RAPID INACTIVATION OF PROSTAGLANDIN ENDOPEROXIDE SYNTHASES BY N-(CARBOXYALKYL)MALEIMIDES

被引：14

作者：

KALGUTKAR, AS ^{[1
]}

MARNETT, LJ ^{[1
]}

机构：

[1] VANDERBILT UNIV,SCH MED,CTR MOLEC TOXICOL,DEPT BIOCHEM,AB HANCOCK JR MEM LAB CANC RES,NASHVILLE,TN 37232

来源：

BIOCHEMISTRY | 1994年 / 33卷 / 29期

关键词：

D O I：

10.1021/bi00195a002

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

N-(Carboxyalkyl)maleimides were synthesized as potential inhibitors of prostaglandin endoperoxide synthase (PGHS). Inactivation of the cyclooxygenase and peroxidase activities of PGHS occurred in a biphasic manner with extremely rapid inactivation followed by slow, time-dependent inactivation. The carboxylic acid moiety was required for rapid inactivation. Optimal inhibition was observed with N-(carboxyheptyl)maleimide, which inhibited the cyclooxygenase activity of ovine PGHS-1 with an IC50 of 0.1 mu M and the peroxidase activity with an IC50 of 3 mu M. Inactivation of peroxidase activity was not prevented by pretreating the enzyme with the cyclooxygenase inhibitor indomethacin. N-(Carboxyheptyl)succinimide inhibited neither enzyme activity, suggesting that covalent modification is critical for rapid as well as time-dependent inactivation. Shortening or increasing the alkyl chain by one methylene unit drastically reduced inhibitory potency. N-(Carboxyalkyl)maleimides also instantaneously inactivated the inducible form of PGHS (PGHS-2) from mouse and human sources but with higher IC50's (4.5 and 14 mu M, respectively). N-(Carboxyheptyl)maleimide is the most potent covalent inactivator of PGHS yet described with an inhibitory potency 3-5 orders of magnitude greater than aspirin.

引用

页码：8625 / 8628

页数：4

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