1932

Abstract

2017 marks the 60th anniversary of Krebs’ seminal paper on the glyoxylate shunt (and coincidentally, also the 80th anniversary of his discovery of the citric acid cycle). Sixty years on, we have witnessed substantial developments in our understanding of how flux is partitioned between the glyoxylate shunt and the oxidative decarboxylation steps of the citric acid cycle. The last decade has shown us that the beautifully elegant textbook mechanism that regulates carbon flux through the shunt in is an oversimplification of the situation in many other bacteria. The aim of this review is to assess how this new knowledge is impacting our understanding of flux control at the TCA cycle/glyoxylate shunt branch point in a wider range of genera, and to summarize recent findings implicating a role for the glyoxylate shunt in cellular functions other than metabolism.

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2018-09-08
2024-04-26
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Literature Cited

  1. 1.  Ahn S, Jung J, Jang I-A, Madsen EL, Park W 2016. Role of glyoxylate shunt in oxidative stress response. J. Biol. Chem. 291:11928–38
    [Google Scholar]
  2. 2.  Ajl SJ 1956. Conversion of acetate and glyoxylate to malate. J. Am. Chem. Soc. 78:133230–31
    [Google Scholar]
  3. 3.  Alston TA, Mela L, Bright HJ 1977. 3-Nitropropionate, the toxic substance of Indigofera, is a suicide inactivator of succinate dehydrogenase. PNAS 74:93767–71
    [Google Scholar]
  4. 4.  Bandyopadhyay A, Elvitigala T, Welsh E, Stockel J, Liberton M et al. 2011. Novel metabolic attributes of the genus Cyanothece, comprising a group of unicellular nitrogen-fixing cyanobacteria. mBio 2:5e00214–11
    [Google Scholar]
  5. 5.  Bartholomae M, Meyer FM, Commichau FM, Burkovski A, Hillen W, Seidel G 2014. Complex formation between malate dehydrogenase and isocitrate dehydrogenase from Bacillus subtilis is regulated by tricarboxylic acid cycle metabolites. FEBS J 281:41132–43
    [Google Scholar]
  6. 6.  Beeckmans S, Khan AS, Driessche E, Kanarek L 1994. A specific association between the glyoxylic-acid-cycle enzymes isocitrate lyase and malate synthase. Eur. J. Biochem. 224:1197–201
    [Google Scholar]
  7. 7.  Bi J, Wang Y, Yu H, Qian X, Wang H et al. 2017. Modulation of central carbon metabolism by acetylation of isocitrate lyase in Mycobacterium tuberculosis. Sci. . Rep 7:44826
    [Google Scholar]
  8. 8.  Britton KL, Abeysinghe ISB, Baker PJ, Barynin V, Diehl P et al. 2001. The structure and domain organization of Escherichia coli isocitrate lyase. Acta Crystallogr. Sect. D Biol. Crystallogr. 57:91209–18
    [Google Scholar]
  9. 9.  Bulutoglu B, Garcia KE, Wu F, Minteer SD, Banta S 2016. Direct evidence for metabolon formation and substrate channeling in recombinant TCA cycle enzymes. ACS Chem. Biol. 11:102847–53
    [Google Scholar]
  10. 10.  Campilongo R, Fung RKY, Little RH, Grenga L, Trampari E et al. 2017. One ligand, two regulators and three binding sites: how KDPG controls primary carbon metabolism in Pseudomonas. . PLOS Genet 13:6e1006839
    [Google Scholar]
  11. 11.  Castano-Cerezo S, Bernal V, Post H, Fuhrer T, Cappadona S et al. 2014. Protein acetylation affects acetate metabolism, motility and acid stress response in Escherichia coli. Mol. Syst. . Biol 10:11762–762
    [Google Scholar]
  12. 12.  Chung JCS, Rzhepishevska O, Ramstedt M, Welch M 2013. Type III secretion system expression in oxygen-limited Pseudomonas aeruginosa cultures is stimulated by isocitrate lyase activity. Open Biol 3:1120131
    [Google Scholar]
  13. 13.  Chung T, Klumpp DJ, LaPorte DC 1988. Glyoxylate bypass operon of Escherichia coli: cloning and determination of the functional map. J. Bacteriol. 170:1386–92
    [Google Scholar]
  14. 14.  Cortay JC, Nègre D, Galinier A, Duclos B, Perrière G, Cozzone AJ 1991. Regulation of the acetate operon in Escherichia coli: purification and functional characterization of the IclR repressor. EMBO J 10:3675–79
    [Google Scholar]
  15. 15.  Cozzone A 1998. Regulation of acetate metabolism by protein phosphorylation in enteric bacteria. Annu. Rev. Microbiol. 52:127–64
    [Google Scholar]
  16. 16.  Crosby HA, Pelletier DA, Hurst GB, Escalante-Semerena JC 2012. System-wide studies of N-lysine acetylation in Rhodopseudomonas palustris reveal substrate specificity of protein acetyltransferases. J. Biol. Chem. 287:1915590–601
    [Google Scholar]
  17. 17.  Daddaoua A, Krell T, Ramos J-L 2009. Regulation of glucose metabolism in Pseudomonas. J. Biol. Chem. 284:3221360–68
    [Google Scholar]
  18. 18.  Dean AM, Golding GB 1997. Protein engineering reveals ancient adaptive replacements in isocitrate dehydrogenase. PNAS 94:73104–9
    [Google Scholar]
  19. 19.  Dean JT, Tran L, Beaven S, Tontonoz P, Reue K et al. 2009. Resistance to diet-induced obesity in mice with synthetic glyoxylate shunt. Cell Metab 9:6525–36
    [Google Scholar]
  20. 20.  Eoh H, Rhee KY 2014. Methylcitrate cycle defines the bactericidal essentiality of isocitrate lyase for survival of Mycobacterium tuberculosis on fatty acids. PNAS 111:134976–81
    [Google Scholar]
  21. 21.  Fahnoe KC, Flanagan ME, Gibson G, Shanmugasundaram V, Che Y, Tomaras AP 2012. Non-traditional antibacterial screening approaches for the identification of novel inhibitors of the glyoxylate shunt in gram-negative pathogens. PLOS ONE 7:121–7
    [Google Scholar]
  22. 22.  Fang FC, Libby SJ, Castor ME, Fung AM 2005. Isocitrate lyase (AceA) is required for Salmonella persistence but not for acute lethal infection in mice. Infect. Immun. 73:42547–49
    [Google Scholar]
  23. 23.  Garnak M, Reeves HC 1979. Phosphorylation of isocitrate dehydrogenase of Escherichia coli. . Science 203:43851111–12
    [Google Scholar]
  24. 24.  Gerstmeir R, Cramer A, Dangel P, Schaffer S, Eikmanns BJ 2004. RamB, a novel transcriptional regulator of genes involved in acetate metabolism of Corynebacterium glutamicum. J. Bacteriol. 186:92798–809
    [Google Scholar]
  25. 25.  Gould TA, van de Langemheen H, Munoz-Elias EJ, McKinney JD, Sacchettini JC 2006. Dual role of isocitrate lyase 1 in the glyoxylate and methylcitrate cycles in Mycobacterium tuberculosis. Mol. Microbiol. 61:4940–47
    [Google Scholar]
  26. 26.  Gründel M, Knoop H, Steuer R 2017. Activity and functional properties of the isocitrate lyase in the cyanobacterium Cyanothece sp. PCC 7424. Microbiology 163:5731–44
    [Google Scholar]
  27. 27.  Gui L, Sunnarborg A, LaPorte DC 1996. Regulated expression of a repressor protein: FadR activates iclR. J. Bacteriol 178:154704–9
    [Google Scholar]
  28. 28.  Hauser AR 2009. The type III secretion system of Pseudomonas aeruginosa: infection by injection. Nat. Rev. Microbiol. 7:9654–65
    [Google Scholar]
  29. 29.  Hayden JD, Brown LR, Gunawardena HP, Perkowski EF, Chen X, Braunstein M 2013. Reversible acetylation regulates acetate and propionate metabolism in Mycobacterium smegmatis. . Microbiology 159:Pt 91986–99
    [Google Scholar]
  30. 30.  Höner zu Bentrup K, Miczak A, Swenson DL, Russell DG 1999. Characterization of activity and expression of isocitrate lyase in Mycobacterium avium and Mycobacterium tuberculosis. J. Bacteriol 181:237161–67
    [Google Scholar]
  31. 31.  Ishii A, Suzuki M, Sahara T, Takada Y, Sasaki S, Fukunaga N 1993. Genes encoding two isocitrate dehydrogenase isozymes of a psychrophilic bacterium, Vibrio sp. strain ABE-1. J. Bacteriol. 175:216873–80
    [Google Scholar]
  32. 32.  Kornberg H 2000. Krebs and his trinity of cycles. Nat. Rev. Mol. Cell Biol. 1:3225–28
    [Google Scholar]
  33. 33.  Kornberg HL 1958. The metabolism of C2 compounds in micro-organisms. I. The incorporation of [2-14C]acetate by Pseudomonas fluorescens, and by a Corynebacterium, grown on ammonium acetate. Biochem. J. 68:3535–42
    [Google Scholar]
  34. 34.  Kornberg HL 1966. The role and control of the glyoxylate cycle in Escherichia coli. Biochem. J. 99:11–11
    [Google Scholar]
  35. 35.  Kornberg HL, Krebs HA 1957. Synthesis of cell constituents from C2-units by a modified tricarboxylic acid cycle. Nature 179:4568988–91
    [Google Scholar]
  36. 36.  Kornberg HL, Madsen NB 1957. Synthesis of C4-dicarboxylic acids from acetate by a “glyoxylate bypasss” of the tricarboxylic acid cycle. Biochim. Biophys. Acta 24:3651–53
    [Google Scholar]
  37. 37.  Kornberg HL, Quayle JR 1958. The metabolism of C2 compounds in microorganisms. 2. The effect of carbon dioxide on the incorporation of [14C]acetate by acetate-grown Pseudomonas KB1. Biochem. J. 68:3542–49
    [Google Scholar]
  38. 38.  Krebs HA, Johnson WA 1980. The role of citric acid in intermediate metabolism in animal tissues. FEBS Lett 117:K2–10
    [Google Scholar]
  39. 39.  Krieger IV, Freundlich JS, Gawandi VB, Roberts JP, Gawandi VB et al. 2012. Structure-guided discovery of phenyl-diketo acids as potent inhibitors of M. tuberculosis malate synthase. Chem. Biol. 19:121556–67
    [Google Scholar]
  40. 40.  LaPorte DC 1993. The isocitrate dehydrogenase phosphorylation cycle: regulation and enzymology. J. Cell. Biochem. 51:114–18
    [Google Scholar]
  41. 41.  LaPorte DC, Koshland DE Phosphorylation of isocitrate dehydrogenase as a demonstration of enhanced sensitivity in covalent regulation. Nature 305:5932286–90
    [Google Scholar]
  42. 42.  LaPorte DC, Koshland DE 1982. A protein with kinase and phosphatase activities involved in regulation of tricarboxylic acid cycle. Nature 300:5891458–60
    [Google Scholar]
  43. 43.  LaPorte DC, Thornsness PE, Koshland DE 1985. Compensatory phosphorylation of isocitrate dehydrogenase: a mechanism for adaptation to the intracellular environment. J. Biol. Chem. 260:1910563–68
    [Google Scholar]
  44. 44.  LaPorte DC, Walsh K, Koshland DE 1984. The branch point effect: ultrasensitivity and subsensitivity to metabolic control. J. Biol. Chem. 259:2214068–75
    [Google Scholar]
  45. 45.  Lee W, VanderVen BC, Walker S, Russell DG 2017. Novel protein acetyltransferase, Rv2170, modulates carbon and energy metabolism in Mycobacterium tuberculosis. Sci. Rep. 7:172
    [Google Scholar]
  46. 46.  Lin S-J, Defossez PA, Guarente L, Jackson SP, White MF 2000. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. . Science 289:54872126–28
    [Google Scholar]
  47. 47.  Lindsey TL, Hagins JM, Sokol PA, Silo-Suh LA 2008. Virulence determinants from a cystic fibrosis isolate of Pseudomonas aeruginosa include isocitrate lyase. Microbiology 154:61616–27
    [Google Scholar]
  48. 48.  Lorca GL, Ezersky A, Lunin VV, Walker JR, Altamentova S et al. 2007. Glyoxylate and pyruvate are antagonistic effectors of the Escherichia coli IclR transcriptional regulator. J. Biol. Chem. 282:16476–91
    [Google Scholar]
  49. 49.  MacKintosh C, Nimmo HG 1988. Purification and regulatory properties of isocitrate lyase from Escherichia coli ML308. Biochem. J. 250:125–31
    [Google Scholar]
  50. 50.  Mainguet SE, Gronenberg LS, Wong SS, Liao JC 2013. A reverse glyoxylate shunt to build a non-native route from C4 to C2 in Escherichia coli. Metab. Eng. 19:116–27
    [Google Scholar]
  51. 51.  Masiewicz P, Brzostek A, Wolański M, Dziadek J, Zakrzewska-Czerwińska J 2012. A novel role of the PrpR as a transcription factor involved in the regulation of methylcitrate pathway in Mycobacterium tuberculosis. . PLOS ONE 7:8e43651
    [Google Scholar]
  52. 52.  McFadden BA, Purohit S 1977. Itaconate, an isocitrate lyase-directed inhibitor in Pseudomonas indigofera. J. Bacteriol 131:1136–44
    [Google Scholar]
  53. 53.  McKinney JD, Höner zu Bentrup K, Muñoz-Elías EJ, Miczak A et al. 2000. Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase. Nature 406:6797735–38
    [Google Scholar]
  54. 54.  McVey AC, Medarametla P, Chee X, Bartlett S, Poso A et al. 2017. Structural and functional characterization of malate synthase G from opportunistic pathogen Pseudomonas aeruginosa. . Biochemistry 56:415539–49
    [Google Scholar]
  55. 55.  Meylan S, Porter CBM, Yang JH, Belenky P, Gutierrez A et al. 2017. Carbon sources tune antibiotic susceptibility in Pseudomonas aeruginosa via tricarboxylic acid cycle control. Cell Chem. Biol. 24:2195–206
    [Google Scholar]
  56. 56.  Micklinghoff JC, Breitinger KJ, Schmidt M, Geffers R, Eikmanns BJ, Bange F-C 2009. Role of the transcriptional regulator RamB (Rv0465c) in the control of the glyoxylate cycle in Mycobacterium tuberculosis. J. Bacteriol. 191:237260–69
    [Google Scholar]
  57. 57.  Miller SP, Chen R, Karschnia EJ, Romfo C, Dean A, LaPorte DC 2000. Locations of the regulatory sites for isocitrate dehydrogenase kinase/phosphatase. J. Biol. Chem. 275:2833–39
    [Google Scholar]
  58. 58.  Muñoz-Elías EJ, Upton AM, Cherian J, McKinney JD 2006. Role of the methylcitrate cycle in Mycobacterium tuberculosis metabolism, intracellular growth, and virulence. Mol. Microbiol. 60:51109–22
    [Google Scholar]
  59. 59.  Muñoz-Elías EJ, McKinney JD 2005. Mycobacterium tuberculosis isocitrate lyases 1 and 2 are jointly required for in vivo growth and virulence. Nat. Med. 11:6638–44
    [Google Scholar]
  60. 60.  Murima P, Zimmermann M, Chopra T, Pojer F, Fonti G et al. 2016. A rheostat mechanism governs the bifurcation of carbon flux in mycobacteria. Nat. Commun. 7:12527
    [Google Scholar]
  61. 61.  Nandakumar M, Nathan C, Rhee KY 2014. Isocitrate lyase mediates broad antibiotic tolerance in Mycobacterium tuberculosis. Nat. Commun. 5:4306
    [Google Scholar]
  62. 62.  Nimmo GA, Nimmo HG 1984. The regulatory properties of isocitrate dehydrogenase kinase and isocitrate dehydrogenase phosphatase from Escherichia coli ML308 and the roles of these activities in the control of isocitrate dehydrogenase. Eur. J. Biochem. 141:2409–14
    [Google Scholar]
  63. 63.  Ogawa T, Murakami K, Mori H, Ishii N, Tomita M, Yoshin M 2007. Role of phosphoenolpyruvate in the NADP-isocitrate dehydrogenase and isocitrate lyase reaction in Escherichia coli. J. Bacteriol. 189:31176–78
    [Google Scholar]
  64. 64.  Pham TV, Murkin AS, Moynihan MM, Harris L, Tyler PC et al. 2017. Mechanism-based inactivator of isocitrate lyases 1 and 2 from Mycobacterium tuberculosis. . PNAS 114:297617–22
    [Google Scholar]
  65. 65.  Puckett S, Trujillo C, Wang Z, Eoh H, Ioerger TR et al. 2017. Glyoxylate detoxification is an essential function of malate synthase required for carbon assimilation in Mycobacterium tuberculosis. . PNAS 114:11E2225–32
    [Google Scholar]
  66. 66.  Sasikaran J, Ziemski M, Zadora PK, Fleig A, Berg IA 2014. Bacterial itaconate degradation promotes pathogenicity. Nat. Chem. Biol. 10:5371–77
    [Google Scholar]
  67. 67.  Sebbane F, Jarrett CO, Linkenhoker JR, Hinnebusch BJ 2004. Evaluation of the role of constitutive isocitrate lyase activity in Yersinia pestis infection of the flea vector and mammalian host. Infect. Immun. 72:127334–37
    [Google Scholar]
  68. 68.  Sharma V, Sharma S, Hoener zu Bentrup K, McKinney JD, Russell DG et al. 2000. Structure of isocitrate lyase, a persistence factor of Mycobacterium tuberculosis. Nat. Struct. Biol. 7:8663–68
    [Google Scholar]
  69. 69.  Singh SK, Miller SP, Dean A, Banaszak LJ, Laporte DC 2002. Bacillus subtilis isocitrate dehydrogenase: a substrate analogue for Escherichia coli isocitrate dehydrogenase kinase/phosphatase. J. Biol. Chem. 277:97567–73
    [Google Scholar]
  70. 70.  Singh V, Ghosh I 2006. Kinetic modeling of tricarboxylic acid cycle and glyoxylate bypass in Mycobacterium tuberculosis, and its application to assessment of drug targets. Theor. Biol. Med. Model. 3:127
    [Google Scholar]
  71. 71.  Smith RA, Gunsalus IC 1954. Isocitratase: a new tricarboxylic acid cleavage system. J. Am. Chem. Soc. 76:195002–3
    [Google Scholar]
  72. 72.  Smith CV, Huang C, Miczak A, Russell DG, Sacchettini JC, Höner zu Bentrup K 2003. Biochemical and structural studies of malate synthase from Mycobacterium tuberculosis. J. Biol. Chem. 278:31735–43
    [Google Scholar]
  73. 73.  Starai VJ, Escalante-Semerena JC 2004. Identification of the protein acetyltransferase (Pat) enzyme that acetylates acetyl-CoA synthetase in Salmonella enterica. J. Mol. Biol. 340:51005–12
    [Google Scholar]
  74. 74.  Thauer RK 1988. Citric-acid cycle, 50 years on: modifications and an alternative pathway in anaerobic bacteria. Eur. J. Biochem. 176:3497–508
    [Google Scholar]
  75. 75.  Turner KH, Everett J, Trivedi U, Rumbaugh KP, Whiteley M 2014. Requirements for Pseudomonas aeruginosa acute burn and chronic surgical wound infection. PLOS Genet 10:7e1004518
    [Google Scholar]
  76. 76.  Upton AM, McKinney JD 2007. Role of the methylcitrate cycle in propionate metabolism and detoxification in Mycobacterium smegmatis. . Microbiology 153:123973–82
    [Google Scholar]
  77. 77.  Vuoristo KS, Mars AE, Sanders JPM, Eggink G, Weusthuis RA 2016. Metabolic engineering of TCA cycle for production of chemicals. Trends Biotechnol 34:3191–97
    [Google Scholar]
  78. 78.  Walsh K, Koshland DE 1984. Determination of flux through the branch point of two metabolic cycles: the tricarboxylic acid cycle and the glyoxylate shunt. J. Biol. Chem. 259:159646–54
    [Google Scholar]
  79. 79.  Wang Q, Zhang Y, Yang C, Xiong H, Lin Y et al. 2010. Acetylation of metabolic enzymes coordinates carbon source utilization and metabolic flux. Science 327:59681004–7
    [Google Scholar]
  80. 80.  Yates SP, Edwards TE, Bryan CM, Stein AJ, Van Voorhis WC et al. 2011. Structural basis of the substrate specificity of bifunctional isocitrate dehydrogenase kinase/phosphatase. Biochemistry 50:388103–6
    [Google Scholar]
  81. 81.  Yin Y, Li S, Gao Y, Tong L, Zheng J et al. 2016. Loopβ3αC plays an important role in the structure and function of isocitrate dehydrogenase kinase/phosphatase. FEBS Lett 590:183144–54
    [Google Scholar]
  82. 82.  Zhang J, Sprung R, Pei J, Tan X, Kim S et al. 2009. Lysine acetylation is a highly abundant and evolutionarily conserved modification in Escherichia coli. Mol. Cell. Proteom. 8:2215–25
    [Google Scholar]
  83. 83.  Zhang S, Bryant DA 2011. The tricarboxylic acid cycle in cyanobacteria. Science 334:60621551–53
    [Google Scholar]
  84. 84.  Zhang S, Bryant DA 2015. Biochemical validation of the glyoxylate cycle in the cyanobacterium Chlorogloeopsis fritschii strain PCC 9212. J. Biol. Chem. 290:2214019–30
    [Google Scholar]
  85. 85.  Zhang Y, Beard KFM, Swart C, Bergmann S, Krahnert I et al. 2017. Protein-protein interactions and metabolite channelling in the plant tricarboxylic acid cycle. Nat. Commun. 8:15212
    [Google Scholar]
  86. 86.  Zheng J, Jia Z 2010. Structure of the bifunctional isocitrate dehydrogenase kinase/phosphatase. Nature 465:7300961–65
    [Google Scholar]
  87. 87.  Zhu G, Golding GB, Dean AM 2005. The selective cause of an ancient adaptation. Science 307:57131279–82
    [Google Scholar]
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