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在完整细胞中，通过 beauveriolide III 对甾醇 O-酰基转移酶 1 同工酶的选择性抑制。

Selective inhibition of sterolO-acyltransferase 1 isozyme by beauveriolide III in intact cells.

机构信息

Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, 108-8641, Japan.

Section on Lipid Sciences, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.

出版信息

Sci Rep. 2017 Jun 23;7(1):4163. doi: 10.1038/s41598-017-04177-8.

DOI:10.1038/s41598-017-04177-8
PMID:28646165
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5482845/
Abstract

Beauveriolide III (BeauIII) inhibited sterol O-acyltransferases 1 and 2 (SOAT1 and SOAT2), which are endoplasmic reticulum (ER) membrane proteins, in an enzyme-based assay, and selectively inhibited SOAT1 in a cell-based assay using SOAT1-/SOAT2-CHO cells. This discrepancy in SOAT inhibition by BeauIII was investigated. In the enzyme-based assay, BeauIII inhibited SOAT1 and SOAT2 to a similar extent using microsomes prepared from cells disrupted under the strongest sonication condition. In semi-intact SOAT1-/SOAT2-CHO cells prepared by a treatment with digitonin (plasma membrane permeabilized), BeauIII selectively inhibited SOAT1 (IC; 5.0 µM (SOAT1) vs >90 µM (SOAT2)), while in those treated with saponin (plasma membrane and ER membrane permeabilized), BeauIII inhibited SOAT1 (IC, 1.8 µM) and SOAT2 (5.9 µM). SOAT1-selective inhibition by BeauIII was reproduced in intact ER fractions prepared from SOAT1/SOAT2-CHO cells. A Western blotting analysis revealed that biotin-labeled beauveriolide bound to the SOAT1 protein prepared from SOAT1-CHO cells. We concluded that BeauIII binds to a putative active site responsible for SOAT1 that is located on the cytosolic side of the ER, while BeauIII is not accessible to the corresponding active site for SOAT2 located on the luminal side.

摘要

蜂房霉素 III（BeauIII）在基于酶的测定中抑制内质网（ER）膜蛋白甾醇 O-酰基转移酶 1 和 2（SOAT1 和 SOAT2），并在使用 SOAT1-/SOAT2-CHO 细胞的基于细胞的测定中选择性抑制 SOAT1。研究了 BeauIII 对 SOAT 抑制的这种差异。在基于酶的测定中，使用在最强超声条件下破坏细胞制备的微粒体，BeauIII 以相似的程度抑制 SOAT1 和 SOAT2。在用二氢月桂酸（质膜通透）处理制备的半完整 SOAT1-/SOAT2-CHO 细胞中，BeauIII 选择性抑制 SOAT1（IC；5.0µM（SOAT1）比 >90µM（SOAT2）），而在用皂素（质膜和 ER 膜通透）处理时，BeauIII 抑制 SOAT1（IC，1.8µM）和 SOAT2（5.9µM）。BeauIII 对 SOAT1 的选择性抑制作用在从 SOAT1/SOAT2-CHO 细胞制备的完整 ER 级分中得到重现。Western 印迹分析显示，生物素标记的蜂房霉素与从 SOAT1-CHO 细胞制备的 SOAT1 蛋白结合。我们得出结论，BeauIII 结合到位于 ER 胞质侧的负责 SOAT1 的假定活性部位，而 BeauIII 无法到达位于腔侧的对应 SOAT2 活性部位。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1fd0/5482845/fd6ed0b4c2f8/41598_2017_4177_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1fd0/5482845/5eb1c4a2e619/41598_2017_4177_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1fd0/5482845/ebc860b4a479/41598_2017_4177_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1fd0/5482845/05b36eb55202/41598_2017_4177_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1fd0/5482845/38448562343f/41598_2017_4177_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1fd0/5482845/fd6ed0b4c2f8/41598_2017_4177_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1fd0/5482845/5eb1c4a2e619/41598_2017_4177_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1fd0/5482845/ebc860b4a479/41598_2017_4177_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1fd0/5482845/05b36eb55202/41598_2017_4177_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1fd0/5482845/38448562343f/41598_2017_4177_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1fd0/5482845/fd6ed0b4c2f8/41598_2017_4177_Fig5_HTML.jpg

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