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==Introduction==
==Introduction==
Acyl-Coenzyme A Cholesterol Acyltransferase (ACAT), or also known as Sterol ''O''-Acyltransferase (SOAT), is an important enzyme in the body.  
Acyl-Coenzyme A Cholesterol Acyltransferase (ACAT), or also known as Sterol ''O''-Acyltransferase (SOAT), is an important enzyme in the body.  
Cholesterol esters were discovered in arterial lesions in 1910. Between 1980-1995, the interest in ACAT inhibitors grew, but some of the compounds looked at exhibited toxicity. In 1993, an ACAT gene was successfully cloned. This discovery led to more studies with ACAT and atherosclerosis.  
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.  
<ref name=”Farese Jr.”>PMID: 16857957</ref>
<ref name=”Farese Jr.”>PMID: 16857957</ref>
add more history 
[[Image:Screen Shot 2021-03-16 at 3.11.39 PM.png|400 px|right|thumb|Figure 1. ACAT as a Dimer of Dimers - One Monomer is Highlighted]]
[[Image:Screen Shot 2021-03-16 at 3.11.39 PM.png|400 px|right|thumb|Figure 1. ACAT as a Dimer of Dimers - One Monomer is Highlighted]]


== Function ==
[https://en.wikipedia.org/wiki/Sterol_O-acyltransferase 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 [https://en.wikipedia.org/wiki/MBOAT 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 <ref name=”Qian”>PMID:32433614</ref>.
ACAT is an important enzyme that catalyzes the esterification of cholesterol to form cholesterol esters.
 
[[Image:Screen_Shot_2021-04-13_at_2.37.52_PM.jpg|400 px|right|thumb|Figure 2. Dimer in the Membrane]]
 
SOAT article <ref name=”Chengcheng”>PMID:32424158</ref>
SOAT article <ref name=”Chengcheng”>PMID:32424158</ref>
ACAT article <ref name=”Qian”>PMID:32433614</ref>
 


== Disease ==
== Disease ==
Line 19: Line 20:
ACAT is a dimer of dimers, which is also known as a [https://en.wikipedia.org/wiki/Tetramer tetramer].  
ACAT is a dimer of dimers, which is also known as a [https://en.wikipedia.org/wiki/Tetramer tetramer].  
This  
This  
<scene name='87/877604/Tetramer/1'>tetramer</scene>
<scene name='87/877604/Tetramer/2'>tetramer</scene>
is about 260 kDa and is composed completely of helices, with each monomer containing 9 transmembrane helices.  
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. [[Image:Screen_Shot_2021-04-13_at_3.17.02_PM.jpg|400 px|right|thumb|Figure 3. Monomer in the Membrane. This shows the 9 transmembrane helices. Each are labeled and colored according to the active dimer.]]
The  
The  
<scene name='87/877604/Colored_dimer/2'>dimer of ACAT</scene>
<scene name='87/877604/Colored_dimer/3'>dimer of ACAT</scene>
was found to be the active arrangement.
was found to be the active arrangement.
The  
The  
<scene name='87/877604/Dimer_interface/1'>dimer-dimer interface</scene>
<scene name='87/877604/Dimer_interface/16'>dimer-dimer interface</scene>
is mobile and mostly hydrophobic.
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 ==
== Relevance ==
talk about inhibitor CI-976
talk about inhibitor CI-976
<scene name='87/877626/Overlay/6'>Overlay</scene>
<scene name='87/877626/Overlay/10'>overlay</scene>
<scene name='87/877626/Overlay/8'>CI976 vs. Inhibitor</scene>
<scene name='87/877626/Overlay/8'>CI976 vs. Inhibitor</scene>
[[Image: CI-976.jpg|300 px|right|thumb|Figure 2. CI-976 Inhibitor]]
[[Image: CI-976_chemdraw.jpg|300 px|right|thumb|Figure 4. CI-976 Inhibitor]]
</StructureSection>
</StructureSection>
== References ==
== References ==

Latest revision as of 23:05, 20 April 2021

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. [1]

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 [2].

Figure 2. Dimer in the Membrane

SOAT article [3]


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, which have been color-coordinated to help with orientation within structures.

Figure 3. Monomer in the Membrane. This shows the 9 transmembrane helices. Each are labeled and colored according to the active dimer.

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 4. CI-976 Inhibitor

ACAT Tetramer

Drag the structure with the mouse to rotate

ReferencesReferences

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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

Student ContributorsStudent Contributors

  • Tori Templin
  • Haylie Moehlenkamp
  • Megan Fleshman
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