6-氯-2-吡咯酮对酵母脂肪酶(CRL1)和胆固醇酯酶(CRL3)的抑制作用:与猪胆固醇酯酶的比较

Mary Stoddard Hatch , William M Brown , Jason A Deck , Lucy A Hunsaker , Lorraine M Deck , David L Vander Jagt
{"title":"6-氯-2-吡咯酮对酵母脂肪酶(CRL1)和胆固醇酯酶(CRL3)的抑制作用:与猪胆固醇酯酶的比较","authors":"Mary Stoddard Hatch ,&nbsp;William M Brown ,&nbsp;Jason A Deck ,&nbsp;Lucy A Hunsaker ,&nbsp;Lorraine M Deck ,&nbsp;David L Vander Jagt","doi":"10.1016/S0167-4838(01)00304-1","DOIUrl":null,"url":null,"abstract":"<div><p>Previously, it was demonstrated that pancreatic cholesterol esterase is selectively inhibited by 6-chloro-2-pyrones with cyclic aliphatic substituents in the 3-position. Inhibition is reversible and is competitive with substrate. Pancreatic cholesterol esterase is a potential target for treatment of hypercholesterolemia. In the present study, yeast cholesterol esterase from <em>Candida cylindracea</em> (also called <em>C. rugosa</em> CRL3) was compared to porcine pancreatic cholesterol esterase for inhibition by a series of 3-alkyl- or 5-alkyl-6-chloro-2-pyrones. In addition, CRL3 was compared with the related yeast lipase CRL1. Inhibition of CRL3 by substituted 6-chloro-2-pyrones was competitive with binding of the substrate <em>p</em>-nitrophenyl butyrate. Inhibition constants ranged from 0.2 μM to &gt;90 μM. Small changes in the alkyl group had profound effects on binding. The pattern of inhibition of CRL3 is quite distinct from that observed with porcine cholesterol esterase. Molecular modeling studies suggest that the orientation of binding of these inhibitors at the active site of CRL3 can vary but that the pyrone ring consistently occupies a position close to the active site serine. CRL1 is highly homologous to CRL3. Nevertheless, patterns of inhibition of CRL1 by substituted 6-chloro-2-pyrones differ markedly from patterns observed with CRL3. The substituted 6-chloro-2-pyrones are slowly hydrolyzed in the presence of CRL1 and are pseudosubstrates of CRL3, but are simple reversible inhibitors of pancreatic cholesterol esterase</p></div>","PeriodicalId":100166,"journal":{"name":"Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2002-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0167-4838(01)00304-1","citationCount":"20","resultStr":"{\"title\":\"Inhibition of yeast lipase (CRL1) and cholesterol esterase (CRL3) by 6-chloro-2-pyrones: comparison with porcine cholesterol esterase\",\"authors\":\"Mary Stoddard Hatch ,&nbsp;William M Brown ,&nbsp;Jason A Deck ,&nbsp;Lucy A Hunsaker ,&nbsp;Lorraine M Deck ,&nbsp;David L Vander Jagt\",\"doi\":\"10.1016/S0167-4838(01)00304-1\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Previously, it was demonstrated that pancreatic cholesterol esterase is selectively inhibited by 6-chloro-2-pyrones with cyclic aliphatic substituents in the 3-position. Inhibition is reversible and is competitive with substrate. Pancreatic cholesterol esterase is a potential target for treatment of hypercholesterolemia. In the present study, yeast cholesterol esterase from <em>Candida cylindracea</em> (also called <em>C. rugosa</em> CRL3) was compared to porcine pancreatic cholesterol esterase for inhibition by a series of 3-alkyl- or 5-alkyl-6-chloro-2-pyrones. In addition, CRL3 was compared with the related yeast lipase CRL1. Inhibition of CRL3 by substituted 6-chloro-2-pyrones was competitive with binding of the substrate <em>p</em>-nitrophenyl butyrate. Inhibition constants ranged from 0.2 μM to &gt;90 μM. Small changes in the alkyl group had profound effects on binding. The pattern of inhibition of CRL3 is quite distinct from that observed with porcine cholesterol esterase. Molecular modeling studies suggest that the orientation of binding of these inhibitors at the active site of CRL3 can vary but that the pyrone ring consistently occupies a position close to the active site serine. CRL1 is highly homologous to CRL3. Nevertheless, patterns of inhibition of CRL1 by substituted 6-chloro-2-pyrones differ markedly from patterns observed with CRL3. The substituted 6-chloro-2-pyrones are slowly hydrolyzed in the presence of CRL1 and are pseudosubstrates of CRL3, but are simple reversible inhibitors of pancreatic cholesterol esterase</p></div>\",\"PeriodicalId\":100166,\"journal\":{\"name\":\"Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2002-04-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1016/S0167-4838(01)00304-1\",\"citationCount\":\"20\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0167483801003041\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0167483801003041","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 20

摘要

先前的研究表明,胰腺胆固醇酯酶被3位环脂肪取代基的6-氯-2-吡咯选择性抑制。抑制作用是可逆的,并与底物竞争。胰胆固醇酯酶是治疗高胆固醇血症的潜在靶点。在本研究中,比较了来自圆柱假丝酵母的酵母胆固醇酯酶(也称为C. rugosa CRL3)与猪胰腺胆固醇酯酶被一系列3-烷基或5-烷基-6-氯-2-吡咯酮抑制的情况。此外,还将CRL3与相关酵母脂肪酶CRL1进行了比较。取代的6-氯-2-吡咯酮对CRL3的抑制作用与底物对硝基苯丁酸酯的结合具有竞争性。抑制常数范围为0.2 μM ~ 90 μM。烷基的微小变化对结合有深远的影响。CRL3的抑制模式与猪胆固醇酯酶的抑制模式截然不同。分子模拟研究表明,这些抑制剂在CRL3活性位点的结合方向可以改变,但吡酮环始终占据靠近活性位点丝氨酸的位置。CRL1与CRL3高度同源。然而,取代的6-氯-2-吡咯酮对CRL1的抑制模式与CRL3观察到的模式明显不同。取代的6-氯-2-吡酮在CRL1存在下缓慢水解,是CRL3的假底物,但是胰腺胆固醇酯酶的简单可逆抑制剂
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Inhibition of yeast lipase (CRL1) and cholesterol esterase (CRL3) by 6-chloro-2-pyrones: comparison with porcine cholesterol esterase

Previously, it was demonstrated that pancreatic cholesterol esterase is selectively inhibited by 6-chloro-2-pyrones with cyclic aliphatic substituents in the 3-position. Inhibition is reversible and is competitive with substrate. Pancreatic cholesterol esterase is a potential target for treatment of hypercholesterolemia. In the present study, yeast cholesterol esterase from Candida cylindracea (also called C. rugosa CRL3) was compared to porcine pancreatic cholesterol esterase for inhibition by a series of 3-alkyl- or 5-alkyl-6-chloro-2-pyrones. In addition, CRL3 was compared with the related yeast lipase CRL1. Inhibition of CRL3 by substituted 6-chloro-2-pyrones was competitive with binding of the substrate p-nitrophenyl butyrate. Inhibition constants ranged from 0.2 μM to >90 μM. Small changes in the alkyl group had profound effects on binding. The pattern of inhibition of CRL3 is quite distinct from that observed with porcine cholesterol esterase. Molecular modeling studies suggest that the orientation of binding of these inhibitors at the active site of CRL3 can vary but that the pyrone ring consistently occupies a position close to the active site serine. CRL1 is highly homologous to CRL3. Nevertheless, patterns of inhibition of CRL1 by substituted 6-chloro-2-pyrones differ markedly from patterns observed with CRL3. The substituted 6-chloro-2-pyrones are slowly hydrolyzed in the presence of CRL1 and are pseudosubstrates of CRL3, but are simple reversible inhibitors of pancreatic cholesterol esterase

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信