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Miled, N ; Roussel, A ; Bussetta, C ; Berti-Dupuis, L ; Riviere, M ; Buono, G ; Verger, R ; Cambillau, C ; Canaan, S

Inhibition of dog and human gastric lipases by enantiomeric phosphonate inhibitors : A structure-activity study

Biochemistry 42 (40) 11587-11593

par Administrateur - publié le

Abstract :

The crystal structures of gastric lipases in the apo form [Roussel, A., et al. (1999) J. Biol. Chem. 274, 16995-17002] or in complex with the (R-p)-undecyl butyl phosphonate [C11Y4(+)] [Roussel, A., et al. (2002) J. Biol. Chem. 277, 2266-2274] have improved our understanding of the structure-activity relationships of acid lipases. In this report, we have performed a kinetic study with dog and human gastric lipases (DGL and HGL, respectively) using several phosphonate inhibitors by varying the absolute configuration of the phosphorus atom and the chain length of the alkyl/alkoxy substitutents. Using the two previously determined structures and that of a new crystal structure obtained with the other (S-p)-phosphonate enantiomer [C11Y4(-)], we constructed models of phosphonate inhibitors fitting into the active site crevices of DGL and HGL.