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Structure, function and selective inhibition of bacterial acetyl-coa carboxylase

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Abstract

Acetyl-CoA carboxylase (ACC) catalyses the first committed step in fatty acid biosynthesis: a metabolic pathway required for several important biological processes including the synthesis and maintenance of cellular membranes. ACC employs a covalently attached biotin moiety to bind a carboxyl anion and then transfer it to acetyl-CoA, yielding malonyl-CoA. These activities occur at two different subsites: the biotin carboxylase (BC) and carboxyltransferase (CT). Structural biology, together with small molecule inhibitor studies, has provided new insights into the molecular mechanisms that govern ACC catalysis, specifically the BC and CT subunits. Here, we review these recent findings and highlight key differences between the bacterial and eukaryotic isozymes with a view to establish those features that provide an opportunity for selective inhibition. Especially important are examples of highly selective small molecule inhibitors capable of differentiating between ACCs from different phyla. The implications for early stage antibiotic discovery projects, stemming from these studies, are discussed.

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References

  • Abdel-Hamid AM, Cronan JE (2007) Coordinate expression of the acetyl coenzyme A carboxylase genes, accB and accC, is necessary for normal regulation of biotin synthesis in Escherichia coli. J Bacteriol 189:369–376

    Article  CAS  Google Scholar 

  • Alban C, Job D, Douce R (2000) Biotin metabolism in plants. Annu Rev Plant Physiol Plant Mol Biol 51:17–47

    Article  CAS  Google Scholar 

  • Annis DA, Shipps GW Jr, Deng Y, Popovici-Muller J, Siddiqui MA, Curran PJ, Gowen M, Windsor WT (2007) Method for quantitative protein-ligand affinity measurements in compound mixtures. Anal Chem 79:4538–4542

    Article  CAS  Google Scholar 

  • Arabolaza A, Shillito ME, Lin TW, Diacovich L, Melgar M, Pham H, Amick D, Gramajo H, Tsai SC (2010) Crystal structures and mutational analyses of acyl-CoA carboxylase beta subunit of Streptomyces coelicolor. Biochemistry 49:7367–7376

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Balemans W, Lounis N, Gilissen R, Guillemont J, Simmen K, Andries K, Koul A (2010) Essentiality of FASII pathway for Staphylococcus aureus. Nature 463:E3, discussion E4

    Article  CAS  Google Scholar 

  • 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. Biochemistry 45:1712–1722

    Article  CAS  Google Scholar 

  • Blanchard CZ, Lee YM, Frantom PA, Waldrop GL (1999) Mutations at four active site residues of biotin carboxylase abolish substrate-induced synergism by biotin. Biochemistry 38:3393–3400

    Article  CAS  Google Scholar 

  • Chan DI, Vogel HJ (2010) Current understanding of fatty acid biosynthesis and the acyl carrier protein. Biochem J 430:1–19

    Article  CAS  Google Scholar 

  • 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  CAS  Google Scholar 

  • 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  CAS  Google Scholar 

  • 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  CAS  Google Scholar 

  • Choi-Rhee E, Cronan JE (2003) The biotin carboxylase-biotin carboxyl carrier protein complex of Escherichia coli acetyl-CoA carboxylase. J Biol Chem 278:30806–30812

    Article  CAS  Google Scholar 

  • Chou CY, 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  CAS  Google Scholar 

  • Chou CY, Yu LP, 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  CAS  Google Scholar 

  • Cronan JE, Thomas J (2009) Bacterial fatty acid synthesis and its relationships with polyketide synthetic pathways. Methods Enzymol 459:395–433

    Article  CAS  Google Scholar 

  • Deleo FR, Otto M, Kreiswirth BN, Chambers HF (2010) Community-associated meticillin-resistant Staphylococcus aureus. Lancet 375:1557–1568

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Donadio S, Maffioli S, Monciardini P, Sosio M, Jabes D (2010) Antibiotic discovery in the twenty-first century: current trends and future perspectives. J Antibiot (Tokyo) 63:423–430

    Article  CAS  Google Scholar 

  • Fischbach MA, Walsh CT (2009) Antibiotics for emerging pathogens. Science 325:1089–1093

    Article  CAS  Google Scholar 

  • Forsyth RA, Haselbeck RJ, Ohlsen KL, Yamamoto RT, Xu H, Trawick JD, Wall D, Wang L, Brown-Driver V, Froelich JM, King KGCP, McCarthy M, Malone C, Misiner B, Robbins D, Tan Z, Zhu Zy ZY, Carr G, Mosca DA, Zamudio C, Foulkes JG, Zyskind JW (2002) A genome-wide strategy for the identification of essential genes in Staphylococcus aureus. Mol Microbiol 43:1387–1400

    Article  CAS  Google Scholar 

  • Freiberg C, Brunner NA, Schiffer G, Lampe T, Pohlmann J, Brands M, Raabe M, Habich D, Ziegelbauer K (2004) Identification and characterization of the first class of potent bacterial acetyl-CoA carboxylase inhibitors with antibacterial activity. J Biol Chem 279:26066–26073

    Article  CAS  Google Scholar 

  • Freiberg C, Pohlmann J, Nell PG, Endermann R, Schuhmacher J, Newton B, Otteneder M, Lampe T, Habich D, Ziegelbauer K (2006) Novel bacterial acetyl coenzyme A carboxylase inhibitors with antibiotic efficacy in vivo. Antimicrob Agents Chemother 50:2707–2712

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Gerdes SY, Scholle MD, Campbell JW, Balazsi G, Ravasz E, Daugherty MD, Somera AL, Kyrpides NC, Anderson I, Gelfand MS, Bhattacharya A, Kapatral V, D'Souza M, Baev MV, Grechkin Y, Mseeh F, Fonstein MY, Overbeek R, Barabasi AL, Oltvai ZN, Osterman AL (2003) Experimental determination and system level analysis of essential genes in Escherichia coli MG1655. J Bacteriol 185:5673–5684

    Article  CAS  Google Scholar 

  • Graves SF, Kobayashi SD, DeLeo FR (2010) Community-associated methicillin-resistant Staphylococcus aureus immune evasion and virulence. J Mol Med 88:109–114

    Article  CAS  Google Scholar 

  • Jacobs MA, Alwood A, Thaipisuttikul I, Spencer D, Haugen E, Ernst S, Will O, Kaul R, Raymond C, Levy R, Chun-Rong L, Guenthner D, Bovee D, Olson MV, Manoil C (2003) Comprehensive transposon mutant library of Pseudomonas aeruginosa. Proc Natl Acad Sci USA 100:14339–14344

    Article  CAS  Google Scholar 

  • 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  CAS  Google Scholar 

  • Karow M, Fayet O, Georgopoulos C (1992) The lethal phenotype caused by null mutations in the Escherichia coli htrB gene is suppressed by mutations in the accBC operon, encoding two subunits of acetyl coenzyme A carboxylase. J Bacteriol 174:7407–7418

    CAS  Google Scholar 

  • Kim CW, Moon YA, 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 synthesis. Proc Natl Acad Sci USA 107:9626–9631

    Article  CAS  Google Scholar 

  • Kondo S, Nakajima Y, Sugio S, Yong-Biao J, Sueda S, Kondo H (2004) Structure of the biotin carboxylase subunit of pyruvate carboxylase from Aquifex aeolicus at 2.2 A resolution. Acta Crystallogr D Biol Crystallogr 60:486–492

    Article  Google Scholar 

  • Kondo S, Nakajima Y, Sugio S, Sueda S, Islam MN, Kondo H (2007) Structure of the biotin carboxylase domain of pyruvate carboxylase from Bacillus thermodenitrificans. Acta Crystallogr D Biol Crystallogr 63:885–890

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Lin TW, Melgar MM, Kurth D, Swamidass SJ, Purdon J, Tseng T, Gago G, Baldi P, Gramajo H, Tsai SC (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  CAS  Google Scholar 

  • 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 Sec D-Biol Cryst 65:449–461

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Miller JR, Dunham S, Mochalkin I, Banotai C, Bowman M, Buist S, Dunkle B, Hanna D, Harwood HJ, Huband MD, Karnovsky A, Kuhn M, Limberakis C, Liu JY, Mehrens S, Mueller WT, Narasimhan L, Ogden A, Ohren J, Prasad JV, 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  CAS  Google Scholar 

  • 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 

  • Mochalkin I, Miller JR, Narasimhan L, Thanabal V, Erdman P, Cox PB, Prasad JV, 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  CAS  Google Scholar 

  • Parsons JB, Rock CO (2011) Is bacterial fatty acid synthesis a valid target for antibacterial drug discovery? Curr Opin Microbiol 14:544–549

    Article  CAS  Google Scholar 

  • Payne DJ (2008) Microbiology. Desperately seeking new antibiotics. Science 321:1644–1645

    Article  CAS  Google Scholar 

  • Payne DJ, Gwynn MN, Holmes DJ, Pompliano DL (2007) Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Discov 6:29–40

    Article  CAS  Google Scholar 

  • Polyak SW, Chapman-Smith A (2004) Biotin. In: Lennarz WJ, Lane MD (eds) Encyclopedia of biological chemistry. Elsevier, Oxford, pp 174–178

    Chapter  Google Scholar 

  • Salama NR, Shepherd B, Falkow S (2004) Global transposon mutagenesis and essential gene analysis of Helicobacter pylori. J Bacteriol 186:7926–7935

    Article  CAS  Google Scholar 

  • Sassetti CM, Boyd DH, Rubin EJ (2003) Genes required for mycobacterial growth defined by high density mutagenesis. Mol Microbiol 48:77–84

    Article  CAS  Google Scholar 

  • Schreiber M, Res I, Matter A (2009) Protein kinases as antibacterial targets. Curr Opin Cell Biol 21:325–330

    Article  CAS  Google Scholar 

  • 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  CAS  Google Scholar 

  • Takayama K, Wang C, Besra GS (2005) Pathway to synthesis and processing of mycolic acids in Mycobacterium tuberculosis. Clin Microbiol Rev 18:81–101

    Article  CAS  Google Scholar 

  • Thanassi JA, Hartman-Neumann SL, Dougherty TJ, Dougherty BA, Pucci MJ (2002) Identification of 113 conserved essential genes using a high-throughput gene disruption system in Streptococcus pneumoniae. Nucleic Acids Res 30:3152–3162

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Triola G, Wetzel S, Ellinger B, Koch MA, Hubel K, Rauh D, Waldmann H (2009) ATP competitive inhibitors of d-alanine–d-alanine ligase based on protein kinase inhibitor scaffolds. Bioorg Med Chem 17:1079–1087

    Article  CAS  Google Scholar 

  • Turnidge JD, Kotsanas D, Munckhof W, Roberts S, Bennett CM, Nimmo GR, Coombs GW, Murray RJ, Howden B, Johnson PD, Dowling K (2009) Staphylococcus aureus bacteraemia: a major cause of mortality in Australia and New Zealand. Med J Aust 191:368–373

    Google Scholar 

  • Vahlensieck HF, Pridzun L, Reichenbach H, Hinnen A (1994) Identification of the yeast ACC1 gene product (acetyl-CoA carboxylase) as the target of the polyketide fungicide soraphen A. Curr Genet 25:95–100

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • 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  CAS  Google Scholar 

  • Wright HT, Reynolds KA (2007) Antibacterial targets in fatty acid biosynthesis. Curr Opin Microbiol 10:447–453

    Article  CAS  Google Scholar 

  • 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  CAS  Google Scholar 

  • Yu LP, 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  CAS  Google Scholar 

  • 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  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Zhang H, Tweel B, Tong L (2004b) 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  CAS  Google Scholar 

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Acknowledgements

The authors wish to thank the National Health and Medical Research Council of Australia for funding (applications 565506 and 1011806).

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Authors and Affiliations

  1. School of Molecular and Biomedical Science, University of Adelaide, North Tce, Adelaide, South Australia, 5005, Australia

    S. W. Polyak & G. W. Booker

  2. School of Chemistry and Physics, University of Adelaide, Adelaide, South Australia, 5005, Australia

    A. D. Abell

  3. School of Biomedical Science, Monash University, Victoria, 3800, Australia

    M. C. J. Wilce

  4. Chinese Academy of Sciences, Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100190, China

    L. Zhang

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  1. S. W. Polyak
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  2. A. D. Abell
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  3. M. C. J. Wilce
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  4. L. Zhang
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  5. G. W. Booker
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Correspondence to S. W. Polyak.

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Polyak, S.W., Abell, A.D., Wilce, M.C.J. et al. Structure, function and selective inhibition of bacterial acetyl-coa carboxylase. Appl Microbiol Biotechnol 93, 983–992 (2012). https://doi.org/10.1007/s00253-011-3796-z

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