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Structure and function of biotin-dependent carboxylases

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Abstract

Biotin-dependent carboxylases include acetyl-CoA carboxylase (ACC), propionyl-CoA carboxylase (PCC), 3-methylcrotonyl-CoA carboxylase (MCC), geranyl-CoA carboxylase, pyruvate carboxylase (PC), and urea carboxylase (UC). They contain biotin carboxylase (BC), carboxyltransferase (CT), and biotin-carboxyl carrier protein components. These enzymes are widely distributed in nature and have important functions in fatty acid metabolism, amino acid metabolism, carbohydrate metabolism, polyketide biosynthesis, urea utilization, and other cellular processes. ACCs are also attractive targets for drug discovery against type 2 diabetes, obesity, cancer, microbial infections, and other diseases, and the plastid ACC of grasses is the target of action of three classes of commercial herbicides. Deficiencies in the activities of PCC, MCC, or PC are linked to serious diseases in humans. Our understanding of these enzymes has been greatly enhanced over the past few years by the crystal structures of the holoenzymes of PCC, MCC, PC, and UC. The structures reveal unanticipated features in the architectures of the holoenzymes, including the presence of previously unrecognized domains, and provide a molecular basis for understanding their catalytic mechanism as well as the large collection of disease-causing mutations in PCC, MCC, and PC. This review will summarize the recent advances in our knowledge on the structure and function of these important metabolic enzymes.

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Abbreviations

ACC:

Acetyl-CoA carboxylase

BC:

Biotin carboxylase

BCCP:

Biotin carboxyl carrier protein

BT:

BC-CT interaction

CT:

Carboxyltransferase

GCC:

Geranyl-CoA carboxylase

GCD:

Glutaconyl-CoA decarboxylase

HCS:

Holocarboxylase synthase

MCC:

3-methylcrotonyl-CoA carboxylase

MCG:

3-methylcrotonylglycinuria

PA:

Propionic acidemia

PC:

Pyruvate carboxylase

PCC:

Propionyl-CoA carboxylase

PT:

PC tetramerization

UA:

Urea amidolyase

UC:

Urea carboxylase

YCC:

Acyl-CoA carboxylase (generic name)

References

  1. Wakil SJ, Stoops JK, Joshi VC (1983) Fatty acid synthesis and its regulation. Ann. Rev. Biochem. 52:537–579

    Article  PubMed  CAS  Google Scholar 

  2. Cronan JE Jr, Waldrop GL (2002) Multi-subunit acetyl-CoA carboxylases. Prog Lipid Res 41:407–435

    Article  PubMed  CAS  Google Scholar 

  3. Tong L (2005) Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery. Cell Mol Life Sci 62:1784–1803

    Article  PubMed  CAS  Google Scholar 

  4. Jitrapakdee S, St. Maurice M, Rayment I, Cleland WW, Wallace JC, Attwood PV (2008) Structure, mechanism and regulation of pyruvate carboxylase. Biochem J 413:369–387

    Article  PubMed  CAS  Google Scholar 

  5. Berg IA, Kockelkorn D, Ramos-Vera WH, Say RF, Zarzycki J, Hugler M, Alber BE, Fuchs G (2010) Autotrophic carbon fixation in archaea. Nat Rev Microbiol 8:447–460

    Article  PubMed  CAS  Google Scholar 

  6. Pratscher J, Dumont MG, Conrad R (2011) Ammonia oxidation coupled to CO2 fixation by archaea and bacteria in an agricultural soil. Proc Natl Acad Sci USA 108:4170–4175

    Article  PubMed  CAS  Google Scholar 

  7. Smejkalova H, Erb TJ, Fuchs G (2010) Methanol assimilation in Methylobacterium extorquens AM1: demonstration of all enzymes and their regulation. PLoS One 5:e13001

    Article  PubMed  CAS  Google Scholar 

  8. Erb TJ, Berg IA, Brecht V, Muller M, Fuchs G, Alber BE (2007) Synthesis of C5-dicarboxylic acids from C2-units involving crotonyl-CoA carboxylase/reductase: the ethylmalonyl-CoA pathway. Proc Natl Acad Sci USA 104:10631–10636

    Article  PubMed  CAS  Google Scholar 

  9. Khomyakova M, Bukmez O, Thomas LK, Erb TJ, Berg IA (2011) A methylaspartate cycle in haloarchaea. Science 331:334–337

    Article  PubMed  CAS  Google Scholar 

  10. Alber BE (2011) Biotechnological potential of the ethylmalonyl-CoA pathway. Appl Microbiol Biotechnol 89:17–25

    Article  PubMed  CAS  Google Scholar 

  11. Schneider K, Asao M, Carter MS, Alber BE (2012) Rhodobacter sphaeroides uses a reductive route via propionyl coenzyme A to assimilate 3-hydroxypropionate. J Bacteriol 194:225–232

    Article  PubMed  CAS  Google Scholar 

  12. Gago G, Diacovich L, Arabolaza A, Tsai S-C, Gramajo H (2011) Fatty acid biosynthesis in actinomycetes. FEMS Microbiol Rev 35:475–497

    Article  PubMed  CAS  Google Scholar 

  13. Zhang H, Boghigian BA, Pfeifer BA (2010) Investigating the role of native propionyl-CoA and methylmalonyl-CoA metabolism on heterologous polyketide production in Escherichia coli. Biotechnol Bioeng 105:567–573

    Article  PubMed  CAS  Google Scholar 

  14. Forster-Fromme K, Jendrossek D (2010) Catabolism of citronellol and related acyclic terpenoids in pseudomonads. Appl Microbiol Biotechnol 87:859–869

    Article  PubMed  CAS  Google Scholar 

  15. Navarathna DHMLP, Harris SD, Roberts DD, Nickerson KW (2010) Evolutionary aspects of urea utilization by fungi. FEMS Yeast Res 10:209–213

    Article  PubMed  CAS  Google Scholar 

  16. Strope PK, Nickerson KW, Harris SD, Moriyama EN (2011) Molecular evolution of urea amidolyase and urea carboxylase in fungi. BMC Evol Biol 11:80

    Article  PubMed  CAS  Google Scholar 

  17. Knowles JR (1989) The mechanism of biotin-dependent enzymes. Ann Rev Biochem 58:195–221

    Article  PubMed  CAS  Google Scholar 

  18. Attwood PV, Wallace JC (2002) Chemical and catalytic mechanisms of carboxyl transfer reactions in biotin-dependent enzymes. Acc Chem Res 35:113–120

    Article  PubMed  CAS  Google Scholar 

  19. Perham RN (2000) Swinging arms and swinging domains in multifunctional enzymes: catalytic machines for multistep reactions. Ann Rev Biochem 69:961–1004

    Article  PubMed  CAS  Google Scholar 

  20. St. Maurice M, Reinhardt L, Surinya KH, Attwood PV, Wallace JC, Cleland WW, Rayment I (2007) Domain architecture of pyruvate carboxylase, a biotin-dependent multifunctional enzyme. Science 317:1076–1079

    Article  PubMed  CAS  Google Scholar 

  21. Xiang S, Tong L (2008) Crystal structures of human and Staphylococcus aureus pyruvate carboxylase and molecular insights into the carboxyltransfer reaction. Nat Struct Mol Biol 15:295–302

    Article  PubMed  CAS  Google Scholar 

  22. Huang CS, Sadre-Bazzaz K, Shen Y, Deng B, Zhou ZH, Tong L (2010) Crystal structure of the a6b6 holoenzyme of propionyl-coenzyme A carboxylase. Nature 466:1001–1005

    Article  PubMed  CAS  Google Scholar 

  23. Huang CS, Ge P, Zhou ZH, Tong L (2012) An unanticipated architecture of the 750-kDa a6b6 holoezyme of 3-methylcrotonyl-CoA carboxylase. Nature 481:219–223

    Article  CAS  Google Scholar 

  24. Fan C, Chou C-Y, Tong L, Xiang S (2012) Crystal structure of urea carboxylase provides insights into the carboxyltransfer reaction. J Biol Chem 287:9389–9398

    Article  PubMed  CAS  Google Scholar 

  25. Benning MM, Haller T, Gerlt JA, Holden HM (2000) New reactions in the crotonase superfamily: structure of methylmalonyl CoA decarboxylase from Escherichia coli. Biochem 39:4630–4639

    Article  CAS  Google Scholar 

  26. Dimroth P, Jockel P, Schmid M (2001) Coupling mechanism of the oxaloacetate decarboxylase Na+ pump. Biochim Biophys Acta 1505:1–14

    Article  PubMed  CAS  Google Scholar 

  27. Wendt KS, Schall I, Huber R, Buckel W, Jacob U (2003) Crystal structure of the carboxyltransferase subunit of the bacterial sodium ion pump glutaconyl-coenzyme A decarboxylase. EMBO J 22:3493–3502

    Article  PubMed  CAS  Google Scholar 

  28. Boiangiu CD, Jayamani E, Brugel D, Herrmann G, Kim J, Forzi L, Hedderich R, Vgenopoulou I, Pierik AJ, Steuber J, Buckel W (2005) Sodium ion pumps and hydrogen production in glutamate fermenting anaerobic bacteria. J Mol Microbiol Biotechnol 10:105–119

    Article  PubMed  CAS  Google Scholar 

  29. Studer R, Dahinden P, Wang W-W, Auchli Y, Li X-D, Dimroth P (2007) Crystal structure of the carboxyltransferase domain of the oxaloacetate decarboxylase Na+ pump from Vibrio cholerae. J Mol Biol 367:547–557

    Article  PubMed  CAS  Google Scholar 

  30. Kress D, Brugel D, Schall I, Linder D, Buckel W, Essen L-O (2009) An asymmetric model for Na+-translocating glutaconyl-CoA decarboxylase. J Biol Chem 284:28401–28409

    Article  PubMed  CAS  Google Scholar 

  31. Hall PR, Wang Y-F, Rivera-Hainaj RE, Zheng X, Pustai-Carey M, Carey PR, Yee VC (2003) Transcarboxylase 12S crystal structure: hexamer assembly and substrate binding to a multienzyme core. EMBO J 22:2334–2347

    Article  PubMed  CAS  Google Scholar 

  32. Hall PR, Zheng R, Antony L, Pustai-Carey M, Carey PR, Yee VC (2004) Transcarboxylase 5S structures: assembly and catalytic mechanism of a multienzyme complex subunit. EMBO J 23:3621–3631

    Article  PubMed  CAS  Google Scholar 

  33. Carey PR, Sonnichsen FD, Yee VC (2004) Transcarboxylase: one of nature’s early nanomachines. IUBMB Life 56:575–583

    Article  PubMed  CAS  Google Scholar 

  34. Hugler M, Krieger RS, Jahn M, Fuchs G (2003) Characterization of acetyl-CoA/propionyl-CoA carboxylase in Metallosphaera sedula. Eur J Biochem 270:736–744

    Article  PubMed  CAS  Google Scholar 

  35. Jordan IK, Henze K, Fedorova ND, Koonin EV, Galperin MY (2003) Phylogenomic analysis of the Giardia intestinalis transcarboxylase reveals multiple instances of domain fusion and fission in the evolution of biotin-dependent enzymes. J Mol Microbiol Biotechnol 5:172–189

    Article  PubMed  CAS  Google Scholar 

  36. Lombard J, Moreira D (2011) Early evolution of the biotin-dependent carboxylase family. BMC Evol Biol 11:232

    Article  PubMed  CAS  Google Scholar 

  37. Saggerson D (2008) Malonyl-CoA, a key signaling molecule in mammalian cells. Annu Rev Nutr 28:253–272

    Article  PubMed  CAS  Google Scholar 

  38. Hoja U, Marthol S, Hofmann J, Stegner S, Schulz R, Meier S, Greiner E, Schweizer E (2004) HFA1 encoding an organelle-specific acetyl-CoA carboxylase controls mitochondrial fatty acid synthesis in Saccharomyces cerevisiae. J Biol Chem 279:21779–21786

    Article  PubMed  CAS  Google Scholar 

  39. Tehlivets O, Scheuringer K, Kohlwein SD (2007) Fatty acid synthesis and elongation in yeast. Biochim Biophys Acta 1771:255–270

    Article  PubMed  CAS  Google Scholar 

  40. Hiltunen JK, Chen Z, Haapalainen AM, Wierenga RK, Kastaniotis AJ (2010) Mitochondrial fatty acid synthesis—an adopted set of enzymes making a pathway of major importance for the cellular metabolism. Prog Lipid Res 49:27–45

    Article  PubMed  CAS  Google Scholar 

  41. Witkowski A, Thweatt J, Smith S (2011) Mammalian ACSF3 protein is a malonyl-CoA synthetase that supplies the chain extender units for mitochondrial fatty acid synthesis. J Biol Chem 286:33729–33736

    Article  PubMed  CAS  Google Scholar 

  42. Chen H, Kim HU, Weng H, Browse J (2011) Malonyl-CoA synthetase, encoded by ACYL ACTIVATING ENZYME 13, is essential for growth and development of Arabidopsis. Plant Cell 23:2247–2262

    Article  PubMed  CAS  Google Scholar 

  43. Abu-Elheiga L, Brinkley WR, Zhong L, Chirala SS, Woldegiorgis G, Wakil SJ (2000) The subcellular localization of acetyl-CoA carboxylase 2. Proc Natl Acad Sci USA 97:1444–1449

    Article  PubMed  CAS  Google Scholar 

  44. McGarry JD, Brown NF (1997) The mitochondrial carnitine palmitoyl transferase system: from concept to molecular analysis. Eur J Biochem 244:1–14

    Article  PubMed  CAS  Google Scholar 

  45. Ramsay RR, Gandour RD, van der Leij FR (2001) Molecular enzymology of carnitine transfer and transport. Biochim Biophys Acta 1546:21–43

    Article  PubMed  CAS  Google Scholar 

  46. Kreuz S, Schoelch C, Thomas L, Rist W, Rippmann JF, Neubauer H (2009) Acetyl-CoA carboxylases 1 and 2 show distinct expression patterns in rats and humans and alterations in obesity and diabetes. Diabetes Metab Res Rev 25:577–586

    Article  PubMed  CAS  Google Scholar 

  47. Castle JC, Hara Y, Raymond CK, Garrett-Engele P, Ohwaki K, Kan Z, Kusunoki J, Johnson JM (2009) ACC2 is expressed at high levels human white adipose and has an isoform with a novel N-terminus. PLoS One 4:e4369

    Article  PubMed  CAS  Google Scholar 

  48. Diaz FJ, Meary A, Arranz MJ, Ruano G, Windermuth A, de Leon J (2009) Acetyl-coenzyme A carboxylase alpha gene variations may be associated with the direct effects of some antipsychotics on triglyceride levels. Schizophr Res 115:136–140

    Article  PubMed  Google Scholar 

  49. Gallardo D, Quintanilla R, Varona L, Diaz I, Ramirez O, Pena RN, Amills M (2009) Polymorphism of the pig acetyl-coenzyme A carboxylase alpha gene is associated with fatty acid composition in a Duroc commercial line. Anim Genet 40:410–417

    Article  PubMed  CAS  Google Scholar 

  50. Tian J, Wang S, Wang Q, Leng L, Hu X, Li H (2010) A single nucleotide polymorphism of chicken acetyl-CoA carboxylase A gene associated with fatness traits. Anim Biotechnol 21:42–50

    Article  PubMed  CAS  Google Scholar 

  51. Zhang S, Knight TJ, Reecy JM, Wheeler TL, Shackelford SD, Cundiff LV, Beitz DC (2009) Associations of polymorphisms in the promoter I of bovine acetyl-CoA carboxylase-alpha gene with beef fatty acid composition. Anim Genet 41:417–420

    PubMed  Google Scholar 

  52. Federica S, Francesco N, Giovanna DM, Carmela SM, Gennaro C, Carmela T, Bianca M (2009) Identification of novel single nucleotide polymorphisms in promoter III of the acetyl-CoA carboxylase-alpha gene in goats affecting milk production traits. J Heredity 100:386–389

    Article  CAS  Google Scholar 

  53. Brownsey RW, Boone AN, Elliot JE, Kulpa JE, Lee WM (2006) Regulation of acetyl-CoA carboxylase. Biochem Soc Trans 34:223–227

    Article  PubMed  CAS  Google Scholar 

  54. Kaushik VK, Kavana M, Volz JM, Weldon SC, Hanrahan S, Xu J, Caplan SL, Hubbard BK (2009) Characterization of recombinant human acetyl-CoA carboxylase-2 steady-state kinetics. Biochim Biophys Acta 1794:961–967

    Article  PubMed  CAS  Google Scholar 

  55. Locke GA, Cheng D, Witmer MR, Tamura JK, Haque T, Carney RF, Rendina AR, Marcinkeviciene J (2008) Differential activation of recombinant human acetyl-CoA carboxylases 1 and 2 by citrate. Arch Biochem Biophys 475:72–79

    Article  PubMed  CAS  Google Scholar 

  56. Kim CW, Moon Y-A, Park SW, Cheng D, Kwon HJ, Horton JD (2010) Induced polymerization of mammalian acetyl-CoA carboxylase by MIG12 provides a tertiary level of regulation of fatty acid biosynthesis. Proc Natl Acad Sci USA 107:9626–9631

    Article  PubMed  CAS  Google Scholar 

  57. Colbert CL, Kim CW, Moon Y-A, Henry L, Palnitkar M, McKean WB, Fitzgerald K, Deisenhofer J, Horton JD, Kwon HJ (2010) Crystal structure of Spot 14, a modulator of fatty acid synthesis. Proc Natl Acad Sci USA 107:18820–18825

    Article  PubMed  CAS  Google Scholar 

  58. Ray H, Moreau K, Dizin E, Callebaut I, Venezia ND (2006) ACCA phosphopeptide recognition by the BRCT repeats of BRCA1. J Mol Biol 359:973–982

    Article  PubMed  CAS  Google Scholar 

  59. Ray H, Suau F, Vincent A, Venezia ND (2009) Cell cycle regulation of the BRCA1/acetyl-CoA-carboxylase complex. Biochem Biophys Res Commun 378:615–619

    Article  PubMed  CAS  Google Scholar 

  60. Shen Y, Tong L (2008) Structural evidence for direct interactions between the BRCT domains of human BRCA1 and a phospho-peptide from human ACC1. Biochemical 47:5767–5773

    Article  CAS  Google Scholar 

  61. Nikolau BJ, Ohlrogge JB, Wurtele ES (2003) Plant biotin-containing carboxylases. Arch Biochem Biophys 414:211–222

    Article  PubMed  CAS  Google Scholar 

  62. Chalupska D, Lee HY, Faris JD, Evrard A, Chalhoub B, Haselkorn R, Gornicki P (2008) Acc homoeoloci and the evolution of wheat genomes. Proc Natl Acad Sci USA 105:9691–9696

    Article  PubMed  CAS  Google Scholar 

  63. Lu S, Zhao H, Parsons EP, Xu C, Kosma DK, Xu X, Chao D, Lohrey G, Bangarusamy DK, Wang G, Bressan RA, Jenks MA (2011) The glossyhead1 allele of ACC1 reveals a principal role for multidomain acetyl-coenzyme A carboxylase in the biosynthesis of cuticular waxes by Arabidopsis. Plant Physiol 157:1079–1092

    Article  PubMed  CAS  Google Scholar 

  64. Li ZG, Yin WB, Guo H, Song LY, Chen YH, Guan RZ, Wang JQ, Wang RRC, Hu ZM (2010) Genes encoding the alpha-carboxyltransferase subunit of acetyl-CoA carboxylase from Brassica napus and parental species: cloning, expression patterns, and evolution. Genome 53:360–370

    Article  PubMed  CAS  Google Scholar 

  65. Li ZG, Yin WB, Song LY, Chen YH, Guan RZ, Wang JQ, Wang RRC, Hu ZM (2011) Genes encoding the biotin carboxylase subunit of acetyl-CoA carboxylase from Brassica napus and parental species: cloning, expression patterns, and evolution. Genome 54:202–211

    Article  PubMed  CAS  Google Scholar 

  66. Bourrellier ABF, Valot B, Guillot A, Ambard-Bretteville F, Vidal J, Hodges M (2010) Chloroplast acetyl-CoA carboxylase activity is 2-oxoglutarate-regulated by interaction of PII with the biotin carboxyl carrier subunit. Proc Natl Acad Sci USA 107:502–507

    Article  CAS  Google Scholar 

  67. Li X, Ilarslan H, Brachova L, Qian HR, Li L, Che P, Wurtele ES, Nikolau BJ (2011) Reverse-genetic analysis of the two biotin-containing subunit genes of the heteromeric acetyl-coenzyme A carboxylase in Arabidopsis indicates a unidirectional functional redundancy. Plant Physiol 155:293–314

    Article  PubMed  CAS  Google Scholar 

  68. Olinares PDB, Ponnala L, van Wijk KJ (2010) Megadalton complexes in the chroloplast stroma of Arabidopsis thaliana characterized by size exclusion chromatography, mass spectrometry, and hierarchical clustering. Mol Cell Proteomics 9:1594–1615

    Article  PubMed  CAS  Google Scholar 

  69. Gornicki P (2003) Apicoplast fatty acid biosynthesis as a target for medical intervention in apicoplexan parasites. Int J Parasitol 33:885–896

    Article  PubMed  CAS  Google Scholar 

  70. Vigueira PA, Paul KS (2011) Requirement for acetyl-CoA carboxylase in Trypanosoma brucei is dependent upon the growth environment. Mol Microbiol 80:117–132

    Article  PubMed  CAS  Google Scholar 

  71. Alabaster A, Isoe J, Zhou G, Lee A, Murphy A, Day WA, Miesfeld RL (2011) Deficiencies in acetyl-CoA carboxylase and fatty acid synthase 1 differentially affect eggshell formation and blood meal digestion in Aedes aegypti. Insect Biochem Mol Biol 41:946–955

    Article  PubMed  CAS  Google Scholar 

  72. Spencer CM, Schafer XL, Moorman NJ, Munger J (2011) Human cytomegalovirus induces the activity and expression of acetyl-coenzyme A carboxylase, a fatty acid biosynthetic enzyme whose inhibition attenuates viral replication. J Virol 85:5814–5824

    Article  PubMed  CAS  Google Scholar 

  73. Campbell JW, Cronan JE Jr (2001) Bacterial fatty acid biosynthesis: targets for antibacterial drug discovery. Ann Rev Microbiol 55:305–332

    Article  CAS  Google Scholar 

  74. Tong L, Harwood HJ Jr (2006) Acetyl-coenzyme A carboxylases: versatile targets for drug discovery. J Cell Biochem 99:1476–1488

    Article  PubMed  CAS  Google Scholar 

  75. Wakil SJ, Abu-Elheiga LA (2009) Fatty acid metabolism: target for metabolic syndrome. J Lipid Res 50:S138–S143

    Article  PubMed  CAS  Google Scholar 

  76. Schreurs M, Kuipers F, van der Leij FR (2010) Regulatory enzymes of mitochondrial beta-oxidation as targets for treatment of the metabolic syndrome. Obes Rev 11:380–388

    Article  PubMed  CAS  Google Scholar 

  77. Lenhard JM (2011) Lipogenic enzymes as therapeutic targets for obesity and diabetes. Curr Pharm Des 17:325–331

    Article  PubMed  CAS  Google Scholar 

  78. Harwood HJ Jr (2004) Acetyl-CoA carboxylase inhibition for the treatment of metabolic syndrome. Curr Opin Investig Drugs 5:283–289

    PubMed  CAS  Google Scholar 

  79. Grundy SM (2006) Drug therapy of the metabolic syndrome: minimizing the emerging crisis in polypharmacy. Nat Rev Drug Discov 5:295–309

    Article  PubMed  CAS  Google Scholar 

  80. Reaven GM (2011) Insulin resistance: the link between obesity and cardiovascular disease. Med Clin North Amer 95:875–892

    Article  CAS  Google Scholar 

  81. Wang YC, McPherson K, Marsh T, Gortmaker SI, Brown M (2011) Health and economic burden of the projected obesity trends in the USA and the UK. Lancet 378:815–825

    Article  PubMed  Google Scholar 

  82. Abu-Elheiga L, Matzuk MM, Abo-Hashema KAH, Wakil SJ (2001) Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science 291:2613–2616

    Article  PubMed  CAS  Google Scholar 

  83. Abu-Elheiga L, Oh W, Kordari P, Wakil SJ (2003) Acetyl-CoA carboxylase 2 mutant mice are protected against obesity and diabetes induced by high-fat/high-carbohydrate diets. Proc Natl Acad Sci USA 100:10207–10212

    Article  PubMed  CAS  Google Scholar 

  84. Choi CS, Savage DB, Abu-Elheiga L, Liu Z-X, Kim S, Kulkarni A, Distefano A, Hwang Y-J, Reznick RM, Codella R, Zhang D, Cline GW, Wakil SJ, Shulman GI (2007) Continuous fat oxidation in acetyl-CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity. Proc Natl Acad Sci USA 104:16480–16485

    Article  PubMed  CAS  Google Scholar 

  85. Essop MF, Camp HS, Choi CS, Sharma S, Fryer RM, Reinhart GA, Guthrie PH, Bentebibel A, Gu Z, Shulman GI, Taegtmeyer H, Wakil SJ, Abu-Elheiga L (2008) Reduced heart size and increased myocardial fuel substrate oxidation in ACC2 mutant mice. Am J Physiol Heart Cir Physiol 295:H256–H265

    Article  CAS  Google Scholar 

  86. Abu-Elheiga L, Wu H, Gu Z, Bressler R, Wakil SJ (2012) Acetyl-CoA carboxylase 2−/− protects mutant mice against fatty liver under high-fat, high-carbohydrate dietary and de novo lipogenic conditions. J Biol Chem 287:12578–12588

    Article  PubMed  CAS  Google Scholar 

  87. Lane MD, Wolfgang M, Cha SH, Dai Y (2008) Regulation of food intake and energy expenditure by hypothalamic malonyl-CoA. Int J Obesity 32:S49–S54

    Article  CAS  Google Scholar 

  88. Fantino M (2011) Role of lipids in the control of food intake. Curr Opin Clin Nutr Metab Care 14:138–144

    Article  PubMed  CAS  Google Scholar 

  89. Abu-Elheiga L, Matzuk MM, Kordari P, Oh W, Shaikenov T, Gu Z, Wakil SJ (2005) Mutant mice lacking acetyl-CoA carboxylase 1 are embryonically lethal. Proc Natl Acad Sci USA 102:12011–12016

    Article  PubMed  CAS  Google Scholar 

  90. Mao J, Demayo FJ, Li H, Abu-Elheiga L, Gu Z, Shaikenov T, Kordari P, Chirala SS, Heird WC, Wakil SJ (2006) Liver-specific deletion of acetyl-CoA carboxylase 1 reduces hepatic triglyceride accumulation without affecting glucose homeostasis. Proc Natl Acad Sci USA 103:8552–8557

    Article  PubMed  CAS  Google Scholar 

  91. Mao J, Yang T, Gu Z, Heird WC, Finegold MJ, Lee B, Wakil SJ (2009) aP2-Cre-mediated inactivation of acetyl-CoA carboxylase 1 causes growth retardation and reduced lipid accumulation in adipose tissues. Proc Natl Acad Sci USA 106:17576–17581

    Article  PubMed  CAS  Google Scholar 

  92. Savage DB, Choi CS, Samuel VT, Liu ZX, Zhang D, Wang A, Zhang XM, Cline GW, Yu XX, Geisler JG, Bhanot S, Monia BP, Shulman GI (2006) Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2. J Clin Investig 116:817–824

    Article  PubMed  CAS  Google Scholar 

  93. Schreurs M, van Dijk TH, Gerding A, Havinga R, Reijngoud DJ, Kuipers F (2009) Soraphen, an inhibitor of the acetyl-CoA carboxylase system, improves peripheral insulin sensitivity in mice fed a high-fat diet. Diabetes Obesity Metab 11:987–991

    Article  CAS  Google Scholar 

  94. Peterson JM, Aja S, Wei Z, Wong GW (2012) CTRP1 protein enhances fatty acid oxidation via AMP-activated protein kinase (AMPK) activation and acetyl-CoA carboxylase (ACC) inhibition. J Biol Chem 287:1576–1587

    Article  PubMed  CAS  Google Scholar 

  95. Kobayashi MA, Watada H, Kawamori R, Maeda S (2010) Overexpression of acetyl-coenzyme A carboxylase beta increases proinflammatory cytokines in cultured human renal proximal tubular epithelial cells. Clin Exp Nephrol 14:315–324

    Article  PubMed  CAS  Google Scholar 

  96. Tang SCW, Leung VTM, Chan LYY, Wong SSH, Chu DWS, Leung JCK, Ho YW, Lai KN, Ma L, Elbein SC, Bowden DW, Hicks PJ, Comeau ME, Langefeld CD, Freedman BI (2010) The acetyl-coenzyme A carboxylase beta (ACACB) gene is associated with nephropathy in Chinese patients with type 2 diabetes. Nephrol Dial Transplant 25:3931–3934

    Article  PubMed  CAS  Google Scholar 

  97. Maeda S, Kobayashi MA, Araki SI, Babazono T, Freedman BI, Bostrom MA, Cooke JN, Toyoda M, Umezono T, Tarnow L, Hansen T, Gaede P, Jorsal A, Ng DPK, Ikeda M, Yanagimoto T, Tsunoda T, Unoki H, Kawai K, Imanishi M, Suzuki D, Shi HD, Park KS, Kashiwagi A, Iwamoto Y, Kaku K, Kawamori R, Parving HH, Bowden DW, Pedersen O, Nakamura Y (2010) A single nucleotide polymorphism within the acetyl-coenzyme A carboxylase beta gene is associated with proteinuria in patients with type 2 diabetes. PLoS Genet 6:e1000842

    Article  PubMed  CAS  Google Scholar 

  98. Riancho JA, Vazquez L, Garcia-Perez MA, Sainz J, Olmos JM, Hernandez JL, Perez-Lopez J, Amado JA, Zarrabeitia MT, Cano A, Rodriguez-Rey JC (2011) Association of ACACB polymorphisms with obesity and diabetes. Mol Gen Metab 104:670–676

    Article  CAS  Google Scholar 

  99. Phillips CM, Goumidi L, Bertrais S, Field MR, Cupples LA, Ordovas JM, McMonagle J, Defoort C, Lovegrove JA, Drevon CA, Blaak EE, Kiec-Wilk B, Riserus U, Lopez-Miranda J, McManus R, Hercberg S, Lairon D, Planells R, Roche HM (2010) ACC2 gene polymorphisms, metabolic syndrome, and gene-nutrient interactions with dietary fat. J Lipid Res 51:3500–3507

    Article  PubMed  CAS  Google Scholar 

  100. Hoehn KL, Turner N, Swarbrick MM, Wilks D, Preston E, Phua Y, Joshi H, Furler SM, Larance M, Hegarty BD, Leslie SJ, Pickford R, Hoy AJ, Kraegen EW, James DE, Cooney GJ (2010) Acute or chronic upregulation of mitochondrial fatty acid oxidation has no net effect on whole-body energy expenditure or adiposity. Cell Metab 11:70–76

    Article  PubMed  CAS  Google Scholar 

  101. Olson DP, Pulinilkunnil T, Cline GW, Shulman GI, Lowell BB (2010) Gene knockout of Acc2 has little effect on body weight, fat mass, or food intake. Proc Natl Acad Sci USA 107(16):7598–7603

    Article  PubMed  CAS  Google Scholar 

  102. Alkhateeb H, Holloway GP, Bonen A (2011) Skeletal muscle fatty acid oxidation is not directly associated with AMPK or ACC2 phosphorylation. Appl Physiol Nutr Metab 36:361–367

    Article  PubMed  CAS  Google Scholar 

  103. Hoehn KL, Turner N, Cooney GJ, James DE (2012) Phenotypic discrepancies in acetyl-CoA carboxylase 2-deficient mice. J Biol Chem 287:15801

    Article  PubMed  CAS  Google Scholar 

  104. Abu-Elheiga L, Wu H, Gu Z, Wakil SJ (2012) Reply to Hoehn et al.: phenotypic discrepancies in acetyl-CoA carboxylase 2-deficient mice. J Biol Chem 287:15802

    Article  CAS  Google Scholar 

  105. Harwood HJ Jr, Petras SF, Shelly LD, Zaccaro LM, Perry DA, Makowski MR, Hargrove DM, Martin KA, Tracey WR, Chapman JG, Magee WP, Dalvie DK, Soliman VF, Martin WH, Mularski CJ, Eisenbeis SA (2003) Isozyme-nonselective N-substituted bipiperidylcarboxamide acetyl-CoA carboxylase inhibitors reduce tissue malonyl-CoA concentrations, inhibit fatty acid synthesis, and increase fatty acid oxidation in cultured cells and in experimental animals. J Biol Chem 278:37099–37111

    Article  PubMed  CAS  Google Scholar 

  106. Corbett JW (2009) Review of recent acetyl-CoA carboxylase inhibitor patents: mid-2007-2008. Expert Opin Ther Pat 19:943–956

    Article  PubMed  CAS  Google Scholar 

  107. Jonas M, LaMarr WA, Ozbal C (2009) Mass spectrometry in high-throughput screening: a case study on acetyl-coenzyme A carboxylase using RapidFire-mass spectrometry (RF-MS). Comb Chem High Throughput Screen 12:752–759

    Article  PubMed  CAS  Google Scholar 

  108. Corbett JW, Freeman-Cook KD, Elliott R, Vajdos F, Rajamohan F, Kohls D, Marr E, Zhang H, Tong L, Tu M, Murdande S, Doran SD, Houser JA, Song W, Jones CJ, Coffey SB, Buzon L, Minich ML, Dirico KJ, Tapley S, McPherson RK, Sugarman E, Harwood HJ Jr, Esler W (2010) Discovery of small molecule isozyme non-specific inhibitors of mammalian acetyl-CoA carboxylase 1 and 2. Bioorg Med Chem Lett 20:2383–2388

    Article  PubMed  CAS  Google Scholar 

  109. Keil S, Muller M, Zoller G, Haschke G, Schroeter K, Glien M, Ruf S, Focken I, Herling AW, Schmoll D (2010) Identification and synthesis of novel inhibitors of acetyl-CoA carboxylase with in vitro and in vivo efficacy on fat oxidation. J Med Chem 53:8679–8687

    Article  PubMed  CAS  Google Scholar 

  110. Marjanovic J, Chalupska D, Patenode C, Coster A, Arnold E, Ye A, Anesi G, Lu Y, Okun I, Tkachenko S, Haselkorn R, Gornicki P (2010) Recombinant yeast screen for new inhibitors of human acetyl-CoA carboxylase 2 identifies potential drugs to treat obesity. Proc Natl Acad Sci USA 107:9093–9098

    Article  PubMed  CAS  Google Scholar 

  111. Abramson HN (2011) The lipogenesis pathway as a cancer target. J Med Chem 54:5615–5638

    Article  PubMed  CAS  Google Scholar 

  112. Bengtsson C, Blaho S, Saitton DB, Brickmann K, Broddefalk J, Dadidsson O, Drmota T, Folmer R, Hallberg K, Hallen S, Hovland R, Isin E, Johannesson P, Kull B, Larsson LO, Lofgren L, Nilsson KE, Noeske T, Oakes N, Plowright AT, Schnecke V, Stahlberg P, Sorme P, Wan H, Wellner E, Oster L (2011) Design of small molecule inhibitors of acetyl-CoA carboxylase 1 and 2 showing reduction of hepatic malonyl-CoA levels in vivo in obese Zucker rats. Bioorg Med Chem 19:3039–3053

    Article  PubMed  CAS  Google Scholar 

  113. Jump DB, Torres-Gonzalez M, Olson LK (2011) Soraphen A, an inhibitor of acetyl CoA carboxylase activity, interferes with fatty acid elongation. Biochem Pharmacol 81:649–660

    Article  PubMed  CAS  Google Scholar 

  114. Yamashita T, Kamata M, Endo S, Yamamoto M, Kakegawa K, Watanabe H, Miwa K, Yamano T, Funata M, Sakamoto JI, Tani A, Mol CD, Zou H, Dougan DR, Sang B, Snell G, Fukatsu K (2011) Design, synthesis, and structure-activity relationships of spirolactones bearing 2-ureidobenzothiophene a acetyl-CoA carboxylase inhibitors. Bioorg Med Chem Lett 21:6314–6318

    Article  PubMed  CAS  Google Scholar 

  115. Bagley SW, Southers JA, Cabral S, Rose CR, Bernhardson DJ, Edmonds DJ, Polivkova J, Yang X, Kung DW, Griffith DA, Bader SJ (2012) Synthesis of 7-oxo-dihydrospiro [indazole-5,4′-piperidine] acetyl-CoA carboxylase inhibitors. J Org Chem 77:1497–1506

    Article  PubMed  CAS  Google Scholar 

  116. Freeman-Cook KD, Amor P, Bader S, Buzon LM, Coffey SB, Corbett JW, Dirico KJ, Doran SD, Elliott RL, Esler W, Guzman-Perez A, Henegar KE, Houser JA, Jones CJ, Limberakis C, Loomis K, McPherson K, Murdande S, Nelson KL, Phillion D, Pierce BS, Song W, Sugarman E, Tapley S, Tu M, Zhao Z (2012) Maximizing lipophilic efficiency: the use of free-Wilson analysis in the design of inhibitors of acetyl-CoA carboxylase. J Med Chem 55:935–942

    Article  PubMed  CAS  Google Scholar 

  117. Glien M, Haschke G, Schroeter K, Pfenninger A, Zoller G, Keil S, Muller M, Herling AW, Schmoll D (2011) Stimulation of fat oxidation, but no sustained reduction of hepatic lipids by prolonged pharmacological inhibition of acetyl CoA carboxylase. Horm Metab Res 43:601–606

    Article  PubMed  CAS  Google Scholar 

  118. Ronnebaum SM, Joseph JW, Ilkayeva O, Burgess SC, Lu D, Becker TC, Sherry AD, Newgard CB (2008) Chronic suppression of acetyl-CoA carboxylase 1 in beta-cells impairs insulin secretion via inhibition of glucose rather than lipid metabolism. J Biol Chem 283:14248–14256

    Article  PubMed  CAS  Google Scholar 

  119. Swinnen JV, Brusselmans K, Verhoeven G (2006) Increased lipogenesis in cancer cells: new players, novel targets. Curr Opin Clin Nutr Metab Care 9:358–365

    Article  PubMed  CAS  Google Scholar 

  120. Chajes V, Cambot M, Moreau K, Lenoir GM, Joulin V (2006) Acetyl-CoA carboxylase alpha is essential to breast cancer cell survival. Cancer Res 66:5287–5294

    Article  PubMed  CAS  Google Scholar 

  121. Yoon S, Lee M-Y, Park SW, Moon J-S, Koh YK, Ahn Y-H, Park BW, Kim KS (2007) Up-regulation of acetyl-CoA carboxylase alpha and fatty acid synthase by human epidermal growth factor receptor 2 at the translational level in breast cancer cells. J Biol Chem 282:26122–26131

    Article  PubMed  CAS  Google Scholar 

  122. Hilvo M, Denkert C, Lehtinen L, Muller B, Brockmoller S, Seppanen-Laakso T, Budczies J, Bucher E, Yetukuri L, Castillo S, Berg E, Nygren H, Sysi-Aho M, Griffin JL, Fiehn O, Loibl S, Richter-Ehrenstein C, Radke C, Hyotylainen T, Kallioniemi O, Iljin K, Oresic M (2011) Novel theranostic opportunities offered by characterization of altered membrane lipid metabolism in breast cancer progression. Mol Cell Pathobiol 71:3236–3245

    CAS  Google Scholar 

  123. Beckers A, Organe S, Timmermans L, Scheys K, Peeters A, Brusselmans K, Verhoeven G, Swinnen JV (2007) Chemical inhibition of acetyl-CoA carboxylase induces growth arrest and cytotoxicity selectively in cancer cells. Cancer Res 67:8180–8187

    Article  PubMed  CAS  Google Scholar 

  124. Wang C, Rajput S, Watabe K, Liao DF, Cao D (2010) Acetyl-CoA carboxylase-alpha as a novel target for cancer therapy. Front Biosci 2:15–26

    Google Scholar 

  125. Olsen AM, Eisenberg BL, Kuemmerle NB, Flanagan AJ, Morganelli PM, Lombardo PS, Swinnen JV, Kinlaw WB (2010) Fatty acid synthesis is a therapeutic target in human liposarcoma. Int J Oncology 36:1309–1314

    CAS  Google Scholar 

  126. Scott KEN, Wheeler FB, Davis AL, Thomas MJ, Ntambi JM, Seals DF, Kridel SJ (2012) Metabolic regulation of invadopodia and invasion by acetyl-CoA carboxylase 1 and de novo lipogenesis. PLoS One 7:e29761

    Article  PubMed  CAS  Google Scholar 

  127. Ma J, Yan R, Zu X, Cheng JM, Rao K, Liao DF, Cao D (2008) Aldo-keto reductase family 1 B10 affects fatty acid synthesis by regulating the stability of acetyl-CoA carboxylase-alpha in breast cancer cells. J Biol Chem 283:3418–3423

    Article  PubMed  CAS  Google Scholar 

  128. Gronwald JW (1991) Lipid biosynthesis inhibitors. Weed Sci 39:435–449

    CAS  Google Scholar 

  129. Hofer U, Muehlebach M, Hole S, Zoschke A (2006) Pinoxaden—for broad spectrum grass weed management in cereal crops. J Plant Dis Protection 20:989–995

    Google Scholar 

  130. Muehlebach M, Boeger M, Cederbaum F, Cornes D, Friedmann AA, Glock J, Niderman T, Stoller A, Wagner T (2009) Aryldiones incorporating a [1,4,5]oxadiazepane ring. Part I: discovery of the novel cereal herbicide pinoxaden. Bioorg Med Chem 17:4241–4256

    Article  PubMed  CAS  Google Scholar 

  131. Yang X, Guschina IA, Hurst S, Wood S, Langford M, Hawkes T, Harwood JL (2010) The action of herbicides on fatty acid biosynthesis and elongation in barley and cucumber. Pest Manag Sci 66:794–800

    Article  PubMed  CAS  Google Scholar 

  132. Devine MD, Shukla A (2000) Altered target sites as a mechanism of herbicide resistance. Crop Protection 19:881–889

    Article  CAS  Google Scholar 

  133. Yu Q, Collavo A, Zheng MQ, Owen M, Sattin M, Powles SB (2007) Diversity of acetyl-coenzyme A carboxylase mutations in resistant Lolium populations: evaluation using clethodim. Plant Physiol 145:547–558

    Article  PubMed  CAS  Google Scholar 

  134. Liu W, Harrison DK, Chalupska D, Gornicki P, O’donnell CC, Adkins SW, Haselkorn R, Williams RR (2007) Single-site mutations in the carboxyltransferase domain of plastid acetyl-CoA carboxylase confer resistance to grass-specific herbicides. Proc Natl Acad Sci USA 104:3627–3632

    Article  PubMed  CAS  Google Scholar 

  135. Delye C, Matejicek A, Michel S (2008) Cross-resistance patterns to ACCase-inhibiting herbicides conferred by mutant ACCase isoforms in Alopecurus myosuroides Huds. (black-grass), re-examined at the recommended herbicide field rate. Pest Manag Sci 64:1179–1186

    Article  PubMed  CAS  Google Scholar 

  136. Cruz-Hipolito H, Osuna MD, Dominguez-Valenzuela JA, Espinoza N, de Prado R (2011) Mechanism of resistance to ACCase-inhibiting herbicides in wild oat (Avena fatua) from Latin America. J Agric Food Chem 59:7261–7267

    Article  PubMed  CAS  Google Scholar 

  137. Petit C, Bay G, Pernin F, Delye C (2010) Prevalence of cross- or multiple resistance to the acetyl-coenzyme A carboxylase inhibitors fenoxaprop, clodinafop and pinoxaden in black-grass (Alopecurus myosuroides Huds.) in France. Pest Manag Sci 66:168–177

    PubMed  CAS  Google Scholar 

  138. Scarabel L, Panozzo S, Varotto S, Sattin M (2011) Allelic variation of the ACCase gene and response to ACCase-inhibiting herbicides in pinoxaden-resistant Lolium spp. Pest Manag Sci 67:932–941

    Article  PubMed  CAS  Google Scholar 

  139. Kaundun SS (2010) An aspartate to glycine change in the carboxyl transferase domain of acetyl CoA carboxylase and non-target-site mechanism(s) confer resistance to ACCase inhibitor herbicides in a Lolium multiflorum population. Pest Manag Sci 66:1249–1256

    Article  PubMed  CAS  Google Scholar 

  140. Wang T, Picard JC, Tian X, Darmency H (2010) A herbicide-resistant ACCase 1781 Setaria mutant shows higher fitness than wild type. Heredity 105:394–400

    Article  PubMed  CAS  Google Scholar 

  141. Louie T, Goodman CD, Holloway GA, McFadden GI, Mollard V, Watson KG (2010) Dimeric cyclohexane-1,3-dione oximes inhibit wheat acetyl-CoA carboxylase and show anti-malarial activity. Bioorg Med Chem Lett 20:4611–4613

    Article  PubMed  CAS  Google Scholar 

  142. Miller JR, Dunham S, Mochalkin I, Banotai C, Bowman M, Buist S, Dunkle B, Hanna D, Harwood HJ Jr, Huband MD, Karnovsky A, Kuhn M, Limberakis C, Liu JY, Mehrens S, Mueller WT, Narasimhan L, Ogden A, Ohren J, Prasad JVNV, Shelly JA, Skerlos L, Sulavik M, Thomas VH, VanderRoest S, Wang L, Wang Z, Whitton A, Zhu T, Stover CK (2009) A class of selective antibacterials derived from a protein kinase inhibitor pharmacophore. Proc Natl Acad Sci USA 106:1737–1742

    Article  PubMed  CAS  Google Scholar 

  143. Mochalkin I, Miller JR, Narasimhan L, Thanabal V, Erdman P, Cox PB, Prasad JVNV, Lightle S, Huband MD, Stover CK (2009) Discovery of antibacterial biotin carboxylase inhibitors by virtual screening and fragment-based approaches. ACS Chem Biol 4:473–483

    Article  PubMed  CAS  Google Scholar 

  144. Cheng CC, Shipps GW Jr, Yang Z, Sun B, Kawahata N, Soucy KA, Soriano A, Orth P, Xiao L, Mann P, Black T (2009) Discovery and optimization of antibacterial AccC inhibitors. Bioorg Med Chem Lett 19:6507–6514

    Article  PubMed  CAS  Google Scholar 

  145. Waldrop GL (2009) Smaller is better for antibiotic discovery. ACS Chem Biol 4:397–399

    Article  PubMed  CAS  Google Scholar 

  146. Polyak SW, Abell AD, Wilce MCJ, Zhang L, Booker GW (2012) Structure, function and selective inhibition of bacterial acetyl-coa carboxylase. Appl Microbiol Biotechnol 93:983–992

    Article  PubMed  CAS  Google Scholar 

  147. Liu X, Fortin PD, Walsh CT (2008) Andrimid producers encode an acetyl-CoA carboxyltransferase subunit resistant to the action of the antibiotic. Proc Natl Acad Sci USA 105:13321–13326

    Article  PubMed  CAS  Google Scholar 

  148. Meades G Jr, Henken RL, Waldrop GL, Rahman MM, Gilman SD, Kamatou GPP, Viljoen AM, Gibbons S (2010) Constituents of cinnamon inhibit bacterial acetyl CoA carboxylase. Planta Med 76:1570–1575

    Article  PubMed  CAS  Google Scholar 

  149. Waldrop GL, Rayment I, Holden HM (1994) Three-dimensional structure of the biotin carboxylase subunit of acetyl-CoA carboxylase. Biochem 33:10249–10256

    Article  CAS  Google Scholar 

  150. Shen Y, Volrath SL, Weatherly SC, Elich TD, Tong L (2004) A mechanism for the potent inhibition of eukaryotic acetyl-coenzyme A carboxylase by soraphen A, a macrocyclic polyketide natural product. Mol Cell 16:881–891

    Article  PubMed  CAS  Google Scholar 

  151. Thoden JB, Blanchard CZ, Holden HM, Waldrop GL (2000) Movement of the biotin carboxylase B-domain as a result of ATP binding. J Biol Chem 275:16183–16190

    Article  PubMed  CAS  Google Scholar 

  152. Mochalkin I, Miller JR, Evdokimov A, Lightle S, Yan C, Stover CK, Waldrop GL (2008) Structural evidence for substrate-induced synergism and half-sites reactivity in biotin carboxylase. Prot Sci 17:1706–1718

    Article  CAS  Google Scholar 

  153. Cho YS, Lee JI, Shin D, Kim HT, Cheon YH, Seo CI, Kim YE, Hyun YL, Lee YS, Sugiyama K, Park SY, Ro S, Cho JM, Lee TG, Heo YS (2008) Crystal structure of the biotin carboxylase domain of human acetyl-CoA carboxylase 2. Proteins 70:268–272

    Article  PubMed  CAS  Google Scholar 

  154. Chou C-Y, Yu LPC, Tong L (2009) Crystal structure of biotin carboxylase in complex with substrates and implications for its catalytic mechanism. J Biol Chem 284:11690–11697

    Article  PubMed  CAS  Google Scholar 

  155. Raymer B, Kavana M, Price A, Wang B, Corcoran L, Kulathila R, Groarke J, Mann T (2009) Synthesis and characterization of a BODIPY-labeled derivative of soraphen A that binds to acetyl-CoA carboxylase. Bioorg Med Chem Lett 19:2804–2807

    Article  PubMed  CAS  Google Scholar 

  156. Cho YS, Lee JI, Shin D, Kim HT, Jung HY, Lee TG, Kang LW, Ahn YJ, Cho HS, Heo YS (2010) Molecular mechanism for the regulation of human ACC2 through phosphorylation by AMPK. Biochem Biophys Res Commun 391:187–192

    Article  PubMed  CAS  Google Scholar 

  157. Chou C-Y, Tong L (2011) Structural and biochemical studies on the regulation of biotin carboxylase by substrate inhibition and dimerization. J Biol Chem 286:24417–24425

    Article  PubMed  CAS  Google Scholar 

  158. Bordelon T, Lill SON, Waldrop GL (2009) The utility of molecular dynamics simulations for understanding site-directed mutagenesis of gycine residues in biotin carboxylase. Proteins 74:808–819

    Article  PubMed  CAS  Google Scholar 

  159. Janiyani K, Bordelon T, Waldrop GL, Cronan JE Jr (2001) Function of Escherichia coli biotin carboxylase requires catalytic activity of both subunits of the homodimer. J Biol Chem 276:29864–29870

    Article  PubMed  CAS  Google Scholar 

  160. de Queiroz MS, Waldrop GL (2007) Modeling and numerical simulation of biotin carboxylase kinetics: implications for half-sites reactivity. J Theoretical Biol 246:167–175

    Article  CAS  Google Scholar 

  161. Shen Y, Chou C-Y, Chang G-G, Tong L (2006) Is dimerization required for the catalytic activity of bacterial biotin carboxylase? Mol. Cell 22:807–818

    CAS  Google Scholar 

  162. Smith AC, Cronan JE (2012) Dimerization of the bacterial biotin carboxylase subunit is required for acetyl coenzyme A carboxylase activity in vivo. J Bacteriol 194:72–78

    Article  PubMed  CAS  Google Scholar 

  163. Weatherly SC, Volrath SL, Elich TD (2004) Expression and characterization of recombinant fungal acetyl-CoA carboxylase and isolation of a soraphen-binding domain. Biochem J 380:105–110

    Article  PubMed  CAS  Google Scholar 

  164. Yao X, Soden C Jr, Summers MF, Beckett D (1999) Comparison of the backbone dynamics of the apo- and holo-carboxy-terminal domain of the biotin carboxyl carrier subunit of Escherichia coli acetyl-CoA carboxylase. Prot Sci 8:307–317

    Article  CAS  Google Scholar 

  165. Athappilly FK, Hendrickson WA (1995) Structure of the biotinyl domain of acetyl-coenzyme A carboxylase determined by MAD phasing. Structure 3:1407–1419

    Article  PubMed  CAS  Google Scholar 

  166. Solbiati J, Chapman-Smith A, Cronan JE Jr (2002) Stabilization of the biotinoyl domain of Escherichia coli acetyl-CoA carboxylase by interactions between the attached biotin and the protruding “thumb” structure. J Biol Chem 277:21604–21609

    Article  PubMed  CAS  Google Scholar 

  167. Lee CK, Cheong HK, Ryu KS, Lee JI, Lee W, Jeon YH, Cheong C (2008) Biotinoyl domain of human acetyl-CoA carboxylase: structural insights into the carboxyl transfer mechanism. Proteins 72:613–624

    Article  PubMed  CAS  Google Scholar 

  168. Healy S, McDonald MK, Wu X, Yue WW, Kochan G, Oppermann U, Gravel RA (2010) Structural impact of human and Escherichia coli biotin carboxyl carrier proteins on biotin attachment. Biochem 49:4687–4694

    Article  CAS  Google Scholar 

  169. Zhang H, Yang Z, Shen Y, Tong L (2003) Crystal structure of the carboxyltransferase domain of acetyl-coenzyme A carboxylase. Science 299:2064–2067

    Article  PubMed  CAS  Google Scholar 

  170. Bilder P, Lightle S, Bainbridge G, Ohren J, Finzel B, Sun F, Holley S, Al-Kassim L, Spessard C, Melnick M, Newcomer M, Waldrop GL (2006) The structure of the carboxyltransferase component of acetyl-CoA carboxylase reveals a zinc-binding motif unique to the bacterial enzyme. Biochem 45:1712–1722

    Article  CAS  Google Scholar 

  171. Zhang H, Tweel B, Tong L (2004) Molecular basis for the inhibition of the carboxyltransferase domain of acetyl-coenzyme A carboxylase by haloxyfop and diclofop. Proc Natl Acad Sci USA 101:5910–5915

    Article  PubMed  CAS  Google Scholar 

  172. Xiang S, Callaghan MM, Watson KG, Tong L (2009) A different mechanism for the inhibition of the carboxyltransferase domain of acetyl-coenzyme A carboxylase by tepraloxydim. Proc Natl Acad Sci USA 106:20723–20727

    Article  PubMed  CAS  Google Scholar 

  173. Yu LPC, Kim YS, Tong L (2010) Mechanism for the inhibition of the carboxyltransferase domain of acetyl-coenzyme A carboxylase by pinoxaden. Proc Natl Acad Sci USA 107:22072–22077

    Article  PubMed  CAS  Google Scholar 

  174. Zhang H, Tweel B, Li J, Tong L (2004) Crystal structure of the carboxyltransferase domain of acetyl-coenzyme A carboxylase in complex with CP-640186. Structure 12:1683–1691

    Article  PubMed  CAS  Google Scholar 

  175. Madauss KP, Burkhart WA, Consler TG, Cowan DJ, Gottschalk WK, Miller AB, Short SA, Tran TB, Williams SP (2009) The human ACC2 CT-domain C-terminus is required for full functionality and has a novel twist. Acta Cryst D65:449–461

    CAS  Google Scholar 

  176. Rajamohan F, Marr E, Reyes AR, Landro JA, Anderson MD, Corbett JW, Dirico KJ, Harwood HJ Jr, Tu M, Vajdos FF (2011) Structure-guided inhibitor design for human acetyl-coenzyme A carboxylase by interspecies active site conversion. J Biol Chem 286:41510–41519

    Article  PubMed  CAS  Google Scholar 

  177. Meades G Jr, Benson BK, Grove A, Waldrop GL (2010) A tale of two functions: enzymatic activity and translational repression by carboxyltransferase. Nucl Acids Res 38:1217–1227

    Article  PubMed  CAS  Google Scholar 

  178. Benson BK, Meades G Jr, Grove A, Waldrop GL (2008) DNA inhibits catalysis by the carboxyltransferase subunit of acetyl-CoA carboxylase: implications for active site communication. Prot Sci 17:34–42

    Article  CAS  Google Scholar 

  179. Giorgio AJ, Plaut GWE (1967) The effect of univalent cations on activities catalyzed by bovine-liver propionyl-CoA carboxylase. Biochim Biophys Acta 139:487–501

    Article  PubMed  CAS  Google Scholar 

  180. Edwards JB, Keech DB (1968) Activation of pig heart propionyl-CoA carboxylase by potassium ions. Biochim Biophys Acta 159:167–175

    Article  PubMed  CAS  Google Scholar 

  181. Kalousek F, Darigo MD, Rosenberg LE (1980) Isolation and characterization of propionyl-CoA carboxylase from normal human liver. Evidence for a protomeric tetramer of nonidentical subunits. J Biol Chem 255:60–65

    PubMed  CAS  Google Scholar 

  182. Ugarte M, Perez-Cerda C, Rodriguez-Pombo P, Desviat LR, Perez B, Richard E, Muro S, Campeau E, Ohura T, Gravel RA (1999) Overview of mutations in the PCCA and PCCB genes causing propionic acidemia. Hum Mutat 14:275–282

    Article  PubMed  CAS  Google Scholar 

  183. Yang X, Sakamoto O, Matsubara Y, Kure S, Suzuki Y, Aoki Y, Yamaguchi S, Takahashi Y, Nishikubo T, Kawaguchi C, Yoshioka A, Kimura T, Hayasaka K, Kohno Y, Iinuma K, Ohura T (2004) Mutation spectrum of the PCCA and PCCB genes in Japanese patients with propionic acidemia. Mol Gen Metab 81:335–342

    Article  CAS  Google Scholar 

  184. Desviat LR, Perez B, Perez-Cerda C, Rodriguez-Pombo P, Clavero S, Ugarte M (2004) Propionic acidemia: mutation update and functional and structural effects of the variant alleles. Mol Gen Metab 83:28–37

    Article  CAS  Google Scholar 

  185. Desviat LR, Clavero S, Perez-Cerda C, Navarrete R, Ugarte M, Perez B (2006) New splicing mutations in propionic acidemia. J Hum Genet 51:992–997

    Article  PubMed  CAS  Google Scholar 

  186. Desviat LR, Sanchez-Alcudia R, Perez B, Perez-Cerda C, Navarrete R, Vijzelaar R, Ugarte M (2009) High frequency of large genomic deletions in the PCCA gene causing propionic acidemia. Mol Gen Metab 96:171–176

    Article  CAS  Google Scholar 

  187. Perez B, Angaroni C, Sanchez-Alcudia R, Merinero B, Perez-Cerda C, Specola N, Rodriguez-Pombo P, Wajner M, de Kremer RD, Cornejo V, Desviat LR, Ugarte M (2010) The molecular landscape of propionic acidemia and methylmalonic aciduria in Latin America. J Inher Metab Dis 33:S307–S314

    Article  PubMed  CAS  Google Scholar 

  188. Scholl-Burgi S, Sass JO, Zschocke J, Karall D (2012) Amino acid metabolism in patients with propionic acidemia. J Inher Metab Dis 35:65–70

    Article  PubMed  CAS  Google Scholar 

  189. Kraus JP, Spector E, Venezia S, Estes P, Chiang PW, Creadon-Swindell G, Mullerleile S, de Silva L, Barth M, Walter M, Walter K, Meissner T, Lindner M, Ensenauer R, Santer R, Bodamer OA, Baumgartner MR, Brunner-Krainz M, Karall D, Haase C, Knerr I, Marquardt T, Hennermann JB, Steinfeld R, Beblo S, Koch H-G, Konstantopoulou V, Scholl-Burgi S, van Teeffelen-Heithoff A, Suormala T, Ugarte M, Sperl W, Superti-Furga A, Schwab KO, Grunert SC, Sass JO (2012) Mutation analysis in 54 propionic acidemia patients. J Inher Metab Dis 35:51–63

    Article  PubMed  CAS  Google Scholar 

  190. Ballhausen D, Mittaz L, Boulat O, Bonafe L, Braissant O (2009) Evidence for catabolic pathway of propionate metabolism in CNS: expression pattern of methylmalonyl-CoA mutase and propionyl-CoA carboxylase alpha-subunit in developing and adult rat brain. Neurosci 164:578–587

    Article  CAS  Google Scholar 

  191. Haberlandt E, Canestrini C, Brunner-Krainz M, Moslinger D, Mussner K, Plecko B, Scholl-Burgi S, Sperl W, Rostasy K, Karall D (2009) Epilepsy in patients with propionic acidemia. Neuropediatrics 40:120–125

    Article  PubMed  CAS  Google Scholar 

  192. Rigo FK, Pasquetti L, Malfatti CRM, Fighera MR, Coelho RC, Petri CZ, Mello CF (2006) Propionic acid induces convulsions and protein carboxylation in rats. Neurosci Lett 408:151–154

    Article  PubMed  CAS  Google Scholar 

  193. Miyazaki T, Ohura T, Kobayashi M, Shigematsu Y, Yamaguchi S, Suzuki Y, Hata I, Aoki Y, Yang X, Minjares C, Haruta I, Uto H, Ito Y, Muller U (2001) Fatal propionic acidemia in mice lacking propionyl-CoA carboxylase and its rescue by postnatal, liver-specific supplementation via a transgene. J Biol Chem 276:35995–35999

    Article  PubMed  CAS  Google Scholar 

  194. Rincon A, Aguado C, Desviat LR, Sanchez-Alcudia R, Ugarte M, Perez B (2007) Propionic and methylmalonic acidemia: antisense therapeutics for intronic variations causing aberrantly spliced messenger RNA. Am J Hum Genet 81:1262–1270

    Article  PubMed  CAS  Google Scholar 

  195. Sanchez-Alcudia R, Perez B, Perez-Cerda C, Ugarte M, Desviat LR (2011) Overexpression of adapted U1snRNA in patients’ cells to correct a 5′ splice site mutation in propionic acidemia. Mol Gen Metab 102:134–138

    Article  CAS  Google Scholar 

  196. Hofherr SE, Senac JS, Chen CY, Palmer DJ, Ng P, Barry MA (2009) Short-term rescue of neonatal lethality in a mouse model of propionic acidemia by gene therapy. Hum Gene Ther 20:169–180

    Article  PubMed  CAS  Google Scholar 

  197. Chandler RJ, Chandrasekaran S, Carrillo-Carrasco N, Senac JS, Hofherr SE, Barry MA, Venditti CP (2011) Adeno-associated virus serotype 8 gene transfer rescues a neonatal lethal murine model of propionic acidemia. Hum Gene Ther 22:477–481

    Article  PubMed  CAS  Google Scholar 

  198. Diacovich L, Mitchell DL, Pham H, Gago G, Melgar MM, Khosla C, Gramajo H, Tsai S-C (2004) Crystal structure of the b-subunit of acyl-CoA carboxylase: structure-based engineering of substrate specificity. Biochem 43:14027–14036

    Article  CAS  Google Scholar 

  199. Lin TW, Melgar MM, Kurth D, Swamidass SJ, Purdon J, Tseng T, Gago G, Baldi P, Gramajo H, Tsai S-C (2006) Structure-based inhibitor design of AccD5, an essential acyl-CoA carboxylase carboxyltransferase domain of Mycobacterium tuberculosis. Proc Natl Acad Sci USA 103:3072–3077

    Article  PubMed  CAS  Google Scholar 

  200. Arabolaza A, Shillito ME, Lin TW, Diacovich L, Melgar MM, Pham H, Amick D, Gramajo H, Tsai S-C (2010) Crystal structures and mutational analyses of acyl-CoA carboxylase b subunit of Streptomyces coelicolor. Biochemical 49:7367–7376

    Article  CAS  Google Scholar 

  201. Muro S, Perez B, Desviat LR, Rodriguez-Pombo P, Perez-Cerda C, Clavero S, Ugarte M (2001) Effect of PCCB gene mutations on the heteromeric and homomeric assembly of propionyl-CoA carboxylase. Mol Gen Metab 74:476–483

    Article  CAS  Google Scholar 

  202. Chloupkova M, Maclean KN, Alkhateeb A, Kraus JP (2002) Propionic acidemia: analysis of mutant propionyl-CoA carboxylase enzymes expressed in Escherichia coli. Hum Mutat 19:629–640

    Article  PubMed  CAS  Google Scholar 

  203. Clavero S, Martinez MA, Perez B, Perez-Cerda C, Ugarte M, Desviat LR (2002) Functional characterization of PCCA mutations causing propionic acidemia. Biochim Biophys Acta 1588:119–125

    Article  PubMed  CAS  Google Scholar 

  204. Perez-Cerda C, Clavero S, Perez B, Rodriguez-Pombo P, Desviat LR, Ugarte M (2003) Functional analysis of PCCB mutations causing propionic acidemia based on expression studies in deficient human skin fibroblasts. Biochim Biophys Acta 1638:43–49

    Article  PubMed  CAS  Google Scholar 

  205. Sloane V, Waldrop GL (2004) Kinetic characterization of mutations found in propionic acidemia and methylcrotonylglycinuria. J Biol Chem 279:15772–15778

    Article  PubMed  CAS  Google Scholar 

  206. Jiang H, Rao KS, Yee VC, Kraus JP (2005) Characterization of four variant forms of human propionyl-CoA carboxylase expressed in Escherichia coli. J Biol Chem 280:27719–27727

    Article  PubMed  CAS  Google Scholar 

  207. Rodriguez-Pombo P, Perez-Cerda C, Perez B, Desviat LR, Sanchez-Pulido L, Ugarte M (2005) Towards a model to explain the intragenic complementation in the heteromultimeric protein propionyl-CoA carboxylase. Biochim Biophys Acta 1740:489–498

    Article  PubMed  CAS  Google Scholar 

  208. Diaz-Perez AL, Zavala-Hernandez AN, Cervantes C, Campos-Garcia J (2004) The gny RDBHAL cluster is involved in acyclic isoprenoid degradation in Pseudomonas aeruginosa. Appl Environ Microbiol 70:5102–5110

    Article  PubMed  CAS  Google Scholar 

  209. Hoschle B, Gnau V, Jendrossek D (2005) Methylcrotonyl-CoA and geranyl-CoA carboxylases are involved in leucine/isovalerate utilization (Liu) and acyclic terpene utilization (Atu), and are encoded by liuB/liuD and atuC/atuF, in Pseudomonas aeruginosa. Microbiol 151:3649–3656

    Article  CAS  Google Scholar 

  210. Forster-Fromme K, Hoschle B, Mack C, Bott M, Armbruster W, Jendrossek D (2006) Identification of genes and proteins necessary for catabolism of acyclic terpenes and leucine/isovalerate in Pseudomonas aeruginosa. Appl Environmental Microbiol 72:4819–4828

    Article  CAS  Google Scholar 

  211. Aguilar JA, Zavala AN, Diaz-Perez C, Cervantes C, Diaz-Perez AL, Campos-Garcia J (2006) The atu and liu clusters are involved in the catabolic pathways for acyclic monoterpenes and leucine in Pseudomonas aeruginosa. Appl Environmental Microbiol 72:2070–2079

    Article  CAS  Google Scholar 

  212. Aguilar JA, Diaz-Perez C, Diaz-Perez AL, Rodriguez-Zavala JS, Nikolau BJ, Campos-Garcia J (2008) Substrate specificity of the 3-methylcrotonyl coenzyme A (CoA) and geranyl-CoA carboxylases from Pseudomonas aeruginosa. J Bacteriol 190:4888–4893

    Article  PubMed  CAS  Google Scholar 

  213. Ding G, Che P, Ilarslan H, Wurtele ES, Nikolau BJ (2012) Genetic dissection of methylcrotonyl CoA carboxylase indicates a complex role for mitochondrial leucine catabolism during seed development and germination. Plant J 70(4):562–577

    Article  PubMed  CAS  Google Scholar 

  214. Tomaszycki ML, Peabody C, Replogle K, Clayton DF, Tempelman RJ, Wade J (2009) Sexual differentiation of the zebra finch song system: potential roles for sex chromosome genes. BMC Neurosci 10:24

    Article  PubMed  CAS  Google Scholar 

  215. Stadler SC, Polanetz R, Meier S, Mayerhofer PU, Herrmann JM, Anslinger K, Roscher AA, Roschinger W, Holzinger A (2005) Mitochondrial targeting signals and mature peptides of 3-methylcrotonyl-CoA carboxylase. Biochem Biophys Res Commun 334:939–946

    Article  PubMed  CAS  Google Scholar 

  216. Chu C-H, Cheng D (2007) Expression, purification, characterization of human 3-methylcrotonyl-CoA carboxylase (MCCC). Prot Expr Purif 53:421–427

    Article  CAS  Google Scholar 

  217. Baumgartner MR, Almashanu S, Suormala T, Obie C, Cole RN, Packman S, Baumgartner ER, Valle D (2001) The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency. J Clin Investig 107:495–504

    Article  PubMed  CAS  Google Scholar 

  218. Gallardo ME, Desviat LR, Rodriguez JM, Esparza-Gordillo J, Perez-Cerda C, Perez B, Rodriguez-Pombo P, Criado O, Sanz R, Morton DH, Gibson KM, Le TP, Ribes A, Rodriguez de Cordoba S, Ugarte M, Penalva MA (2001) The molecular basis of 3-methylcrotonylglycinuria, a disorder of leucine metabolism. Am J Hum Genet 68:334–346

    Article  PubMed  CAS  Google Scholar 

  219. Holzinger A, Roschinger W, Lagler F, Mayerhofer PU, Lichtner P, Kattenfeld T, Thuy LP, Nyhan WL, Koch H-G, Muntau AC, Roscher AA (2001) Cloning of the human MCCA and MCCB genes and mutations therein reveal the molecular cause of 3-methylcrotonyl-CoA carboxylase deficiency. Human Mol Gen 10:1299–1306

    Article  CAS  Google Scholar 

  220. Desviat LR, Perez-Cerda C, Perez B, Esparza-Gordillo J, Rodriguez-Pombo P, Penalva MA, Rodriguez de Cordoba S, Ugarte M (2003) Functional analysis of MCCA and MCCB mutations causing methylcrotonylglycinuria. Mol Gen Metab 80:315–320

    Article  CAS  Google Scholar 

  221. Stadler SC, Polanetz R, Maier EM, Heidenreich SC, Niederer B, Mayerhofer PU, Lagler F, Koch H-G, Santer R, Fletcher JM, Ranieri E, Das AM, Spiekerkotter U, Schwab KO, Potzsch S, Marquardt I, Hennermann JB, Knerr I, Mercimek-Mahmutoglu S, Kohlschmidt N, Liebl B, Fingerhut R, Olgemoller B, Muntau AC, Roscher AA, Roschinger W (2006) Newborn screening for 3-methylcrotonyl-CoA carboxylase deficiency: population heterogeneity of MCCA and MCCB mutations and impact on risk assessment. Hum Mutat 27:748–759

    Article  PubMed  CAS  Google Scholar 

  222. Uematsu M, Sakamoto O, Sugawara N, Kumagai N, Morimoto T, Yamaguchi S, Hasegawa Y, Kobayashi H, Ihara K, Yoshino M, Watanabe Y, Inokuchi T, Yokoyama T, Kiwaki K, Nakamura K, Endo F, Tsuchiya S, Ohura T (2007) Novel mutations in five Japanese patients with 3-methylcrotonyl-CoA carboxylase deficiency. J Hum Genet 52:1040–1043

    Article  PubMed  CAS  Google Scholar 

  223. Stucki M, Suormala T, Fowler B, Valle D, Baumgartner MR (2009) Cryptic exon activation by disruption of exon splice enhancer. Novel mechanism causing 3-methylcrotonyl-CoA carboxylase deficiency. J Biol Chem 284:28953–28957

    Article  PubMed  CAS  Google Scholar 

  224. Nguyen KV, Naviaux RK, Patra S, Barshop BA, Nyhan WL (2011) Novel mutations in the human MCCA and MCCB gene causing methylcrotonylglycinuria. Mol Gen Metab 102:218–221

    Article  CAS  Google Scholar 

  225. Morscher RJ, Grunert SC, Burer C, Burda P, Suormala T, Fowler B, Baumgartner MR (2012) A single mutation in MCCC1 or MCCC2 as a potential cause of positive screening for 3-methylcrotonyl-CoA carboxylase deficiency. Mol Gen Metab 105:602–606

    Article  CAS  Google Scholar 

  226. Jung CW, Lee BH, Kim JH, Kim GH, Lee J, Choi JH, Yoo HW (2012) Uneventful clinical courses of Korean patients with methylcrotonylglycinuria and their common mutations. J Hum Genet 57:62–64

    Article  PubMed  CAS  Google Scholar 

  227. Forster-Fromme K, Jendrossek D (2010) AtuR is a repressor of acyclic terpene utilization (Atu) gene cluster expression and specifically binds two 13 bp inverted repeat sequences of the atuA-atuR intergenic region. FEMS Microbiol Lett 308:166–174

    PubMed  Google Scholar 

  228. Guan X, Diez T, Prasad TK, Nikolau BJ, Wurtele ES (1999) Geranoyl-CoA carboxylase: a novel biotin-containing enzyme in plants. Arch Biochem Biophys 362:12–21

    Article  PubMed  CAS  Google Scholar 

  229. Demirev AV, Khanal A, Hanh NPK, Nam KT, Nam DH (2011) Biochemical characterization of propionyl-coenzyme A carboxylase complex of Streptomyces toxytricini. J Microbiol 49:407–412

    Article  PubMed  CAS  Google Scholar 

  230. Gago G, Kurth D, Diacovich L, Tsai S-C, Gramajo H (2006) Biochemical and structural characterization of an essential acyl-coenzyme A carboxylase from Mycobacterium tuberculosis. J Bacteriol 188:477–486

    Article  PubMed  CAS  Google Scholar 

  231. Daniel J, Oh TJ, Lee CM, Kolattukudy PE (2007) AccD6, a member of the Fas II locus, is a functional carboxyltransferase subunit of the acyl-coenzyme A carboxylase in Mycobacterium tuberculosis. J Bacteriol 189:911–917

    Article  PubMed  CAS  Google Scholar 

  232. Diacovich L, Peiru S, Kurth D, Rodriguez E, Podesta F, Khosla C, Gramajo H (2002) Kinetic and structural analysis of a new group of acyl-CoA carboxylases found in Streptomyces coelicolor A3(2). J Biol Chem 277:31228–31236

    Article  PubMed  CAS  Google Scholar 

  233. Oh TJ, Daniel J, Kim HJ, Sirakova TD, Kolattukudy PE (2006) Identification and characterization of Rv3281 as a novel subunit of a biotin-dependent acyl-CoA carboxylase in Mycobacterium tuberculosis H37Rv. J Biol Chem 281:3899–3908

    Article  PubMed  CAS  Google Scholar 

  234. Kurth DG, Gago GM, de la Iglesia A, Lyonnet BB, Lin TW, Morbidoni HR, Tsai S-C, Gramajo H (2009) ACCase 6 is the essential acetyl-CoA carboxylase involved in fatty acid and mycolic acid biosynthesis in mycobacteria. Microbiol 155:2664–2675

    Article  CAS  Google Scholar 

  235. Gande R, Dover LG, Krumbach K, Besra GS, Sahm H, Oikawa T, Eggeling L (2007) The two carboxylases of Corynebacterium glutamicum essential for fatty acid and mycolic acid synthesis. J Bacteriol 189:5257–5264

    Article  PubMed  CAS  Google Scholar 

  236. Pawelczyk J, Brzostek A, Kremer L, Dziadek B, Rumijowska-Galewicz A, Fiolka M, Dziadek J (2011) AccD6, a key carboxyltransferase essential for mycolic acid synthesis in Mycobacterium tuberculosis, is dispensable in a nonpathogenic strain. J Bacteriol 193:6960–6972

    Article  PubMed  CAS  Google Scholar 

  237. Holton SJ, King-Scott S, Eddine AN, Kaufmann SHE, Wilmanns M (2006) Structural diversity in the six-fold redundant set of acyl-CoA carboxyltransferases in Mycobacterium tuberculosis. FEBS Lett 580:6898–6902

    Article  PubMed  CAS  Google Scholar 

  238. Dunn MF, Araiza G, Mora J (2004) Biochemical characterization of a Rhizobium etli monovalent cation-stimulated acyl-coenzyme A carboxylase with a high substrate specficity constant for propionyl-coenzyme A. Microbiol 150:399–406

    Article  CAS  Google Scholar 

  239. Attwood PV (1995) The structure and the mechanism of action of pyruvate carboxylase. Int J Biochem Cell Biol 27:231–249

    Article  PubMed  CAS  Google Scholar 

  240. Wallace JC, Jitrapakdee S, Chapman-Smith A (1998) Pyruvate carboxylase. Int J Biochem Cell Biol 30:1–5

    Article  PubMed  CAS  Google Scholar 

  241. Jitrapakdee S, Wallace JC (1999) Structure, function and regulation of pyruvate carboxylase. Biochem J 340:1–16

    Article  PubMed  CAS  Google Scholar 

  242. Jitrapakdee S, Vidal-Puig A, Wallace JC (2006) Anaplerotic roles of pyruvate carboxylase in mammalian tissues. Cell Mol Life Sci 63:843–854

    Article  PubMed  CAS  Google Scholar 

  243. Wallace JC (2010) My favorite pyruvate carboxylase. IUBMB Life 62:535–538

    Article  PubMed  CAS  Google Scholar 

  244. Owen OE, Kalhan SC, Hanson RW (2002) The key role of anaplerosis and cataplerosis for citric acid cycle function. J Biol Chem 277:30409–30412

    Article  PubMed  CAS  Google Scholar 

  245. Cheng T, Sudderth J, Yang C, Mullen AR, Jin ES, Mates JM, DeBerardinis RJ (2011) Pyruvate carboxylase is required for glutamine-independent growth of tumor cells. Proc Natl Acad Sci USA 108:8674–8679

    Article  PubMed  CAS  Google Scholar 

  246. Xu J, Han J, Long YS, Epstein PN, Liu YQ (2008) The role of pyruvate carboxylase in insulin secretion and proliferation in rat pancreatic beta cells. Diabetologia 51:2022–2030

    Article  PubMed  CAS  Google Scholar 

  247. Hasan NM, Longacre MJ, Stoker SW, Boonsaen T, Jitrapakdee S, Kendrick MA, Wallace JC, MacDonald MJ (2008) Impaired anaplerosis and insulin secretion in insulinoma cells caused by small interfering RNA-mediated suppression of pyruvate carboxylase. J Biol Chem 283:28048–28059

    Article  PubMed  CAS  Google Scholar 

  248. MacDonald MJ, Longacre MJ, Stoker SW, Kendrick M, Thonpho A, Brown LJ, Hasan NM, Jitrapakdee S, Fukao T, Hanson MS, Fernandez LA, Odorico J (2011) Differences between human and rodent pancreatic islets. Low pyruvate carboxylase, ATP citrate lyase, and pyruvate carboxylation and high glucose-stimulated acetoacetate in human pancreatic islets. J Biol Chem 286:18383–18396

    Article  PubMed  CAS  Google Scholar 

  249. Ozimek P, van Dijk R, Latchev K, Gancedo C, Wang DY, van der Klei IJ, Veenhuis M (2003) Pyruvate carboxylase is an essential protein in the assembly of yeast peroximal oligomeric alcohol oxidase. Mol Biol Cell 14:786–797

    Article  PubMed  CAS  Google Scholar 

  250. Klompmaker SH, Kilic A, Baerends RJ, Veenhuis M, van der Klei IJ (2010) Activation of a peroximal Pichia pastoris D-amino acid oxidase, which uses d-alanine as a preferred substrate, depends on pyruvate carboxylase. FEMS Yeast Res 10:708–716

    Article  PubMed  CAS  Google Scholar 

  251. Ozimek PZ, Klompmaker SH, Visser N, Veenhuis M, van der Klei IJ (2007) The transcarboxylase domain of pyruvate carboxylase is essential for assembly of the peroxisomal flavoenzyme alcohol oxidase. FEMS Yeast Res 7:1082–1092

    Article  PubMed  CAS  Google Scholar 

  252. Huberts DHEW, Venselaar H, Vriend G, Veenhuis M, van der Klei IJ (2010) The moonlighting function of pyruvate carboxylase resides in the non-catalytic end of the TIM barrel. Biochim Biophys Acta 1803:1038–1042

    Article  PubMed  CAS  Google Scholar 

  253. Schar J, Stoll R, Schauer K, Loeffler DIM, Eylert E, Joseph B, Eisenreich W, Fuchs TM, Goebel W (2010) Pyruvate carboxylase plays a crucial role in carbon metabolism of extra- and intracellularly replicating Listeria monocytogenes. J Bacteriol 192:1774–1784

    Article  PubMed  CAS  Google Scholar 

  254. Lai H, Kraszewski JL, Purwantini E, Mukhopadhyay B (2006) Identification of pyruvate carboxylase genes in Pseudomonas aeruginosa PAO1 and development of a P. aeruginosa-based overexpression system for a4- and a4b4-type pyruvate carboxylases. Appl Environ Microbiol 72:7785–7792

    Article  PubMed  CAS  Google Scholar 

  255. Zeczycki TN, Menefee AL, Jitrapakdee S, Wallace JC, Attwood PV, St. Maurice M, Cleland WW (2011) Activation and inhibition of pyruvate carboxylase from Rhizobium etli. Biochemical 50:9694–9707

    Article  CAS  Google Scholar 

  256. Adina-Zada A, Zeczycki TN, Attwood PV (2012) Regulation of the structure and activity of pyruvate carboxylase by acetyl CoA. Arch Biochem Biophys 519:118–130

    Article  PubMed  CAS  Google Scholar 

  257. Adina-Zada A, Hazra R, Sereeruk C, Jitrapakdee S, Zeczycki TN, St. Maurice M, Cleland WW, Wallace JC, Attwood PV (2011) Probing the allosteric activation of pyruvate carboxylase using 2′,3′-O-(2,4,6-trinitrophenyl) adenosine 5′-triphosphate as a fluorescent mimic of the allosteric activator acetyl CoA. Arch Biochem Biophys 509:117–126

    Article  PubMed  CAS  Google Scholar 

  258. Zeczycki TN, St. Maurice M, Attwood PV (2010) Inhibitors of pyruvate carboxylase. Open Enzyme Inhib J 3:8–26

    Article  PubMed  CAS  Google Scholar 

  259. Carbone MA, MacKay N, Ling M, Cole DEC, Douglas C, Rigat B, Feigenbaum A, Clarke JTR, Haworth JC, Greenberg CR, Seargeant L, Robinson BH (1998) Amerindian pyruvate carboxylase deficiency is associated with two distinct missense mutations. Am J Hum Genet 62:1312–1319

    Article  PubMed  CAS  Google Scholar 

  260. Wexler ID, Kerr DS, Du Y, Kaung MM, Stephenson W, Lusk MM, Wappner RS, Higgins JJ (1998) Molecular characterization of pyruvate carboxylase deficiency in two consanguineous families. Pediatr Res 43:579–584

    Article  PubMed  CAS  Google Scholar 

  261. Robinson BH (2006) Lactic acidemia and mitochondrial disease. Mol Gen Metab 89:3–13

    Article  CAS  Google Scholar 

  262. Wang D, Yang H, de Braganca KC, Lu J, Shih LY, Briones P, Lang T, de Vivo DC (2008) The molecular basis of pyruvate carboxylase deficiency: mosaicism correlates with prolonged survival. Mol Gen Metab 95:31–38

    Article  CAS  Google Scholar 

  263. Monnot S, Serre V, Chadefaux-Vekemans B, Aupetit J, Romano S, de Lonlay P, Rival JM, Munnich A, Steffann J, Bonnefont JP (2009) Structural insights on pathogenic effects of novel mutations causing pyruvate carboxylase deficiency. Hum Mutat 30:734–740

    Article  PubMed  CAS  Google Scholar 

  264. Marin-Valencia I, Roe CR, Pascual JM (2010) Pyruvate carboxylase deficiency: mechanisms, mimics and anaplerosis. Mol Gen Metab 101:9–17

    Article  CAS  Google Scholar 

  265. Lietzan AD, Menefee AL, Zeczycki TN, Kumar S, Attwood PV, Wallace JC, Cleland WW, St. Maurice M (2011) Interaction between the biotin carboxyl carrier domain and the biotin carboxylase domain in pyruvate carboxylase from Rhizobium etli. Biochemical 50:9708–9723

    Article  CAS  Google Scholar 

  266. Yu LPC, Xiang S, Lasso G, Gil D, Valle M, Tong L (2009) A symmetrical tetramer for S. aureus pyruvate carboxylase in complex with coenzyme A. Structure 17:823–832

    Article  PubMed  CAS  Google Scholar 

  267. Balsera M, Buey RM, Li X-D (2011) Quaternary structure of the oxaloacetate decarboxylase membrane complex and mechanistic relationships to pyruvate carboxylase. J Biol Chem 286:9457–9467

    Article  PubMed  CAS  Google Scholar 

  268. Zeczycki TN, St. Maurice M, Jitrapakdee S, Wallace JC, Attwood PV, Cleland WW (2009) Insight into the carboxyl transferase domain mechanism of pyruvate carboxylase from Rhizobium etli. Biochemical 48:4305–4313

    Article  CAS  Google Scholar 

  269. Duangpan S, Jitrapakdee S, Adina-Zada A, Byrne L, Zeczycki TN, St. Maurice M, Cleland WW, Wallace JC, Attwood PV (2010) Probing the catalytic roles of Arg548 and Gln552 in the carboxyl transferase domain of the Rhizobium etli pyruvate carboxylase by site-directed mutagenesis. Biochemical 49:3296–3304

    Article  CAS  Google Scholar 

  270. Zeczycki TN, Menefee AL, Adina-Zada A, Jitrapakdee S, Surinya KH, Wallace JC, Attwood PV, St Maurice M, Cleland WW (2011) Novel insights into the biotin carboxylase domain reactions of pyruvate carboxylase from Rhizobium etli. Biochemical 50:9724–9737

    Article  CAS  Google Scholar 

  271. Lasso G, Yu LPC, Gil D, Xiang S, Tong L, Valle M (2010) Cryo-EM analysis reveals new insights into the mechanism of action of pyruvate carboxylase. Structure 18:1300–1310

    Article  PubMed  CAS  Google Scholar 

  272. Kanamori T, Kanou N, Atomi H, Imanaka T (2004) Enzymatic characterization of a prokaryotic urea carboxylase. J Bacteriol 186:2532–2539

    Article  PubMed  CAS  Google Scholar 

  273. Andersen G, Bjornberg O, Polakova S, Pynyaha Y, Rasmussen A, Moller K, Hofer A, Moritz T, Sandrini MPB, Merico A-M, Compagno C, Akerlund HE, Gojkovic Z, Piskur J (2008) A second pathway to degrade pyrimidine nucleic acid precursors in eukaryotes. J Mol Biol 380:656–666

    Article  PubMed  CAS  Google Scholar 

  274. Ghosh S, Navarathna DHMLP, Roberts DD, Cooper JT, Atkin AL, Petro TM, Nickerson KW (2009) Arginine-induced germ tube formation in Candida albicans is essential for escape from murine macrophage line RAW 264.7. Infection Immunity 77:1596–1605

    Article  PubMed  CAS  Google Scholar 

  275. Collette JR, Lorenz MC (2011) Mechanisms of immune evasion in fungal pathogens. Curr Opin Microbiol 14:668–675

    Article  PubMed  CAS  Google Scholar 

  276. Jacques DA, Langley DB, Hynson RMG, Whitten AE, Kwan A, Guss JM, Trewhella J (2011) A novel structure of an antikinase and its inhibitor. J Mol Biol 405:214–226

    Article  PubMed  CAS  Google Scholar 

  277. Jacques DA, Langley DB, Kuramitsu S, Yokoyama S, Trewhella J, Guss JM (2011) The structure of TTHA0988 from Thermus thermophilus, a KipI-KipA homolgue incorrectly annotated as an allophanate hydrolase. Acta Cryst D67:105–111

    CAS  Google Scholar 

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Acknowledgments

I thank Matthew Callaghan, Chi-Yuan Chou, Daniel Floyd, Christine Huang, Yi Seul Kim, Jiang Li, Svetlana Novoseletskaya, Kianoush Sadre-Bazzaz, Yang Shen, Timothy Tran, Benjamin Tweel, Jia Wei, Song Xiang, Zhiru Yang, Linda Yu, and Hailong Zhang for contributions to this project and for helpful discussions. I apologize for not being able to cite many of the earlier publications due to space limitations. This research was supported in part by a grant from the NIH to LT (DK067238).

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    Liang Tong

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Tong, L. Structure and function of biotin-dependent carboxylases. Cell. Mol. Life Sci. 70, 863–891 (2013). https://doi.org/10.1007/s00018-012-1096-0

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