User:Tori Templin/Sandbox 1: Difference between revisions
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== Function == | == Function == | ||
ACAT is an important enzyme that catalyzes the esterification of cholesterol to form cholesterol esters. | [https://en.wikipedia.org/wiki/Sterol_O-acyltransferase ACAT] is an important enzyme that catalyzes the esterification of cholesterol to form cholesterol esters. | ||
SOAT article <ref name=”Chengcheng”>PMID:32424158</ref> | SOAT article <ref name=”Chengcheng”>PMID:32424158</ref> | ||
ACAT article <ref name=”Qian”>PMID:32433614</ref> | ACAT article <ref name=”Qian”>PMID:32433614</ref> | ||
Revision as of 21:40, 6 April 2021
Acyl-Coenzyme A Cholesterol AcyltransferaseAcyl-Coenzyme A Cholesterol Acyltransferase
IntroductionAcyl-Coenzyme A Cholesterol Acyltransferase (ACAT), or also known as Sterol O-Acyltransferase (SOAT), is an important enzyme in the body. Cholesterol esters were found in arterial lesions in 1910, but the first ACAT activity was discovered in the mid 1900's. This led to the inhibition of ACAT as being looked at as a possible strategy of preventing or treating atherosclerosis. Between 1980-1995, the interest in ACAT inhibitors grew, but some of the compounds looked at exhibited toxicity. As they were looking into the function of the ACAT1 gene, ACAT2 was discovered. In 1993, an ACAT gene was successfully cloned. This discovery led to more studies with ACAT and atherosclerosis. Some of these studies used mice and showed cellular toxicity. ACAT inhibition is still being looked into as a strategy for treatment or prevention of atherosclerosis and related diseases. [1]  FunctionACAT is an important enzyme that catalyzes the esterification of cholesterol to form cholesterol esters. SOAT article [2] ACAT article [3] Diseaseatherosclerosis, Alzheimer's Disease Structural highlightsACAT is a dimer of dimers, which is also known as a tetramer. This is about 260 kDa and is composed completely of helices, with each monomer containing 9 transmembrane helices, which have been color-coordinated to help with orientation within structures. The was found to be the active arrangement. The is mobile and mostly hydrophobic, and the residues interact in a shape-complementary manner. It was also found that the reaction chamber is shielded by a lid from the cytosolic side, which leads to low catalytic activity. The binding of acyl-CoA and cholesterol induce conformational changes that activate the tunnels. Work is still being done to fully determine the mechanism of this reaction, but this is the proposed pathway. The cholesterol enters through the T tunnel while the acyl-CoA enters through the C tunnel. The reaction is catalyzed at the intersection of the two tunnels, where the His460 residue is located. The CoASH is released to the cytosol from the C tunnel, but the cholesterol ester either exits from the T tunnel to the membrane or through the L tunnel to the lumen. Relevancetalk about inhibitor CI-976
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ReferencesReferences
- ↑ Farese RV Jr. The nine lives of ACAT inhibitors. Arterioscler Thromb Vasc Biol. 2006 Aug;26(8):1684-6. doi:, 10.1161/01.ATV.0000227511.35456.90. PMID:16857957 doi:http://dx.doi.org/10.1161/01.ATV.0000227511.35456.90
- ↑ Guan C, Niu Y, Chen SC, Kang Y, Wu JX, Nishi K, Chang CCY, Chang TY, Luo T, Chen L. Structural insights into the inhibition mechanism of human sterol O-acyltransferase 1 by a competitive inhibitor. Nat Commun. 2020 May 18;11(1):2478. doi: 10.1038/s41467-020-16288-4. PMID:32424158 doi:http://dx.doi.org/10.1038/s41467-020-16288-4
- ↑ Qian H, Zhao X, Yan R, Yao X, Gao S, Sun X, Du X, Yang H, Wong CCL, Yan N. Structural basis for catalysis and substrate specificity of human ACAT1. Nature. 2020 May;581(7808):333-338. doi: 10.1038/s41586-020-2290-0. Epub 2020 May, 13. PMID:32433614 doi:http://dx.doi.org/10.1038/s41586-020-2290-0
Student ContributorsStudent Contributors
- Tori Templin
- Haylie Moehlenkamp
- Megan Fleshman