester hydrolysis were synthesized and investigated as potential inact ivators of human pancreatic (HPL) and gastric (HGL) lipases. Their eff iciency as inactivators was studied on the basis of the alkyl chain le ngth, the nature of the leaving group and the influence of the eater s ubstituent. 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-pentyl phosphonate (4A), which has a short alkyl chain, a small methoxy subst ituent and a good leaving group.