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• W2011185005 abstract "Triacylglycerols (triglycerides) (TGs) are the major storage molecules of metabolic energy and FAs in most living organisms. Excessive accumulation of TGs, however, is associated with human diseases, such as obesity, diabetes mellitus, and steatohepatitis. The final and the only committed step in the biosynthesis of TGs is catalyzed by acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes. The genes encoding two DGAT enzymes, DGAT1 and DGAT2, were identified in the past decade, and the use of molecular tools, including mice deficient in either enzyme, has shed light on their functions. Although DGAT enzymes are involved in TG synthesis, they have distinct protein sequences and differ in their biochemical, cellular, and physiological functions. Both enzymes may be useful as therapeutic targets for diseases. Here we review the current knowledge of DGAT enzymes, focusing on new advances since the cloning of their genes, including possible roles in human health and diseases. Triacylglycerols (triglycerides) (TGs) are the major storage molecules of metabolic energy and FAs in most living organisms. Excessive accumulation of TGs, however, is associated with human diseases, such as obesity, diabetes mellitus, and steatohepatitis. The final and the only committed step in the biosynthesis of TGs is catalyzed by acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes. The genes encoding two DGAT enzymes, DGAT1 and DGAT2, were identified in the past decade, and the use of molecular tools, including mice deficient in either enzyme, has shed light on their functions. Although DGAT enzymes are involved in TG synthesis, they have distinct protein sequences and differ in their biochemical, cellular, and physiological functions. Both enzymes may be useful as therapeutic targets for diseases. Here we review the current knowledge of DGAT enzymes, focusing on new advances since the cloning of their genes, including possible roles in human health and diseases. Triacylglycerols (triglycerides) (TGs), a major type of neutral lipid, are a heterogeneous group of molecules with a glycerol backbone and three FAs attached by ester bonds. The physical and chemical properties of TG differ based on chain length and the degree to which their FAs are desaturated. TGs serve multiple important functions in living organisms. Chief among these, they are the major storage molecules of FA for energy utilization and the synthesis of membrane lipids. Because they are highly reduced and anhydrous, TGs store 6-fold more energy than the same amount of hydrated glycogen (1Stryer L. Biochemistry. W.H. Freeman & Co., New York, NY1988: 471Google Scholar). In plants, TGs are a major component of seed oils, which are valuable resources for dietary consumption and industrial uses. TG from plants and microorganisms can also be used for biofuels. In animals, energy stores of TG are concentrated primarily in adipocytes, although TGs are also found prominently in myocytes, hepatocytes, enterocytes, and mammary epithelial cells. In addition to energy storage, TG synthesis in cells may protect them from the potentially toxic effects of excess FA. In the enterocytes and hepatocytes of most mammals, TGs are synthesized for the assembly and secretion of lipoproteins, which transport dietary and endogenously synthesized FA between tissues. Also, TGs in secreted lipids acts as a component of the skin's surface water barrier, and collections of TG in adipose tissue provide insulation for organisms. Although TGs are essential for normal physiology, the excessive accumulation of TG in human adipose tissue results in obesity and, in nonadipose tissues, is associated with organ dysfunction. For example, excessive TG deposition in skeletal muscle and the liver is associated with insulin resistance, in the liver with nonalcoholic steatohepatitis, and in the heart with cardiomyopathy (2Unger R.H. Lipotoxic diseases.Annu. Rev. Med. 2002; 53: 319-336Crossref PubMed Scopus (796) Google Scholar, 3Friedman J. Fat in all the wrong places.Nature. 2002; 415: 268-269Crossref PubMed Scopus (0) Google Scholar). Owing to worldwide increases in the prevalence of obesity and other diseases of excessive TG accumulation, an understanding of the basic processes that govern TG synthesis and storage is of considerable biomedical importance. Two major pathways for TG biosynthesis, elucidated in the 1950s and 1960s, are known: the glycerol phosphate or Kennedy pathway (4Kennedy E. Metabolism of lipides.Annu. Rev. Biochem. 1957; 26: 119-148Crossref PubMed Google Scholar) and the monoacylglycerol (MG) pathway (Fig. 1A) (for reviews of pathway biochemistry, see Refs. 5Bell R.M. Coleman R.A. Enzymes of glycerolipid synthesis in eukaryotes.Annu. Rev. Biochem. 1980; 49: 459-487Crossref PubMed Google Scholar, 6Brindley D.N. Biochemistry of Lipids, Lipoproteins and Membranes. Elsevier, Amsterdam, The Netherlands1991: 171-203Google Scholar, 7Lehner R. Kuksis A. Biosynthesis of triacylglycerols.Prog. Lipid Res. 1996; 35: 169-201Crossref PubMed Scopus (242) Google Scholar, 8Coleman R.A. Lee D.P. Enzymes of triacylglycerol synthesis and their regulation.Prog. Lipid Res. 2004; 43: 134-176Crossref PubMed Scopus (626) Google Scholar). Both pathways use fatty acyl-CoAs, the “activated” forms of FA synthesized by intracellular acyl-CoA synthases, as acyl donors (9Coleman R. Lewin T. Van Horn C. Gonzalez-Baró M. Do long-chain acyl-CoA synthetases regulate fatty acid entry into synthetic versus degradative pathways?.J. Nutr. 2002; 132: 2123-2126Crossref PubMed Google Scholar). The glycerol phosphate pathway is present in most cells. In contrast, the MG pathway is found in specific cell types, such as enterocytes, hepatocytes, and adipocytes, where it may participate in the reesterification of hydrolyzed TG (10Xia T. Mostafa N. Bhat B.G. Florant G.L. Coleman R.A. Selective retention of essential fatty acids: The role of hepatic monoacylglycerol acyltransferase.Am. J. Physiol. 1993; 265: R414-R419PubMed Google Scholar). The MG pathway is the dominant mode of TG synthesis in human small intestine, where TGs are synthesized from components of hydrolyzed dietary fats (11Kayden H.J. Senior J.R. Mattson F.H. The monoglyceride pathway of fat absorption in man.J. Clin. Invest. 1967; 46: 1695-1703Crossref PubMed Google Scholar, 12Mansbach II, C.M. Gorelick F. Development and physiological regulation of intestinal lipid absorption. II. Dietary lipid absorption, complex lipid synthesis, and the intracellular packaging and secretion of chylomicrons.Am. J. Physiol. Gastrointest. Liver Physiol. 2007; 293: G645-G650Crossref PubMed Scopus (105) Google Scholar). In the final reaction of both pathways, a fatty acyl-CoA and diacylglycerol (DG) molecule are covalently joined to form TG. This reaction (Fig. 1B) is catalyzed by acyl-CoA:diacylglycerol acyltransferase (DGAT, E.C. 2.3.1.20) enzymes. TG biosynthesis is believed to occur mainly at the endoplasmic reticulum (ER) (13Weiss S.B. Kennedy E.P. Kiyasu J.Y. The enzymatic synthesis of triglycerides.J. Biol. Chem. 1960; 235: 40-44Abstract Full Text PDF PubMed Google Scholar). Newly synthesized TGs are thought to be released into the associated lipid bilayer, where they are channeled into cytosolic lipid droplets or, in cells that secrete TG, nascent lipoproteins (Fig. 2). The precise mechanism by which TGs are deposited into lipid droplets is unknown. Several models have been proposed (as reviewed in Ref. 14Walther T. Farese Jr., R.V. The life of lipid droplets.Biochim. Biophys. Acta. 2008; (In press.)Google Scholar). Transfer of TG into lipoproteins involves the cotranslational addition of lipids to apolipoprotein B (apoB) in a process catalyzed by the microsomal triglyceride transfer protein (MTP) (as reviewed in Refs. 15Shelness G. Ledford A. Evolution and mechanism of apolipoprotein B-containing lipoprotein assembly.Curr. Opin. Lipidol. 2005; 16: 325-332Crossref PubMed Google Scholar, 16Shelness G.S. Sellers J.A. Very-low-density lipoprotein assembly and secretion.Curr. Opin. Lipidol. 2001; 12: 151-157Crossref PubMed Scopus (216) Google Scholar, 17Hussain M. Shi J. Dreizen P. Microsomal triglyceride transfer protein and its role in apoB-lipoprotein assembly.J. Lipid Res. 2003; 44: 22-32Abstract Full Text Full Text PDF PubMed Scopus (398) Google Scholar).Fig. 2Hypothetical model illustrating the role of DGAT enzymes in triacylglycerol synthesis in the ER. Triacylglycerol products of the DGAT reaction may be channeled into the cores of cytosolic lipid droplets or triacylglycerol-rich lipoproteins for secretion in cells such as enterocytes and hepatocytes. Although the model depicts the reaction at the cytosolic surface of the ER, it has been proposed that the reaction may also take place at the luminal surface (see text for discussion). DGAT1 is shown as a homotetramer (59Yu C. Chen J. Lin S. Liu J. Chang C.C.Y. Chang T.Y. Human acyl-CoA:cholesterol acyltransferase-1 is a homotetrameric enzyme in intact cells and in vitro.J. Biol. Chem. 1999; 274: 36139-36145Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar).View Large Image Figure ViewerDownload Hi-res image Download (PPT) DGAT activity was first reported in 1956 (13Weiss S.B. Kennedy E.P. Kiyasu J.Y. The enzymatic synthesis of triglycerides.J. Biol. Chem. 1960; 235: 40-44Abstract Full Text PDF PubMed Google Scholar, 18Weiss S. Kennedy E. The enzymatic synthesis of triglycerides.J. Biol. Chem. 1960; 235: 40-44Abstract Full Text PDF PubMed Google Scholar). Although there was much interest subsequently in the biochemistry of TG synthesis, the purification of a DGAT proved to be difficult. Only in the last decade have DGAT genes been cloned, and the molecular tools for studying TG synthesis become available. At least two DGAT enzymes exist in a wide variety of eukaryotes. Interestingly, these two DGAT enzymes are not similar at the level of DNA or protein sequences. In this review, we summarize progress over the past decade in understanding these two key enzymes of TG synthesis. 2TG biosynthesis can also occur through acyl-CoA-independent enzymes. For example, DG transacylase, an enzyme present in rodent small intestine, catalyses the direct transfer of a fatty acyl group from one DG to a second DG, yielding TG and MG products (173Lehner R. Kuksis A. Triacylglycerol synthesis by an sn-1,2(2,3)-diacylglycerol transacylase from rat intestinal microsomes.J. Biol. Chem. 1993; 268: 8781-8786Abstract Full Text PDF PubMed Google Scholar), and phospholipid:diacylglycerol transacylase catalyses the production of TG in a similar reaction, in which a fatty acyl group from the sn-2 position of phosphatidylcholine is transferred to DG. This latter pathway accounts for a substantial fraction of TG biosynthesis in yeast and plants (174Oelkers P. Tinkelenberg A. Erdeniz N. Cromley D. Billheimer J.T. Sturley S.L. A lecithin cholesterol acyltransferase-like gene mediates diacylglycerol esterification in yeast.J. Biol. Chem. 2000; 275: 15609-15612Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar). These acyl-CoA-independent mechanisms of TG synthesis will not be reviewed further here. We also will not review bacterial DGAT enzymes, which utilize acyl-CoA but are unrelated by sequence homology to mammalian DGAT1 and DGAT2 (175Kalscheuer R. Steinbüchel A. A novel bifunctional wax ester synthase/acyl-CoA:diacylglycerol acyltransferase mediates wax ester and triacylglycerol biosynthesis in Acinetobacter calcoaceticus ADP1.J. Biol. Chem. 2003; 278: 8075-8082Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar).2TG biosynthesis can also occur through acyl-CoA-independent enzymes. For example, DG transacylase, an enzyme present in rodent small intestine, catalyses the direct transfer of a fatty acyl group from one DG to a second DG, yielding TG and MG products (173Lehner R. Kuksis A. Triacylglycerol synthesis by an sn-1,2(2,3)-diacylglycerol transacylase from rat intestinal microsomes.J. Biol. Chem. 1993; 268: 8781-8786Abstract Full Text PDF PubMed Google Scholar), and phospholipid:diacylglycerol transacylase catalyses the production of TG in a similar reaction, in which a fatty acyl group from the sn-2 position of phosphatidylcholine is transferred to DG. This latter pathway accounts for a substantial fraction of TG biosynthesis in yeast and plants (174Oelkers P. Tinkelenberg A. Erdeniz N. Cromley D. Billheimer J.T. Sturley S.L. A lecithin cholesterol acyltransferase-like gene mediates diacylglycerol esterification in yeast.J. Biol. Chem. 2000; 275: 15609-15612Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar). These acyl-CoA-independent mechanisms of TG synthesis will not be reviewed further here. We also will not review bacterial DGAT enzymes, which utilize acyl-CoA but are unrelated by sequence homology to mammalian DGAT1 and DGAT2 (175Kalscheuer R. Steinbüchel A. A novel bifunctional wax ester synthase/acyl-CoA:diacylglycerol acyltransferase mediates wax ester and triacylglycerol biosynthesis in Acinetobacter calcoaceticus ADP1.J. Biol. Chem. 2003; 278: 8075-8082Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar). The genes encoding murine and human DGAT1 were identified by their similarity to the sequences of acyl-CoA:cholesterol acyltransferase (ACAT) enzymes (Fig. 3) (19Chang C.C.Y. Huh H.Y. Cadigan K.M. Chang T.Y. Molecular cloning and functional expression of human acyl-coenzyme A:cholesterol acyltransferase cDNA in mutant Chinese hamster ovary cells.J. Biol. Chem. 1993; 268: 20747-20755Abstract Full Text PDF PubMed Google Scholar, 20Cases S. Novak S. Zheng Y-W. Myers H.M. Lear S.R. Sande E. Welch C.B. Lusis A.J. Spencer T.A. Krause B.R. et al.ACAT-2, a second mammalian acyl-CoA:cholesterol acyltransferase. Its cloning, expression, and characterization.J. Biol. Chem. 1998; 273: 26755-26764Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar, 21Anderson R.A. Joyce C. Davis M. Reagan J.W. Clark M. Shelness G.S. Rudel L.L. Identification of a form of Acyl-CoA:cholesterol acyltransferase specific to liver and intestine in nonhuman primates.J. Biol. Chem. 1998; 273: 26747-26754Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar, 22Cases S. Smith S.J. Zheng Y-W. Myers H.M. Lear S.R. Sande E. Novak S. Collins C. Welch C.B. Lusis A.J. et al.Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis.Proc. Natl. Acad. Sci. USA. 1998; 95: 13018-13023Crossref PubMed Scopus (792) Google Scholar, 23Oelkers P. Behari A. Cromley D. Billheimer J.T. Sturley S.L. Characterization of two human genes encoding acyl coenzyme A:cholesterol acyltransferase-related enzymes.J. Biol. Chem. 1998; 273: 26765-26771Abstract Full Text Full Text PDF PubMed Scopus (321) Google Scholar, 24Buhman K.K. Chen H.C. Farese Jr., R.V. The enzymes of neutral lipid synthesis.J. Biol. Chem. 2001; 276: 40369-40372Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar) and were shown in 1998 to encode proteins that possess DGAT activity (22Cases S. Smith S.J. Zheng Y-W. Myers H.M. Lear S.R. Sande E. Novak S. Collins C. Welch C.B. Lusis A.J. et al.Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis.Proc. Natl. Acad. Sci. USA. 1998; 95: 13018-13023Crossref PubMed Scopus (792) Google Scholar). Since then, orthologs have been identified in many species of eukaryotes, including yeast, fungi, plants, and invertebrates. In humans, the DGAT1 gene comprises 17 exons and spans 10.62 kb on chromosome 8 (Table 1). In most species, the gene encodes a protein of about 500 amino acids with a calculated molecular mass of ∼55 kDa (Fig. 4).TABLE 1Genes encoding DGAT enzymesEnzymeGene (UniGene)Chromosome LocalizationNumber of ExonsNumber of Amino acidsTissues with High Levels of mRNA ExpressionDGAT1 HumanDGAT1 Hs .5128108q24.3 cM17488Small intestine, testis, adipose tissues, mammary gland, thymus, skeletal muscle, spleen, heart, skin MouseDgat1 Mm. 2263315 D317498Small intestine, testis, adipose tissues, mammary gland, skinDGAT2 HumanDGAT2 Hs. 33430511q13.3 cM8388Liver, adipose tissues, mammary gland, testis, peripheral leukocytes, heart MouseDgat2 Mm. 1801897 E18388Liver, testis, heart, kidney, stomach, small intestine, skeletal muscle, skin, uterus Open table in a new tab Fig. 4Schematic representations of murine DGAT1 and DGAT2 proteins. Possible domains and sites of modification are shown. Transmembrane domains were predicted by the program SOSUI (http://bp.nuap.nagoya-u.ac.jp/sosui/sosui_submit.html). The two transmembrane domains in DGAT2 have been confirmed experimentally (47Stone S.J. Myers H. Brown B.E. Watkins S.M. Feingold K.R. Elias P.M. Farese Jr., R.V. Lipopenia and skin barrier abnormalities in DGAT2-deficient mice.J. Biol. Chem. 2004; 279: 11767-11776Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar). Phosphorylation sites were predicted by PROSEARCH (http://workbench.sdsc.edu/). PKC, PKA, and Tyr represent potential phosphorylation sites for protein kinase C, protein kinase A, and tyrosine kinase, respectively.View Large Image Figure ViewerDownload Hi-res image Download (PPT) DGAT1 expressed in insect or mammalian cells migrates faster than predicted (∼50 kDa) on SDS-PAGE (22Cases S. Smith S.J. Zheng Y-W. Myers H.M. Lear S.R. Sande E. Novak S. Collins C. Welch C.B. Lusis A.J. et al.Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis.Proc. Natl. Acad. Sci. USA. 1998; 95: 13018-13023Crossref PubMed Scopus (792) Google Scholar, 25Yen C-L.E. Monetti M. Burri B.J. Farese Jr., R.V. The triacylglycerol synthesis enzyme DGAT1 also catalyzes the synthesis of diacylglycerols, waxes, and retinyl esters.J. Lipid Res. 2005; 46: 1502-1511Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar). Within species, DGAT1 protein sequences share 15–25% identity, mostly in the C termini, with those of ACAT1 and ACAT2 (22Cases S. Smith S.J. Zheng Y-W. Myers H.M. Lear S.R. Sande E. Novak S. Collins C. Welch C.B. Lusis A.J. et al.Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis.Proc. Natl. Acad. Sci. USA. 1998; 95: 13018-13023Crossref PubMed Scopus (792) Google Scholar). A motif conserved between DGAT1 and ACATs (FYXDWWN; amino acids 360–366 of human DGAT1) has been implicated in binding fatty acyl-CoA, a common substrate for the enzymes (26Guo Z. Cromley D. Billheimer J. Sturley S. Identification of potential substrate-binding sites in yeast and human acyl-CoA sterol acyltransferases by mutagenesis of conserved sequences.J. Lipid Res. 2001; 42: 1282-1291Abstract Full Text Full Text PDF PubMed Google Scholar). However, experimental evidence suggests that the fatty acyl-CoA binding domain is at the N terminus, because a fragment containing the first 116 amino acids of DGAT1 from the rapeseed plant Brassica napus and a fragment of the first 95 amino acids from mouse DGAT1 directly bind fatty acyl-CoA (27Weselake R. Madhavji M. Szarka S. Patterson N. Wiehler W. Nykiforuk C. Burton T. Boora P. Mosimann S. Foroud N. et al.Acyl-CoA-binding and self-associating properties of a recombinant 13.3 kDa N-terminal fragment of diacylglycerol acyltransferase-1 from oilseed rape.BMC Biochem. 2006; 7: 24Crossref PubMed Scopus (38) Google Scholar, 28Siloto R. Madhavji M. Wiehler W. Burton T. Boora P. Laroche A. Weselake R. An N-terminal fragment of mouse DGAT1 binds different acyl-CoAs with varying affinity.Biochem. Biophys. Res. Commun. 2008; 373: 350-354Crossref PubMed Scopus (25) Google Scholar). Animal and plant DGAT1 enzymes share up to 40% amino acid identity, mostly at their C termini. Toward the C-terminal region, DGAT1 also possesses a putative DG binding domain. Both DGATs possess several predicted phosphorylation sites (Fig. 4). DGAT1, like ACAT enzymes, is part of a large family of membrane-bound O-acyltransferases (MBOAT, National Center for Biotechnology Information (NCBI) Conserved Domains Database accession number: pfam03062; discussed below) (29Hofmann K. A superfamily of membrane-bound O-acyltransferases with implications for wnt signaling.Trends Biochem. Sci. 2000; 25: 111-112Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar) (Fig. 3). Other MBOAT family members catalyze reactions that add fatty acyl chains to proteins (30Zhai L. Chaturvedi D. Cumberledge S. Drosophila wnt-1 undergoes a hydrophobic modification and is targeted to lipid rafts, a process that requires porcupine.J. Biol. Chem. 2004; 279: 33220-33227Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 31Kadowaki T. Wilder E. Klingensmith J. Zachary K. Perrimon N. The segment polarity gene porcupine encodes a putative multitransmembrane protein involved in Wingless processing.Genes Dev. 1996; 10: 3116-3128Crossref PubMed Google Scholar, 32Chamon Z. Mann R. Nellen D. von Kessler D. Bellotto M. Beachy P. Basler K. Skinny hedgehog, an acyltransferase required for palmitoylation and activity of the hedgehog signal.Science. 2001; 293: 2080-2084Crossref PubMed Scopus (303) Google Scholar, 33Yang J. Brown M. Liang G. Grishin N. Goldstein J. Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone.Cell. 2008; 132: 387-396Abstract Full Text Full Text PDF PubMed Scopus (850) Google Scholar). This family of membrane-associated enzymes catalyzes O-acylation reactions, transferring fatty acyl moieties onto the hydroxyl or thiol groups of lipid and protein acceptors, and its members are involved in lipid metabolism, signal transduction, and hormone processing. ACAT enzymes catalyze the joining of cholesterol and fatty acyl-CoA to form cholesterol esters (24Buhman K.K. Chen H.C. Farese Jr., R.V. The enzymes of neutral lipid synthesis.J. Biol. Chem. 2001; 276: 40369-40372Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). Other members of the MBOAT family include a protein-cysteine N-palmitoyltransferase (skinny hedgehog, or sightless protein) (32Chamon Z. Mann R. Nellen D. von Kessler D. Bellotto M. Beachy P. Basler K. Skinny hedgehog, an acyltransferase required for palmitoylation and activity of the hedgehog signal.Science. 2001; 293: 2080-2084Crossref PubMed Scopus (303) Google Scholar); porcupine, a putative acyltransferase implicated in Wnt processing and signaling (30Zhai L. Chaturvedi D. Cumberledge S. Drosophila wnt-1 undergoes a hydrophobic modification and is targeted to lipid rafts, a process that requires porcupine.J. Biol. Chem. 2004; 279: 33220-33227Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 31Kadowaki T. Wilder E. Klingensmith J. Zachary K. Perrimon N. The segment polarity gene porcupine encodes a putative multitransmembrane protein involved in Wingless processing.Genes Dev. 1996; 10: 3116-3128Crossref PubMed Google Scholar); and an acyltransferase that attaches an essential eight-carbon fatty acyl moiety to ghrelin, a gut-derived hormone that regulates appetite (33Yang J. Brown M. Liang G. Grishin N. Goldstein J. Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone.Cell. 2008; 132: 387-396Abstract Full Text Full Text PDF PubMed Scopus (850) Google Scholar). A common feature of the MBOAT family is a long hydrophobic region that contains asparagine and histidine residues of the putative active site (corresponding to amino acids 378 and 415, respectively, of human DGAT1; 389 and 426 of mouse DGAT1) (29Hofmann K. A superfamily of membrane-bound O-acyltransferases with implications for wnt signaling.Trends Biochem. Sci. 2000; 25: 111-112Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar, 32Chamon Z. Mann R. Nellen D. von Kessler D. Bellotto M. Beachy P. Basler K. Skinny hedgehog, an acyltransferase required for palmitoylation and activity of the hedgehog signal.Science. 2001; 293: 2080-2084Crossref PubMed Scopus (303) Google Scholar). The existence of DGAT2 was predicted from the finding that mice lacking DGAT1 have abundant TG in tissues (34Smith S.J. Cases S. Jensen D.R. Chen H.C. Sande E. Tow B. Sanan D.A. Raber J. Eckel R.H. Farese Jr., R.V. Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking DGAT.Nat. Genet. 2000; 25: 87-90Crossref PubMed Scopus (684) Google Scholar). In 2001, a second DGAT enzyme was purified from the fungus Mortierella ramanniana (35Lardizabal K.D. Mai J.T. Wagner N.W. Wyrick A. Voelker T. Hawkins D.J. DGAT2 is a new diacylglycerol acyltransferase gene family. Purification, cloning, and expression in insect cells of two polypeptides from Mortierella ramanniana with diacylglycerol acyltransferase activity.J. Biol. Chem. 2001; 276: 38862-38869Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar). This led to the cloning of mammalian DGAT2 and the identification of a seven-member gene family (35Lardizabal K.D. Mai J.T. Wagner N.W. Wyrick A. Voelker T. Hawkins D.J. DGAT2 is a new diacylglycerol acyltransferase gene family. Purification, cloning, and expression in insect cells of two polypeptides from Mortierella ramanniana with diacylglycerol acyltransferase activity.J. Biol. Chem. 2001; 276: 38862-38869Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar, 36Cases S. Stone S.J. Zhou P. Yen E. Tow B. Lardizabal K.D. Voelker T. Farese Jr., R.V. Cloning of DGAT2, a second mammalian diacylglycerol acyltransferase, and related family members.J. Biol. Chem. 2001; 276: 38870-38876Abstract Full Text Full Text PDF PubMed Scopus (585) Google Scholar) (DAGAT, NCBI Conserved Domain Database accession number: pfam 03982) (Fig. 3). In addition to DGAT2, this family includes acyl-CoA:monoacylglycerol acyltransferase-1 (MGAT1) (37Yen C-L.E. Stone S.J. Cases S. Zhou P. Farese Jr., R.V. Identification of a gene encoding MGAT1, a monoacylglylcerol acyltransferase.Proc. Natl. Acad. Sci. USA. 2002; 99: 8512-8517Crossref PubMed Scopus (138) Google Scholar), MGAT2 (38Cao J. Lockwood J. Burn P. Shi Y. Cloning and functional characterization of a mouse intestinal acyl-CoA:monoacylglycerol acyltransferase, MGAT2.J. Biol. Chem. 2003; 278: 13860-13866Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 39Yen C-L.E. Farese Jr., R.V. MGAT2, a monoacylglycerol acyltransferase expressed in the small intestine.J. Biol. Chem. 2003; 278: 18532-18537Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar), MGAT3 (40Cheng D. Nelson T.C. Chen J. Walker S.G. Wardwell-Swanson J. Meegalla R. Taub R. Billheimer J.T. Ramaker M. Feder J.N. Identification of acyl coenzyme A:monoacylglycerol acyltransferase 3, an intestinal specific enzyme implicated in dietary fat absorption.J. Biol. Chem. 2003; 278: 13611-13614Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar), and wax monoester synthases (41Cheng J.B. Russell D.W. Mammalian wax biosynthesis. II. Expression cloning of wax synthase cDNAs encoding a member of the acyltransferase enzyme family.J. Biol. Chem. 2004; 279: 37798-37807Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, 42Turkish A.R. Henneberry A.L. Cromley D. Padamsee M. Oelkers P. Bazzi H. Christiano A.M. Billheimer J.T. Sturley S.L. Identification of two novel human acyl-CoA wax alcohol acyltransferases: members of the diacylglycerol acyltransferase 2 (DGAT2) gene superfamily.J. Biol. Chem. 2005; 280: 14755-14764Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 43Yen C-L.E. Brown IV, C.H. Monetti M. Farese Jr., R.V. A human skin multifunctional O-acyltransferase that catalyzes the synthesis of acylglycerols, waxes, and retinyl esters.J. Lipid Res. 2005; 46: 2388-2397Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). The human DGAT2 gene comprises eight exons and spans 42.03 kb on chromosome 11. It is located ∼37.5 kb from the MGAT2 gene. In most species, the gene encodes a protein of 350–400 amino acids (Fig. 4), and the calculated molecular mass for DGAT2 enzymes ranges from 40 to 44 kDa. DGAT2 is about 50 residues longer at the N terminus than other non-DGAT2 members of the gene family. This region may include domains that confer substrate specificity or provide regulatory functions. DGAT2 and its family members share 40–45% amino acid identity throughout the entire lengths of the proteins. The most conserved regions, probably containing the catalytic domains of the proteins, are found in the C termini (amino acids 200–360 of human and mouse DGAT2; both are composed of 388 amino acids with 95% identity). All DGAT2 family members, from yeast to human, contain the highly conserved sequence of amino acids HPHG (amino acids 161–164 of mouse DGAT2) (36Cases S. Stone S.J. Zhou P. Yen E. Tow B. Lardizabal K.D. Voelker T. Farese Jr., R.V. Cloning of DGAT2, a second mammalian diacylglycerol acyltransferase, and related family members.J. Biol. Chem. 2001; 276: 38870-38876Abstract Full Text Full Text PDF PubMed Scopus (585) Google Scholar, 44Stone S. Levin M. Farese Jr., R.V. Membrane topology and identification of key functional amino acid residues of murine acyl-CoA:diacylglycerol acyltransferase-2.J. Biol. Chem. 2006; 281: 40273-40282Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar), and mutations of this sequence in mouse DGAT2 markedly reduce total DGAT activity in vitro (44Stone S. Levin M. Farese Jr.," @default.
• W2011185005 created "2016-06-24" @default.
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• W2011185005 date "2008-11-01" @default.
• W2011185005 modified "2023-10-18" @default.
• W2011185005 title "Thematic Review Series: Glycerolipids. DGAT enzymes and triacylglycerol biosynthesis" @default.
• W2011185005 cites W125443967 @default.
• W2011185005 cites W1490548175 @default.
• W2011185005 cites W1506403129 @default.
• W2011185005 cites W1527521373 @default.
• W2011185005 cites W1539536801 @default.
• W2011185005 cites W1551220513 @default.
• W2011185005 cites W1585035359 @default.
• W2011185005 cites W1688128216 @default.
• W2011185005 cites W1910630598 @default.
• W2011185005 cites W1963859477 @default.
• W2011185005 cites W1964392625 @default.
• W2011185005 cites W1964837364 @default.
• W2011185005 cites W1965033589 @default.
• W2011185005 cites W1966386844 @default.
• W2011185005 cites W1967000078 @default.
• W2011185005 cites W1969813096 @default.
• W2011185005 cites W1969935074 @default.
• W2011185005 cites W1970332452 @default.
• W2011185005 cites W1971388047 @default.
• W2011185005 cites W1973186908 @default.
• W2011185005 cites W1974115865 @default.
• W2011185005 cites W1974730258 @default.
• W2011185005 cites W1976094170 @default.
• W2011185005 cites W1979107629 @default.
• W2011185005 cites W1980167330 @default.
• W2011185005 cites W1981417007 @default.
• W2011185005 cites W1982164579 @default.
• W2011185005 cites W1983130452 @default.
• W2011185005 cites W1987993677 @default.
• W2011185005 cites W1988312659 @default.
• W2011185005 cites W1989340047 @default.
• W2011185005 cites W1992489770 @default.
• W2011185005 cites W1993281511 @default.
• W2011185005 cites W1993465904 @default.
• W2011185005 cites W1995807591 @default.
• W2011185005 cites W1996218285 @default.
• W2011185005 cites W1996417808 @default.
• W2011185005 cites W1998937576 @default.
• W2011185005 cites W2001840372 @default.
• W2011185005 cites W2003286444 @default.
• W2011185005 cites W2007138284 @default.
• W2011185005 cites W2007396399 @default.
• W2011185005 cites W2007884452 @default.
• W2011185005 cites W2009594625 @default.
• W2011185005 cites W2010299367 @default.
• W2011185005 cites W2010363699 @default.
• W2011185005 cites W2010988196 @default.
• W2011185005 cites W2011647937 @default.
• W2011185005 cites W2012426074 @default.
• W2011185005 cites W2013083923 @default.
• W2011185005 cites W2014290839 @default.
• W2011185005 cites W2018127398 @default.
• W2011185005 cites W2019561793 @default.
• W2011185005 cites W2019981157 @default.
• W2011185005 cites W2021017483 @default.
• W2011185005 cites W2026241394 @default.
• W2011185005 cites W2027906273 @default.
• W2011185005 cites W2027945041 @default.
• W2011185005 cites W2028123717 @default.
• W2011185005 cites W2030901818 @default.
• W2011185005 cites W2031805875 @default.
• W2011185005 cites W2033206973 @default.
• W2011185005 cites W2033396762 @default.
• W2011185005 cites W2033690993 @default.
• W2011185005 cites W2034358314 @default.
• W2011185005 cites W2034797710 @default.
• W2011185005 cites W2034883068 @default.
• W2011185005 cites W2035187068 @default.
• W2011185005 cites W2037381621 @default.
• W2011185005 cites W2037792818 @default.
• W2011185005 cites W2039481955 @default.
• W2011185005 cites W2041270901 @default.
• W2011185005 cites W2044111159 @default.
• W2011185005 cites W2044820772 @default.
• W2011185005 cites W2045182106 @default.
• W2011185005 cites W2045463616 @default.
• W2011185005 cites W2046333439 @default.
• W2011185005 cites W2047737432 @default.
• W2011185005 cites W2049791242 @default.
• W2011185005 cites W2052874497 @default.
• W2011185005 cites W2053150532 @default.
• W2011185005 cites W2053500970 @default.
• W2011185005 cites W2055980308 @default.
• W2011185005 cites W2059275312 @default.
• W2011185005 cites W2059572967 @default.
• W2011185005 cites W2061516468 @default.
• W2011185005 cites W2063086702 @default.
• W2011185005 cites W2065735058 @default.

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