Sterol O-acyltransferase

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sterol O-acyltransferase
Identifiers
EC no. 2.3.1.26
CAS no. 9027-63-8
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO
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PMC articles
PubMed articles
NCBI proteins
sterol O-acyltransferase 1
Identifiers
Symbol SOAT1
Alt. symbolsACAT, SOAT, STAT
NCBI gene 6646
HGNC 11177
OMIM 102642
RefSeq NM_003101
UniProt P35610
Other data
EC number 2.3.1.26
Locus Chr. 1 q25
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Structures Swiss-model
Domains InterPro
sterol O-acyltransferase 2
Identifiers
Symbol SOAT2
Alt. symbolsACAT2
NCBI gene 8435
HGNC 11178
OMIM 601311
RefSeq NM_003578
UniProt O75908
Other data
EC number 2.3.1.26
Locus Chr. 12
Search for
Structures Swiss-model
Domains InterPro

Sterol O-acyltransferase (also called Acyl-CoA cholesterol acyltransferase, Acyl-CoA cholesterin acyltransferase[ citation needed ] or simply ACAT) is an intracellular protein located in the endoplasmic reticulum that forms cholesteryl esters from cholesterol.

Contents

Sterol O-acyltransferase catalyzes the chemical reaction:

acyl-CoA + cholesterol CoA + cholesterol ester

Thus, the two substrates of this enzyme are acyl-CoA and cholesterol, whereas its two products are CoA and cholesteryl ester.

This enzyme belongs to the family of transferases, specifically those acyltransferases transferring groups other than aminoacyl groups, the membrane-bound O-acyltransferases. This enzyme participates in bile acid biosynthesis.

Class and structure

Acyl-CoA cholesterol acyl transferase EC 2.3.1.26, more simply referred to as ACAT, also known as sterol O-acyltransferase (SOAT), belongs to the class of enzymes known as acyltransferases. The role of this enzyme is to transfer fatty acyl groups from one molecule to another. ACAT is an important enzyme in bile acid biosynthesis.

In nearly all mammalian cells, ACAT catalyzes the intracellular esterification of cholesterol and formation of cholesteryl esters. The esterification of cholesterol mediated by ACAT is functionally significant for several reasons. ACAT-mediated esterification of cholesterol limits its solubility in the cell membrane lipids and thus promotes accumulation of cholesterol ester in the fat droplets within cytoplasm; this process is important because the toxic accumulation of free cholesterol in various cell membrane fractions is prevented. Most of the cholesterol absorbed during intestinal transport undergoes ACAT-mediated esterification before incorporation in chylomicrons. In the liver, ACAT-mediated esterification of cholesterol is involved in the production and release of apoB-containing lipoproteins. ACAT also plays an important role in foam cell formation and atherosclerosis by participating in accumulating cholesterol esters in macrophages and vascular tissue. The rate-controlling enzyme in cholesterol catabolism, hepatic cholesterol 7-hydroxylase, is believed to be regulated partly by ACAT. [1]

Mechanism

The mechanism scheme is as follows:
Acyl-CoA + Cholesterol ←→ CoA + Cholesteryl ester [2]

Isoforms

There are two isoforms of SOAT (also sometimes referred to as ACAT) that have been reported to date: SOAT1 and SOAT2. SOAT1 is characterized by its ubiquitous presence in tissues with the exception of the intestine, where SOAT2 is prevalent. The different isoforms are also associated with different pathologies associated with abnormalities in lipid metabolism. [3]

SOAT1 (ACAT1)

Previous studies have shown that SOAT modulates proteolytic processing in cell-based and animal models of Alzheimer's disease. A follow-up study reports that SOAT1 RNAi reduced cellular SOAT1 protein and cholesteryl ester levels while causing a slight increase in free cholesterol content of endoplasmic reticulum membranes. The data also showed that a modest decrease in SOAT activity led to suppressive effects on Abeta generation. [3]

SOAT2 (ACAT2)

In a recent study, it was shown that SOAT2 activity is upregulated as a result of chronic renal failure. This study was specific to hepatic SOAT, which plays a major role in hepatic production and release of very low density lipoprotein (VLDL), release of cholesterol, foam cell formation, and atherogenesis. [3] In another study, non-human primates revealed a positive correlation between liver cholesteryl ester secretion rate and the development of coronal artery atherosclerosis. The results of the experiment are indicative that under all of the conditions of cellular cholesterol availability tested, the relative level of SOAT2 expression affects the cholesteryl ester content, and therefore the atherogenecity of nascent apoB-containing lipoproteins. [4]

Yeast

In yeast, acyl-CoA:sterol acyltransferase (ASAT) is functionally equivalent to ACAT. Although studies in vitro and in yeast suggest that the acyl-CoA binding protein (ACBP) may modulate long-chain fatty acyl-CoA (LCFA-CoA) distribution, the physiological function in mammals is unresolved. Recent research suggests that ACBP expression may play a role in LCFA-CoA metabolism in a physiological context. [5]

In S. cerevisiae , the accumulation of ergosteryl esters accompanies entry into the stationary phase and sporulation. Researchers have identified two genes in yeast, ARE2 and ARE1, that encode the different isozymes of ASAT. In yeast, Are2 is the major catalytic isoform. Mitotic cell growth and spore germination are not compromised when these genes are deleted, but diploids that are homozygous for an ARE2 null mutation exhibit a decrease in sporulation efficiency. [6]

Plant Synthesis of Steryl Esters

In plants cellular sterol ester synthesis is performed by an enzyme different from mammalian ACAT and yeast ASAT; it is performed by Phospholipid:Sterol Acyltransferase (PSAT). A recent study shows that PSAT is involved in the regulation of the pool of free sterols and the amount of free sterol intermediates in the membranes. It is also described as the only intracellular enzyme discovered that catalyzes an acyl-CoA independent sterol ester formation. PSAT is therefore considered to have a similar physiological function in plant cells as ACAT in animal cells. [7]

See also

Related Research Articles

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Cholesterol is the principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils.

<span class="mw-page-title-main">Lipid</span> Substance of biological origin that is soluble in nonpolar solvents

Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins, monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing energy, signaling, and acting as structural components of cell membranes. Lipids have applications in the cosmetic and food industries, and in nanotechnology.

<span class="mw-page-title-main">Lipoprotein</span> Biochemical assembly whose purpose is to transport hydrophobic lipid molecules

A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, surrounded by a phospholipid outer shell, with the hydrophilic portions oriented outward toward the surrounding water and lipophilic portions oriented inward toward the lipid center. A special kind of protein, called apolipoprotein, is embedded in the outer shell, both stabilising the complex and giving it a functional identity that determines its role.

Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown and storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In animals, these fats are obtained from food and are synthesized by the liver. Lipogenesis is the process of synthesizing these fats. The majority of lipids found in the human body from ingesting food are triglycerides and cholesterol. Other types of lipids found in the body are fatty acids and membrane lipids. Lipid metabolism is often considered as the digestion and absorption process of dietary fat; however, there are two sources of fats that organisms can use to obtain energy: from consumed dietary fats and from stored fat. Vertebrates use both sources of fat to produce energy for organs such as the heart to function. Since lipids are hydrophobic molecules, they need to be solubilized before their metabolism can begin. Lipid metabolism often begins with hydrolysis, which occurs with the help of various enzymes in the digestive system. Lipid metabolism also occurs in plants, though the processes differ in some ways when compared to animals. The second step after the hydrolysis is the absorption of the fatty acids into the epithelial cells of the intestinal wall. In the epithelial cells, fatty acids are packaged and transported to the rest of the body.

<span class="mw-page-title-main">Lecithin–cholesterol acyltransferase</span> Mammalian protein found in Homo sapiens

Lecithin–cholesterol acyltransferase is an enzyme, in many animals including humans, that converts free cholesterol into cholesteryl ester, which is then sequestered into the core of a lipoprotein particle, eventually making the newly synthesized HDL spherical and forcing the reaction to become unidirectional since the particles are removed from the surface. The enzyme is bound to high-density lipoproteins (HDLs) (alpha-LCAT) and LDLs (beta-LCAT) in the blood plasma. LCAT deficiency can cause impaired vision due to cholesterol corneal opacities, anemia, and kidney damage. It belongs to the family of phospholipid:diacylglycerol acyltransferases.

<span class="mw-page-title-main">Cholesteryl ester</span> An ester of cholesterol

Cholesteryl ester, a dietary lipid, is an ester of cholesterol. The ester bond is formed between the carboxylate group of a fatty acid and the hydroxyl group of cholesterol. Cholesteryl esters have a lower solubility in water due to their increased hydrophobicity. Esters are formed by replacing at least one –OH (hydroxyl) group with an –O–alkyl (alkoxy) group. They are hydrolyzed by pancreatic enzymes, cholesterol esterase, to produce cholesterol and free fatty acids. They are associated with atherosclerosis.

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<span class="mw-page-title-main">Thiolase</span> Enzymes

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<span class="mw-page-title-main">ACAT1</span> Protein-coding gene in the species Homo sapiens

Acetyl-CoA acetyltransferase, mitochondrial, also known as acetoacetyl-CoA thiolase, is an enzyme that in humans is encoded by the ACAT1 gene.

In enzymology, a long-chain-alcohol O-fatty-acyltransferase is an enzyme that catalyzes the chemical reaction

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<span class="mw-page-title-main">SOAT1</span> Protein-coding gene in the species Homo sapiens

Sterol O-acyltransferase 1, also known as SOAT1, is an enzyme that in humans is encoded by the SOAT1 gene.

<span class="mw-page-title-main">SOAT2</span> Protein-coding gene in the species Homo sapiens

Sterol O-acyltransferase 2, also known as SOAT2, is an enzyme that in humans is encoded by the SOAT2 gene.

<span class="mw-page-title-main">ACAT2</span> Protein-coding gene in the species Homo sapiens

Acetyl-CoA acetyltransferase, cytosolic, also known as cytosolic acetoacetyl-CoA thiolase, is an enzyme that in humans is encoded by the ACAT2 gene

<span class="mw-page-title-main">1-Lysophosphatidylcholine</span>

2-acyl-sn-glycero-3-phosphocholines are a class of phospholipids that are intermediates in the metabolism of lipids. Because they result from the hydrolysis of an acyl group from the sn-1 position of phosphatidylcholine, they are also called 1-lysophosphatidylcholine. The synthesis of phosphatidylcholines with specific fatty acids occurs through the synthesis of 1-lysoPC. The formation of various other lipids generates 1-lysoPC as a by-product.

<span class="mw-page-title-main">C-5 sterol desaturase</span> Class of enzymes

C-5 sterol desaturase is an enzyme that is highly conserved among eukaryotes and catalyzes the dehydrogenation of a C-5(6) bond in a sterol intermediate compound as a step in the biosynthesis of major sterols. The precise structure of the enzyme's substrate varies by species. For example, the human C-5 sterol desaturase oxidizes lathosterol, while its ortholog ERG3 in the yeast Saccharomyces cerevisiae oxidizes episterol.

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<span class="mw-page-title-main">Avasimibe</span> Drug

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References

  1. Katsuren K, Tamura T, Arashiro R, Takata K, Matsuura T, Niikawa N, Ohta T (April 2001). "Structure of the human acyl-CoA:cholesterol acyltransferase-2 (ACAT-2) gene and its relation to dyslipidemia". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1531 (3): 230–40. doi:10.1016/S1388-1981(01)00106-8. PMID   11325614.
  2. "KEGG Reaction: R01461". Kyoto Encyclopedia of Genes and Genomes. Kanehisa Laboratories. Retrieved 2009-05-06.
  3. 1 2 3 Temel RE, Hou L, Rudel LL, Shelness GS (July 2007). "ACAT2 stimulates cholesteryl ester secretion in apoB-containing lipoproteins". Journal of Lipid Research. 48 (7): 1618–27. doi: 10.1194/jlr.M700109-JLR200 . PMID   17438337.
  4. Huttunen HJ, Greco C, Kovacs DM (April 2007). "Knockdown of ACAT-1 Reduces Amyloidogenic Processing of APP". FEBS Letters. 581 (8): 1688–92. doi:10.1016/j.febslet.2007.03.056. PMC   1896096 . PMID   17412327.
  5. Huang H, Atshaves BP, Frolov A, Kier AB, Schroeder F (August 2005). "Acyl-coenzyme A binding protein expression alters liver fatty acyl-coenzyme A metabolism". Biochemistry. 44 (30): 10282–97. doi:10.1021/bi0477891. PMID   16042405.
  6. Yu C, Kennedy NJ, Chang CC, Rothblatt JA (September 1996). "Molecular cloning and characterization of two isoforms of Saccharomyces cerevisiae acyl-CoA:sterol acyltransferase". The Journal of Biological Chemistry. 271 (39): 24157–63. doi: 10.1074/jbc.271.39.24157 . PMID   8798656.
  7. Banas A, Carlsson AS, Huang B, Lenman M, Banas W, Lee M, Noiriel A, Benveniste P, Schaller H, Bouvier-Navé P, Stymne S (October 2005). "Cellular sterol ester synthesis in plants is performed by an enzyme (phospholipid:sterol acyltransferase) different from the yeast and mammalian acyl-CoA:sterol acyltransferases". The Journal of Biological Chemistry. 280 (41): 34626–34. doi: 10.1074/jbc.M504459200 . PMID   16020547.

Further reading