Inhibition of 2,3-oxidosqualene cyclases.
Inhibition of 2,3-oxidosqualene cyclases.
复制标题
抑制 2,3-氧化角鲨烯环化酶。
DOI：
10.1021/bi00149a021
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发表时间：
1992
期刊：
影响因子：
2.9
通讯作者：
Sudhakar,AR
中科院分区：
文献类型：
--
作者：
Taton,M;Benveniste,P;Rahier,A;Johnson,WS;Liu,HT;Sudhakar,AR
摘要：合成了单环和三环化合物，其氮原子位于2，3-氧化角鲨烯环化为四环和五环三萜的高能中间体或过渡态的碳正离子位置。在体外和体内测试这些化合物作为2，3-氧化角鲨烯环阿屯醇、羊毛留醇和β（α）-amino-环化酶的抑制剂，并将它们的亲和力与先前合成的8-氮杂-双环化合物的亲和力进行比较[Taton et al.（1986）Biochem. Biophys.通信资源138，764 -770]。单环N-烷基-羟基哌啶被证明是对来自玉米胚的环阿屯醇-环化酶的系列中最强的抑制剂（150 = 1 mM），但对来自黑莓悬浮培养物或豌豆子叶的β（α）-amino-环化酶的有效性低得多。相比之下，13-氮杂-三环衍生物对2，3-氧化角鲨烯环阿屯醇-、羊毛留醇-和β（α）-甘露糖环化酶显示出很小的抑制。所获得的数据证实了环阿屯醇-（羊毛留醇-）环化酶与β（α）-ammonium-环化酶之间在环化过程中存在的差异。结果进行了讨论与目前的机制假设为2，3-氧化角鲨烯环化。由于其在体内和体外的活性，单环A-烷基-羟基哌啶似乎是一个有效的和有前途的工具，研究甾醇生物合成调控。99.7; 2，3-氧化角鲨烯环化酶）是一种参与类固醇和三萜类生物合成的令人感兴趣的酶（巴顿等人，1975年）。在非光合真核生物（脊椎动物、真菌）中催化（3S）-2，3-氧化角鲨烯环化为羊毛甾醇，在光合真核生物（藻类、高等植物）中催化环化为环阿屯醇（1）（Dean，1971）。此外，在大多数高等植物中，它将2，3-氧化角鲨烯环化成多种四环和五环三萜，例如β-和α-香树脂素（Corey & Ortiz de蒙泰拉诺，1967;货车Tamelen et al.，1972年）。这种酶通常在那些不含甾醇的原核生物（细菌、蓝细菌）中未发现（Rohmer等人，1984年）。我们的实验室对这种独特酶的催化活性的机制差异感兴趣。
Revised Manuscript Received May 28, 1992 abstract: Monocyclic and tricyclic compounds possessing a nitrogen atom situated at a position corre-sponding to the carbenium ion of high energy intermediates or transition states involved during cyclization of 2, 3-oxidosqualene to tetra-and pentacyclic triterpenes have been synthesized. These compounds were tested as inhibitors of 2, 3-oxidosqualene cycloartenol, lanosterol-, and/3 (a)-amyrin-cyclases in vitro and in vivo, and their affinity was compared to that of formerly synthesized 8-aza-bicyclic compounds [Taton et al.(1986) Biochem. Biophys. Res. Commun. 138,764-770]. A monocyclic iV-alkyl-hydroxypiperidine was shown to be the strongest inhibitor of the series upon cycloartenol-cyclase (/50= 1 mM) from maize embryos but was much less effective on the/3 (a)-amyrin-cyclases from Rubus fruticosus suspension cultures or pea cotyledons. In contrast, 13-aza-tricyclic derivatives displayed little inhibition on 2, 3-oxidosqualene cy-cloartenol-, lanosterol-, and/3 (a)-amyrin-cyclases. The obtained data exemplify the differences existing in the cyclization process between cycloartenol-(lanosterol-) cyclases on one hand and/3 (a)-amyrin-cy-clases on the other. The results are discussed with respect to current mechanisms postulated for 2, 3-oxidosqualene cyclization. Because of its activity in vivo and invitro the monocyclic A-alkyl-hydroxypiperidine appears to be a potent and promising tool to study sterol biosynthesis regulation.2, 3-Epoxysqualene cyclase (EC 6.5. 99.7; 2, 3-oxidosqualene cyclase) is a fascinating enzyme involved in steroid and tri-terpenoid biosynthesis (Barton et al., 1975). It catalyzes the cyclization of (3S)-2, 3-oxidosqualene into lanosterol in non-photosynthetic eukaryotic organisms (vertebrates, fungi) and into cycloartenol (1) in photosynthetic eukaryotic organisms (algae, higher plants)(Dean, 1971). In addition, it cyclizes 2, 3-oxidosqualene into a great varietyof tetra-and pentacyclic triterpenes, such as/3-and a-amyrins, in most higher plants (Corey & Ortiz de Montellano, 1967; Van Tamelen et al., 1972). This enzyme has generally not been found in those prokaryotic organisms (bacteria, cyanobacteria) which oth-erwise do not contain sterols (Rohmer et al., 1984). Our laboratories are interested in the mechanistic differences underlying the catalytic activity of this unique enzyme.