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Frontiers in Biology

, 6:177 | Cite as

Membrane-bound O-acyltransferases (MBOATs)

  • Catherine C. Y. Chang
  • Jie Sun
  • Ta-Yuan Chang
Mini-Review

Abstract

The MBOAT enzyme family, identified in 2000, comprises 11 genes in the human genome that participate in a variety of biological processes. MBOAT enzymes contain multiple transmembrane domains and share two active site residues, histidine and asparagine. Several MBOAT members are drug targets for major human diseases, including atherosclerosis, obesity, Alzheimer disease, and viral infections. Here we review the historical aspects of MBOAT enzymes, classify them biochemically into 3 subgroups, and describe the essential features of each member.

Keywords

cholesterol metabolism neutral lipid biosynthesis protein acylation membrane phospholipid remodeling atherosclerosis diabetes obesity cancer nutrient sensing 

References

  1. Abe Y, Kita Y, Niikura T (2008). Mammalian Gup1, a homolog of Saccharomyces cerevisiae glycerol uptake/transporter 1, acts as a negative regulator for N-terminal palmitoylation of Sonic hedgehog. FEBS J, 275(2): 318–331PubMedCrossRefGoogle Scholar
  2. Anderson R A, Joyce C, Davis M, Reagan J W, Clark M, Shelness G S, Rudel L L (1998). Identification of a form of acyl-CoA:cholesterol acyltransferase specific to liver and intestine in nonhuman primates. J Biol Chem, 273(41): 26747–26754PubMedCrossRefGoogle Scholar
  3. Ariyama H, Kono N, Matsuda S, Inoue T, Arai H (2010). Decrease in membrane phospholipid unsaturation induces unfolded protein response. J Biol Chem, 285(29): 22027–22035PubMedCrossRefGoogle Scholar
  4. Bell T A 3rd, Brown J M, Graham M J, Lemonidis K M, Crooke R M, Rudel L L (2006). Liver-specific inhibition of acyl-coenzyme A: cholesterol acyltransferase 2 with antisense oligonucleotides limits atherosclerosis development in apolipoprotein B100-only low-density lipoprotein receptor−/− mice. Arterioscler Thromb Vasc Biol, 26(8): 1814–1820PubMedCrossRefGoogle Scholar
  5. Benghezal M, Roubaty C, Veepuri V, Knudsen J, Conzelmann A (2007). SLC1 and SLC4 encode partially redundant acyl-coenzyme A 1-acylglycerol-3-phosphate O-acyltransferases of budding yeast. J Biol Chem, 282(42): 30845–30855PubMedCrossRefGoogle Scholar
  6. Birch A M, Buckett L K, Turnbull A V (2010). DGAT1 inhibitors as anti-obesity and anti-diabetic agents. Curr Opin Drug Discov Devel, 13(4): 489–496PubMedGoogle Scholar
  7. Bosson R, Jaquenoud M, Conzelmann A (2006). GUP1 of Saccharomyces cerevisiae encodes an O-acyltransferase involved in remodeling of the GPI anchor. Mol Biol Cell, 17(6): 2636–2645PubMedCrossRefGoogle Scholar
  8. Bryleva E Y, Rogers M A, Chang C C, Buen F, Harris B T, Rousselet E, Seidah N G, Oddo S, LaFerla F M, Spencer T A, Hickey WF, Chang T Y (2010). ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD. Proc Natl Acad Sci USA, 107(7): 3081–3086PubMedCrossRefGoogle Scholar
  9. Buglino J A, Resh M D (2008). Hhat is a palmitoylacyltransferase with specificity for N-palmitoylation of Sonic Hedgehog. J Biol Chem, 283(32): 22076–22088PubMedCrossRefGoogle Scholar
  10. Buglino J A, Resh M D (2010). Identification of conserved regions and residues within Hedgehog acyltransferase critical for palmitoylation of Sonic Hedgehog. PLoS ONE, 5(6): e11195PubMedCrossRefGoogle Scholar
  11. Buhman K K, Accad M, Novak S, Choi R S, Wong J S, Hamilton R L, Turley S, Farese R V Jr (2000). Resistance to diet-induced hypercholesterolemia and gallstone formation in ACAT2-deficient mice. Nat Med, 6(12): 1341–1347PubMedCrossRefGoogle Scholar
  12. Cao J, Liu Y, Lockwood J, Burn P, Shi Y (2004). A novel cardiolipin-remodeling pathway revealed by a gene encoding an endoplasmic reticulum-associated acyl-CoA:lysocardiolipin acyltransferase (ALCAT1) in mouse. J Biol Chem, 279(30): 31727–31734PubMedCrossRefGoogle Scholar
  13. Cases S, Novak S, Zheng YW, Myers HM, Lear S R, Sande E, Welch C B, Lusis A J, Spencer T A, Krause B R, Erickson S K, Farese R V Jr (1998a). ACAT-2, a second mammalian acyl-CoA:cholesterol acyltransferase. Its cloning, expression, and characterization. J Biol Chem, 273(41): 26755–26764PubMedCrossRefGoogle Scholar
  14. Cases 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, Erickson S K, Farese R V Jr (1998b). Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis. Proc Natl Acad Sci USA, 95(22): 13018–13023PubMedCrossRefGoogle Scholar
  15. Chamoun Z, Mann R K, Nellen D, Von Kessler D P, Bellotto M, Beachy P A, Basler K (2001). Skinny hedgehog, an acyltransferase required for palmitoylation and activity of the hedgehog signal. Science, 293: 2080–2084PubMedCrossRefGoogle Scholar
  16. Chang C C, Huh H Y, Cadigan K M, Chang T Y (1993). Molecular cloning and functional expression of human acyl-coenzyme A: cholesterol acyltransferase cDNA in mutant Chinese hamster ovary cells. J Biol Chem, 268(28): 20747–20755PubMedGoogle Scholar
  17. Chang C C, Miyazaki A, Dong R, Kheirollah A, Yu C, Geng Y, Higgs H N, Chang T Y (2010). Purification of recombinant acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1) from H293 cells and binding studies between the enzyme and substrates using difference intrinsic fluorescence spectroscopy. Biochemistry, 49(46): 9957–9963PubMedCrossRefGoogle Scholar
  18. Chang C C Y, Lee C Y, Chang E T, Cruz J C, Levesque MC, Chang T Y (1998). Recombinant acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) purified to essential homogeneity utilizes cholesterol in mixed micelles or in vesicles in a highly cooperative manner. J Biol Chem, 273(52): 35132–35141PubMedCrossRefGoogle Scholar
  19. Chang T Y, Li B L, Chang C C, Urano Y (2009). Acyl-coenzyme A: cholesterol acyltransferases. Am J Physiol Endocrinol Metab, 297(1): E1–E9PubMedCrossRefGoogle Scholar
  20. Cheng D, Meegalla R L, He B, Cromley D A, Billheimer J T, Young P R (2001). Human acyl-CoA:diacylglycerol acyltransferase is a tetrameric protein. Biochem J, 359(Pt 3): 707–714PubMedCrossRefGoogle Scholar
  21. Demeure O, Lecerf F, Duby C, Desert C, Ducheix S, Guillou H, Lagarrigue S (2011). Regulation of LPCAT3 by LXR. Gene, 470(1–2): 7–11PubMedCrossRefGoogle Scholar
  22. Ferreira C, Silva S, Faria-Oliveira F, Pinho E, Henriques M, Lucas C (2010). Candida albicans virulence and drug-resistance requires the O-acyltransferase Gup1p. BMC Microbiol, 10(1): 238PubMedCrossRefGoogle Scholar
  23. Fujita M, Umemura M, Yoko-o T, Jigami Y (2006). PER1 is required for GPI-phospholipase A2 activity and involved in lipid remodeling of GPI-anchored proteins. Mol Biol Cell, 17(12): 5253–5264PubMedCrossRefGoogle Scholar
  24. Gijón M A, Riekhof W R, Zarini S, Murphy R C, Voelker D R (2008). Lysophospholipid acyltransferases and arachidonate recycling in human neutrophils. J Biol Chem, 283(44): 30235–30245PubMedCrossRefGoogle Scholar
  25. Goodman D S, Deykin D, Shiratori T (1964). The formation of cholesterol esters with rat liver enzymes. J Biol Chem, 239: 1335–1345PubMedGoogle Scholar
  26. Guo Z Y, Chang C C, Chang T Y (2007). Functionality of the seventh and eighth transmembrane domains of acyl-coenzyme A:cholesterol acyltransferase 1. Biochemistry, 46(35): 10063–10071PubMedCrossRefGoogle Scholar
  27. Gutierrez J A, Solenberg P J, Perkins D R, Willency J A, Knierman MD, Jin Z, Witcher D R, Luo S, Onyia J E, Hale J E (2008). Ghrelin octanoylation mediated by an orphan lipid transferase. Proc Natl Acad Sci USA, 105(17): 6320–6325PubMedCrossRefGoogle Scholar
  28. Harris C A, Hass J T, Streeper R S, Stone S J, Kumari M, Yang K, Han X, Brownell N, Gross R W, Zechner R, Farese R V Jr (2011). DGAT enzymes are required for triacylglycerol synthesis and lipid droplets in adipocytes. J Lipid Res, doi: 10.1194/jlr.M013003Google Scholar
  29. Hartmann T (2006). Role of amyloid precursor protein, amyloid-beta and gamma-secretase in cholesterol maintenance. Neurodegener Dis, 3(4–5): 305–311PubMedCrossRefGoogle Scholar
  30. Herker E, Harris C, Hernandez C, Carpentier A, Kaehlcke K, Rosenberg A R, Farese R V Jr, Ott M (2010). Efficient hepatitis C virus particle formation requires diacylglycerol acyltransferase-1. Nat Med, 16(11): 1295–1298PubMedCrossRefGoogle Scholar
  31. Hishikawa D, Shindou H, Kobayashi S, Nakanishi H, Taguchi R, Shimizu T (2008). Discovery of a lysophospholipid acyltransferase family essential for membrane asymmetry and diversity. Proc Natl Acad Sci USA, 105(8): 2830–2835PubMedCrossRefGoogle Scholar
  32. Hofmann K (2000). A superfamily of membrane-bound O-acyltransferases with implications for wnt signaling. Trends Biochem Sci, 25(3): 111–112PubMedCrossRefGoogle Scholar
  33. Jain S, Stanford N, Bhagwat N, Seiler B, Costanzo M, Boone C, Oelkers P (2007). Identification of a novel lysophospholipid acyltransferase in Saccharomyces cerevisiae. J Biol Chem, 282(42): 30562–30569PubMedCrossRefGoogle Scholar
  34. Kadowaki T, Wilder E, Klingensmith J, Zachary K, Perrimon N (1996). The segment polarity gene porcupine encodes a putative multi-transmembrane protein involved in Wingless processing. Genes Dev, 10(24): 3116–3128PubMedCrossRefGoogle Scholar
  35. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K (1999). Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature, 402(6762): 656–660PubMedCrossRefGoogle Scholar
  36. Lee B, Fast A M, Zhu J, Cheng J X, Buhman K K (2010). Intestine-specific expression of acyl CoA:diacylglycerol acyltransferase 1 reverses resistance to diet-induced hepatic steatosis and obesity in Dgat1−/− mice. J Lipid Res, 51(7): 1770–1780PubMedCrossRefGoogle Scholar
  37. Lee H C, Inoue T, Imae R, Kono N, Shirae S, Matsuda S, Gengyo-Ando K, Mitani S, Arai H (2008). Caenorhabditis elegans mboa-7, a member of the MBOAT family, is required for selective incorporation of polyunsaturated fatty acids into phosphatidylinositol. Mol Biol Cell, 19(3): 1174–1184PubMedCrossRefGoogle Scholar
  38. Lee J J, von Kessler D P, Parks S, Beachy P A (1992). Secretion and localized transcription suggest a role in positional signaling for products of the segmentation gene hedgehog. Cell, 71(1): 33–50PubMedCrossRefGoogle Scholar
  39. Lewin T M, Wang P, Coleman R A (1999). Analysis of amino acid motifs diagnostic for the sn-glycerol-3-phosphate acyltransferase reaction. Biochemistry, 38(18): 5764–5771PubMedCrossRefGoogle Scholar
  40. Lim CT, Kola B, Korbonits M (2011). The ghrelin/GOAT/GHS-R system and energy metabolism. Rev Endocr Metab DisordGoogle Scholar
  41. Logan C Y, Nusse R (2004). The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol, 20(1): 781–810PubMedCrossRefGoogle Scholar
  42. McFie P J, Stone S L, Banman S L, Stone S J (2010). Topological orientation of acyl-CoA:diacylglycerol acyltransferase-1 (DGAT1) and identification of a putative active site histidine and the role of the n terminus in dimer/tetramer formation. J Biol Chem, 285(48): 37377–37387PubMedCrossRefGoogle Scholar
  43. Mohler J, Vani K (1992). Molecular organization and embryonic expression of the hedgehog gene involved in cell-cell communication in segmental patterning of Drosophila. Development, 115(4): 957–971PubMedGoogle Scholar
  44. Mukherjee S, Kunitake G, Alfinslater R B (1958). The esterification of cholesterol with palmitic acid by rat liver homogenates. J Biol Chem, 230(1): 91–96PubMedGoogle Scholar
  45. Nüsslein-Volhard C, Wieschaus E (1980). Mutations affecting segment number and polarity in Drosophila. Nature, 287(5785): 795–801PubMedCrossRefGoogle Scholar
  46. Oelkers P, Behari A, Cromley D, Billheimer J T, Sturley S L (1998). Characterization of two human genes encoding acyl coenzyme A: cholesterol acyltransferase-related enzymes. J Biol Chem, 273(41): 26765–26771PubMedCrossRefGoogle Scholar
  47. Porter JA, Young KE, Beachy PA (1996) Cholesterol modification of hedgehog signaling proteins in animal development. Science, 274: 255–259PubMedCrossRefGoogle Scholar
  48. Repa J J, Buhman K K, Farese R V J Jr, Dietschy JM, Turley S D (2004). ACAT2 deficiency limits cholesterol absorption in the cholesterol-fed mouse: impact on hepatic cholesterol homeostasis. Hepatology, 40(5): 1088–1097PubMedCrossRefGoogle Scholar
  49. Riekhof W R, Wu J, Jones J L, Voelker D R (2007). Identification and characterization of the major lysophosphatidylethanolamine acyltransferase in Saccharomyces cerevisiae. J Biol Chem, 282(39): 28344–28352PubMedCrossRefGoogle Scholar
  50. Shindou H, Eto M, Morimoto R, Shimizu T (2009). Identification of membrane O-acyltransferase family motifs. Biochem Biophys Res Commun, 383(3): 320–325PubMedCrossRefGoogle Scholar
  51. Shindou H, Shimizu T (2009). Acyl-CoA:lysophospholipid acyltransferases. J Biol Chem, 284(1): 1–5PubMedCrossRefGoogle Scholar
  52. Smotrys J E, Linder ME (2004). Palmitoylation of intracellular signaling proteins: regulation and function. Annu Rev Biochem, 73(1): 559–587PubMedCrossRefGoogle Scholar
  53. Tabata T, Eaton S, Kornberg T B (1992). The Drosophila hedgehog gene is expressed specifically in posterior compartment cells and is a target of engrailed regulation. Genes Dev, 6(12b 12B): 2635–2645PubMedCrossRefGoogle Scholar
  54. Takada R, Satomi Y, Kurata T, Ueno N, Norioka S, Kondoh H, Takao T, Takada S (2006). Monounsaturated fatty acid modification of Wnt protein: its role in Wnt secretion. Dev Cell, 11(6): 791–801PubMedCrossRefGoogle Scholar
  55. Tamaki H, Shimada A, Ito Y, Ohya M, Takase J, Miyashita M, Miyagawa H, Nozaki H, Nakayama R, Kumagai H (2007). LPT1 encodes a membrane-bound O-acyltransferase involved in the acylation of lysophospholipids in the yeast Saccharomyces cerevisiae. J Biol Chem, 282(47): 34288–34298PubMedCrossRefGoogle Scholar
  56. Turkish A R, Sturley S L (2009). The genetics of neutral lipid biosynthesis: an evolutionary perspective. Am J Physiol Endocrinol Metab, 297(1): E19–E27PubMedCrossRefGoogle Scholar
  57. Willert K, Brown J D, Danenberg E, Duncan A W, Weissman I L, Reya T, Yates J R 3rd, Nusse R (2003). Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature, 423(6938): 448–452PubMedCrossRefGoogle Scholar
  58. Willner E L, Tow B, Buhman K K, Wilson M, Sanan D A, Rudel L L, Farese R V Jr (2003). Deficiency of acyl CoA:cholesterol acyltransferase 2 prevents atherosclerosis in apolipoprotein Edeficient mice. Proc Natl Acad Sci USA, 100(3): 1262–1267PubMedCrossRefGoogle Scholar
  59. Yang H, Bard M, Bruner D A, Gleeson A, Deckelbaum R J, Aljinovic G, Pohl T M, Rothstein R, Sturtey S L(1996). Sterol esterification in yeast: a two-gene process. Science, 272: 1353–1356PubMedCrossRefGoogle Scholar
  60. Yang J, Brown M S, Liang G, Grishin N V, Goldstein J L (2008). Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell, 132(3): 387–396PubMedCrossRefGoogle Scholar
  61. Yen C L, Monetti M, Burri B J, Farese R V Jr (2005). The triacylglycerol synthesis enzyme DGAT1 also catalyzes the synthesis of diacylglycerols, waxes, and retinyl esters. J Lipid Res, 46(7): 1502–1511PubMedCrossRefGoogle Scholar
  62. Yen C L, Stone S J, Koliwad S, Harris C, Farese R V Jr (2008). Thematic review series: glycerolipids. DGAT enzymes and triacylglycerol biosynthesis. J Lipid Res, 49(11): 2283–2301PubMedCrossRefGoogle Scholar
  63. Yu C, Kennedy N J, Chang C C Y, Rothblatt J A (1996). Molecular cloning and characterization of two isoforms of Saccharomyces cerevisiae acyl-CoA:sterol acyltransferase. J Biol Chem, 271(39): 24157–24163PubMedCrossRefGoogle Scholar
  64. Zhai L, Chaturvedi D, Cumberledge S (2004). Drosophila wnt-1 undergoes a hydrophobic modification and is targeted to lipid rafts, a process that requires porcupine. J Biol Chem, 279(32): 33220–33227PubMedCrossRefGoogle Scholar
  65. Zhao Y, Chen Y Q, Bonacci T M, Bredt D S, Li S, Bensch W R, Moller D E, Kowala M, Konrad R J, Cao G (2008). Identification and characterization of a major liver lysophosphatidylcholine acyltransferase. J Biol Chem, 283(13): 8258–8265PubMedCrossRefGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  1. 1.Department of BiochemistryDartmouth Medical SchoolHanoverUSA

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