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Titolo:
Rational design of alpha-keto triglyceride analogues as inhibitors for Staphylococcus hyicus lipase
Autore:
Simons, JWFA; Cox, RC; Egmond, MR; Verheij, HM;
Indirizzi:
Univomembrane Ctr Biomembranes & Lipid Enzymol, Dept Enymol & Prot Engn, Bi Univ Utrecht Utrecht Netherlands NL-3508 TB Dept Enymol & Prot Engn, Bi
Titolo Testata:
BIOCHEMISTRY
fascicolo: 19, volume: 38, anno: 1999,
pagine: 6346 - 6351
SICI:
0006-2960(19990511)38:19<6346:RDOATA>2.0.ZU;2-#
Fonte:
ISI
Lingua:
ENG
Soggetto:
PEPTIDYL FLUOROMETHYL KETONES; PORCINE PANCREATIC ELASTASE; HUMAN NEUTROPHIL ELASTASE; CANDIDA-RUGOSA LIPASE; SLOW-BINDING; TRIFLUOROMETHYL KETONE; INTERFACIAL ACTIVATION; SUBSTRATE-SPECIFICITY; MICROBIAL LIPASES; CRYSTAL-STRUCTURE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
39
Recensione:
Indirizzi per estratti:
Indirizzo: Egmond, MR Univomembrane Ctr Biomembranes & Lipid Enzymol, Dept Enymol & Prot Engn, Bi Univ Utrecht Padualaan 8,POB 80054 Utrecht Netherlands NL-3508 TB
Citazione:
J.W.F.A. Simons et al., "Rational design of alpha-keto triglyceride analogues as inhibitors for Staphylococcus hyicus lipase", BIOCHEM, 38(19), 1999, pp. 6346-6351

Abstract

We have synthesized a series of alpha-keto triglyceride analogues as inhibitors for the lipase from Staphylococcus hyicus (SHL). Hydrolysis at positions 1 and 2 was prevented by replacement of the ester bonds by nonhydrolyzable ether, carbamoyl, or amide bonds, and an alpha-keto fatty acid was introduced at position 3. Such compounds act as competitive inhibitors of SHL. Inhibition must be caused by the presence of the alpha-keto functions, since the compounds containing an ester or a hydroxyl group in position 3 did not inhibit the enzyme. We propose that our inhibitors react with the activesite Ser of the lipase, hereby mimicking the tetrahedral intermediate occurring in substrate hydrolysis. We conclude that the localization of the alpha-keto triglycerides is very important for inhibition because only those compounds which are insoluble in water are lipase inhibitors. In addition, other specific protein-inhibitor interactions, probably with the carbonyl oxygen at position 1 and/or 2, improve inhibitor binding. This makes the compounds with amide or carbamoyl groups at positions 1 and 2 better inhibitorsthan their ether counterparts. The inhibitory power could be improved further by replacing the oxygen at position 3 by an amido group. The resulting inhibitor 1,2-diethylcarbamoyl-3-amido-alpha-ketodode has a K-i* value of 0.008 mol %, indicating that it binds approximately 125-fold tighter than the substrate. These results illustrate that effective lipase inhibitors can be designed by combining an alpha-keto group with good micellar solubility and optimal protein-inhibitor interactions.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 03/12/20 alle ore 06:08:45