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首页> 外文期刊>Biochemistry >Characterization of an AM404 Analogue, N-(3-Hydroxyphenyl)arachidonoylamide, as a Substrate and Inactivator of Prostaglandin Endoperoxide Synthase
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Characterization of an AM404 Analogue, N-(3-Hydroxyphenyl)arachidonoylamide, as a Substrate and Inactivator of Prostaglandin Endoperoxide Synthase

机译：AM404类似物N-（3-羟苯基）花生四烯酸酰胺作为前列腺素内过氧化物合酶的底物和灭活剂的表征

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摘要

N-(4-Hydroxyphenyl)arachidonoylamide (AM404) is an inhibitor of endocannabinoid inactivationnthat has been used in cellular and animal studies. AM404 is a derivative of arachidonic acid and has beennreported to inhibit arachidonate oxygenation by prostaglandin endoperoxide synthase-1 and -2 (PGHS-1nand -2, respectively). While examining the structural requirements for inhibition of PGHS, we discovered thatnthe meta isomer of AM404, N-(3-hydroxyphenyl)arachidonoylamide (3-HPAA), is a substrate for purifiednPGHS. PGHS-2 efficiently oxygenated 3-HPAA to prostaglandin and hydroxyeicosatetraenoate products.nNo oxidation of the phenolamide moiety was observed. 3-HPAA appeared to be converted by PGHS-1 in ansimilar manner; however, conversion was less efficient than that by PGHS-2. PGHS-2 was selectively, dosedependently,nand irreversibly inactivated in the presence of 3-HPAA. Complete inactivation of PGHS-2 wasnachieved with 10 μM3-HPAA. Preliminary characterization revealed that 3-HPAAinactivation did not resultnfrom covalent modification of PGHS-2 or damage to the heme moiety. These studies provide additionalninsight into the structural requirements for substrate metabolism and inactivation of PGHS and report thenfirst metabolism-dependent, selective inactivator of PGHS-2.
机译：N-（4-羟基苯基）花生四烯酸酰胺（AM404）是内源性大麻素失活的抑制剂，已用于细胞和动物研究。 AM404是花生四烯酸的衍生物，据报道可通过前列腺素内过氧化物合酶-1和-2（分别为PGHS-1n和-2）抑制花生四烯酸的氧合。在研究抑制PGHS的结构要求时，我们发现AM404的间位异构体N-（3-羟苯基）花生四烯酸酰胺（3-HPAA）是纯化nPGHS的底物。 PGHS-2有效地将3-HPAA氧化成前列腺素和羟基二十碳四烯酸酯产物。n未观察到酚酰胺部分的氧化。 3-HPAA似乎以类似的方式被PGHS-1转化；但是，转换效率不如PGHS-2。在存在3-HPAA的情况下，PGHS-2被选择性，剂量依赖性地不可逆地灭活。用10μM3-HPAA实现了PGHS-2的完全灭活。初步表征表明，3-HPAA失活不是由于PGHS-2的共价修饰或血红素部分的损坏而引起的。这些研究提供了对底物代谢和PGHS灭活的结构要求的其他见解，然后报道了PGHS-2的首个代谢依赖性，选择性灭活剂。

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    《Biochemistry》 |2009年第51期|p.12233-12241|共9页
  • 作者

    Melissa V. Turman Philip J. Kingsley and Lawrence J. Marnett;

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    A. B. Hancock, Jr., Memorial Laboratory for Cancer Research, Departments of Biochemistry, Chemistry, and Pharmacology,Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, and Vanderbilt-Ingram Cancer Center, VanderbiltUniversity School of Medicine, Nashville, Tennessee 37232. ‡Current address: Immune Disease Institute and Department ofPathology, Harvard Medical School, Boston, MA 02115.;

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