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Acyl-Coenzyme A Cholesterol AcyltransferaseAcyl-Coenzyme A Cholesterol Acyltransferase

Introduction Acyl-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. Figure 1. ACAT as a Dimer of Dimers - One Monomer is Highlighted ACAT is an important enzyme that catalyzes the esterification of cholesterol to form cholesterol esters, and it belongs to the class of enzymes called acyltransferases. It is also a member of the MBOAT family because it is key in lipid metabolism. This enzyme is biologically important because it affects the solubility of cholesterol in the cell membrane and promotes accumulation of cholesterol ester in the cytoplasm as fat droplets. Accumulation of cholesterol ester as these lipid droplets is a main characteristic of macrophage foaming, which can lead to atherosclerotic diseases . Figure 2. Dimer in the Membrane SOAT article Disease atherosclerosis, Alzheimer's Disease Structural highlights ACAT 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 Figure 3. Monomer in the Membrane. This shows the 9 transmembrane helices. Each are labeled and colored according to the active dimer. , 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. Relevance talk about inhibitor CI-976 Figure 2. CI-976 Inhibitor

spinqualitylabelsall models ACAT Tetramer Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Student ContributorsStudent Contributors

• Tori Templin
• Haylie Moehlenkamp
• Megan Fleshman