Acyl-CoA:cholesterol acyltransferases (ACATs/SOATs): Enzymes with multiple sterols as substrates and as activators.
Acyl-CoA:cholesterol acyltransferases (ACATs/SOATs): Enzymes with multiple sterols as substrates and as activators.
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DOI：
10.1016/j.jsbmb.2014.09.008
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发表时间：
2015-07
期刊：
影响因子：
--
通讯作者：
Chang TY
中科院分区：
文献类型：
--
作者：
Rogers MA;Liu J;Song BL;Li BL;Chang CC;Chang TY
胆固醇对细胞的生长和活力至关重要。胆固醇的代谢产物包括：类固醇、氧化固醇和胆汁酸，它们都发挥重要的生理功能。胆固醇及其代谢产物与多种人类疾病的发病机制有关，包括：动脉粥样硬化、癌症、神经退行性疾病和糖尿病。因此，了解细胞如何维持胆固醇及其代谢物的稳态是一个重要的研究领域。酰基辅酶A：胆固醇酰基转移酶（Acyl-coenzyme A：cholesterol acyltransferases，ACATs，也缩写为SOATs）将胆固醇转化为胆固醇酯，并在细胞胆固醇稳态调节中起关键作用。ACATs是最不寻常的酶，因为（i）它们代谢不同的底物，包括固醇和某些类固醇;（ii）它们含有两个不同的类固醇分子结合位点。在哺乳动物中，有两种ACAT基因编码两种不同的酶，ACAT 1和ACAT 2。两者都是变构酶，可以被多种固醇激活。除胆固醇外，其他在C-3位具有3-β OH的甾醇，包括PREG、氧化甾醇（如24（S）-羟基胆固醇和27-羟基胆固醇等）、和各种植物甾醇，都可能是ACAT底物。所有具有异辛基侧链的甾醇，包括胆固醇、氧化甾醇、各种植物甾醇都可以是ACAT的活化剂。PREG只能是ACAT底物，因为它缺乏成为ACAT活化剂所需的异辛基侧链。非天然胆固醇类似物表-胆固醇（在类固醇环B中具有3-α OH）和内-胆固醇（胆固醇的镜像）含有异辛基侧链，但在C-3处不具有3-β OH。因此，它们只能作为活化剂而不能作为底物。因此，在ACAT全酶内，存在结合作为底物的固醇的位点和结合作为激活剂的固醇的位点;这些位点彼此不同。这些特征构成了进一步进行ACAT结构-功能分析的基础，并且可以探索开发用于治疗目的的新型变构ACAT抑制剂。
Cholesterol is essential to the growth and viability of cells. The metabolites of cholesterol include: steroids, oxysterols, and bile acids, all of which play important physiological functions. Cholesterol and its metabolites have been implicated in the pathogenesis of multiple human diseases, including: atherosclerosis, cancer, neurodegenerative diseases, and diabetes. Thus, understanding how cells maintain the homeostasis of cholesterol and its metabolites is an important area of study. Acyl-coenzyme A:cholesterol acyltransferases (ACATs, also abbreviated as SOATs) converts cholesterol to cholesteryl esters and play key roles in the regulation of cellular cholesterol homeostasis. ACATs are most unusual enzymes because (i) they metabolize diverse substrates including both sterols and certain steroids; (ii) they contain two different binding sites for steroidal molecules. In mammals, there are two ACAT genes that encode two different enzymes, ACAT1 and ACAT2. Both are allosteric enzymes that can be activated by a variety of sterols. In addition to cholesterol, other sterols that possess the 3-beta OH at C-3, including PREG, oxysterols (such as 24(S)-hydroxycholesterol and 27-hydroxycholesterol, etc.), and various plant sterols, could all be ACAT substrates. All sterols that possess the iso-octyl side chain including cholesterol, oxysterols, various plant sterols could all be activators of ACAT. PREG can only be an ACAT substrate because it lacks the isooctyl side chain required to be an ACAT activator. The unnatural cholesterol analogs epi-cholesterol (with 3-alpha OH in steroid ring B) and ent-cholesterol (the mirror image of cholesterol) contain the iso-octyl side chain but do not have the 3-beta OH at C-3. Thus, they can only serve as activators and cannot serve as substrates. Thus, within the ACAT holoenzyme, there are site(s) that bind sterol as substrate and site(s) that bind sterol as activator; these sites are distinct from each other. These features form the basis to further pursue ACAT structure-function analysis, and can be explored to develop novel allosteric ACAT inhibitors for therapeutic purposes.