Mannesse_1995_Biochim.Biophys.Acta_1259_56

Reference

Title : Phosphonate analogues of triacylglycerols are potent inhibitors of lipase - Mannesse_1995_Biochim.Biophys.Acta_1259_56
Author(s) : Mannesse ML , Boots JW , Dijkman R , Slotboom AJ , van der Hijden HT , Egmond MR , Verheij HM , De Haas GH
Ref : Biochimica & Biophysica Acta , 1259 :56 , 1995
Abstract :

1,2-Dioctylcarbamoylglycero-3-O-p-nitrophenyl alkylphosphonates, with alkyl being methyl or octyl, were synthesised and tested as irreversible inhibitors of cutinase from Fusarium solani pisi and Staphylococcus hyicus lipase. Rapid inactivation of these enzymes occurred with a concomitant release of one mole of p-nitrophenol per mole of enzyme. With both lipases a higher reactivity was observed when the alkyl substituent on the phosphonate is a methyl rather than an octyl chain. Both lipases are highly selective for the chirality of these compounds at glycerol and at phosphorus. Rapid inactivation at an inhibitor concentration of 0.1 mol% in 100 mM NaTDOC (t 1/2 < 60 min.) occurred when the glycerol moiety had the (R) configuration, while inhibitors of the (S) configuration react 4-10-fold more slowly. The isomer with the p-nitrophenyl octylphosphonate attached to the secondary hydroxyl group of glycerol hardly inhibited (t 1/2 > 1 day) the lipases. These results reflect the known positional- and stereopreference of these enzymes which preferentially release the fatty acid at sn-3 of natural triacylglycerols. The enzymes appeared to be even more selective for the chirality at phosphorus, the differences in reactivity of the faster and slower reacting isomers being as high as about 250-fold for the methylphosphonates and about 60-fold for the octylphosphonates. These phosphonates can be regarded as true active site-directed inhibitors. The inhibited enzymes can be considered as analogues of the tetrahedral intermediate in the acylation step that occurs during triacylglycerol hydrolysis.

PubMedSearch : Mannesse_1995_Biochim.Biophys.Acta_1259_56
PubMedID: 7492616
Gene_locus related to this paper: fusso-cutas , stahy-lipas

Citations formats

Mannesse ML, Boots JW, Dijkman R, Slotboom AJ, van der Hijden HT, Egmond MR, Verheij HM, De Haas GH (1995)
Phosphonate analogues of triacylglycerols are potent inhibitors of lipase
Biochimica & Biophysica Acta 1259 :56

Mannesse ML, Boots JW, Dijkman R, Slotboom AJ, van der Hijden HT, Egmond MR, Verheij HM, De Haas GH (1995)
Biochimica & Biophysica Acta 1259 :56