1887
No metrics data to plot.
The attempt to load metrics for this article has failed.
The attempt to plot a graph for these metrics has failed.

Regulating the Intersection of Metabolism and Pathogenesis in Gram-positive Bacteria

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.
  • XML
    265.44 Kb
  • HTML
    263.86 Kb
  • PDF
    553.62 Kb
  • Authors: Anthony R. Richardson†1, Greg A. Somerville†2, Abraham L. Sonenshein†3
  • Editors: Tyrrell Conway4, Paul Cohen5
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC; 2: School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE; 3: Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA; 4: Oklahoma State University, Stillwater, OK; 5: University of Rhode Island, Kingston, RI
    • Source: microbiolspec June 2015 vol. 3 no. 3 doi:10.1128/microbiolspec.MBP-0004-2014
  • Received 28 January 2014 Accepted 06 May 2014 Published 11 June 2015
  • Greg Somerville, [email protected]
image of Regulating the Intersection of Metabolism and Pathogenesis in Gram-positive Bacteria
    Preview this microbiology spectrum article:
    Preview Magnify
    Zoom in
    Zoomout

    Regulating the Intersection of Metabolism and Pathogenesis in Gram-positive Bacteria, Page 1 of 2

    | /docserver/preview/fulltext/microbiolspec/3/3/MBP-0004-2014-1.gif /docserver/preview/fulltext/microbiolspec/3/3/MBP-0004-2014-2.gif

  • Abstract:

    Pathogenic bacteria must contend with immune systems that actively restrict the availability of nutrients and cofactors, and create a hostile growth environment. To deal with these hostile environments, pathogenic bacteria have evolved or acquired virulence determinants that aid in the acquisition of nutrients. This connection between pathogenesis and nutrition may explain why regulators of metabolism in nonpathogenic bacteria are used by pathogenic bacteria to regulate both metabolism and virulence. Such coordinated regulation is presumably advantageous because it conserves carbon and energy by aligning synthesis of virulence determinants with the nutritional environment. In Gram-positive bacterial pathogens, at least three metabolite-responsive global regulators, CcpA, CodY, and Rex, have been shown to coordinate the expression of metabolism and virulence genes. In this chapter, we discuss how environmental challenges alter metabolism, the regulators that respond to this altered metabolism, and how these regulators influence the host-pathogen interaction.

  • Citation: Richardson† A, Somerville† G, Sonenshein† A. 2015. Regulating the Intersection of Metabolism and Pathogenesis in Gram-positive Bacteria. Microbiol Spectrum 3(3):MBP-0004-2014. doi:10.1128/microbiolspec.MBP-0004-2014.

References

1. Sadykov MR, Olson ME, Halouska S, Zhu Y, Fey PD, Powers R, Somerville GA. 2008. Tricarboxylic acid cycle-dependent regulation of Staphylococcus epidermidis polysaccharide intercellular adhesin synthesis. J Bacteriol 190:7621–7632. [PubMed][CrossRef]
2. Sadykov MR, Zhang B, Halouska S, Nelson JL, Kreimer LW, Zhu Y, Powers R, Somerville GA. 2010. Using NMR metabolomics to investigate tricarboxylic acid cycle dependent signal transduction in Staphylococcus epidermidis. J Biol Chem 285:36616–36624. [PubMed][CrossRef]
3. Kundig W, Ghosh S, Roseman S. 1964. Phosphate Bound to Histidine in a Protein as an Intermediate in a Novel Phospho-Transferase System. Proc Natl Acad Sci U S A 52:1067–1074. [PubMed][CrossRef]
4. Saier MH, Jr. 1989. Protein phosphorylation and allosteric control of inducer exclusion and catabolite repression by the bacterial phosphoenolpyruvate: sugar phosphotransferase system. Microbiol Rev 53:109–120. [PubMed]
5. Klein HP, Doudoroff M. 1950. The mutation of Pseudomonas putrefaciens to glucose utilization and its enzymatic basis. J Bacteriol 59:739–750. [PubMed]
6. Sanwal BD. 1970. Allosteric controls of amphilbolic pathways in bacteria. Bacteriological Reviews 34:20–39. [PubMed]
7. Blangy D, Buc H, Monod J. 1968. Kinetics of the allosteric interactions of phosphofructokinase from Escherichia coli. J Mol Biol 31:13–35. [CrossRef]
8. Lopez G, Latorre M, Reyes-Jara A, Cambiazo V, Gonzalez M. 2012. Transcriptomic response of Enterococcus faecalis to iron excess. Biometals 25:737–747. [PubMed][CrossRef]
9. Ojha A, Hatfull GF. 2007. The role of iron in Mycobacterium smegmatis biofilm formation: the exochelin siderophore is essential in limiting iron conditions for biofilm formation but not for planktonic growth. Mol Micro 66:468–483. [PubMed][CrossRef]
10. Friedman DB, Stauff DL, Pishchany G, Whitwell CW, Torres VJ, Skaar EP. 2006. Staphylococcus aureus redirects central metabolism to increase iron availability. PLoS Pathog 2:e87. [PubMed][CrossRef]
11. Somerville G, Mikoryak CA, Reitzer L. 1999. Physiological characterization of Pseudomonas aeruginosa during exotoxin A synthesis: glutamate, iron limitation, and aconitase activity. J Bacteriol 181:1072–1078. [PubMed]
12. Zhang B, Halouska S, Schiaffo CE, Sadykov MR, Somerville GA, Powers R. 2011. NMR analysis of a stress response metabolic signaling network. J Proteome Res 10:3743–3754. [PubMed][CrossRef]
13. Craig JE, Ford MJ, Blaydon DC, Sonenshein AL. 1997. A null mutation in the Bacillus subtilis aconitase gene causes a block in Spo0A-phosphate-dependent gene expression. J Bacteriol 179:7351–7359. [PubMed]
14. Dickens F. 1938. Oxidation of phosphohexonate and pentose phosphoric acids by yeast enzymes: Oxidation of phosphohexonate. II. Oxidation of pentose phosphoric acids. Biochem J 32:1626–1644. [PubMed]
15. Warburg O, Christian W, Griese A. 1935. Hydrogen-transferring coenzyme, its composition and mode of action. Biochem Z 282:157–205.
16. Horecker BL, Smyrniotis PZ. 1955. Purification and properties of yeast transaldolase. J Biol Chem 212:811–825. [PubMed]
17. Scott DB, Cohen SS. 1953. The oxidative pathway of carbohydrate metabolism in Escherichia coli. 1. The isolation and properties of glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase. Biochem J 55:23–33. [PubMed]
18. Dutow P, Schmidl SR, Ridderbusch M, Stulke J. 2010. Interactions between glycolytic enzymes of Mycoplasma pneumoniae. J Mol Microbiol Biotechnol 19:134–139. [PubMed][CrossRef]
19. Tettelin H, Nelson KE, Paulsen IT, Eisen JA, Read TD, Peterson S, Heidelberg J, DeBoy RT, Haft DH, Dodson RJ, Durkin AS, Gwinn M, Kolonay JF, Nelson WC, Peterson JD, Umayam LA, White O, Salzberg SL, Lewis MR, Radune D, Holtzapple E, Khouri H, Wolf AM, Utterback TR, Hansen CL, McDonald LA, Feldblyum TV, Angiuoli S, Dickinson T, Hickey EK, Holt IE, Loftus BJ, Yang F, Smith HO, Venter JC, Dougherty BA, Morrison DA, Hollingshead SK, Fraser CM. 2001. Complete genome sequence of a virulent isolate of Streptococcus pneumoniae. Science 293:498–506. [PubMed][CrossRef]
20. Guimaraes AM, Santos AP, SanMiguel P, Walter T, Timenetsky J, Messick JB. 2011. Complete genome sequence of Mycoplasma suis and insights into its biology and adaption to an erythrocyte niche. PloS One 6:e19574. [PubMed][CrossRef]
21. Bergman NH, Anderson EC, Swenson EE, Janes BK, Fisher N, Niemeyer MM, Miyoshi AD, Hanna PC. 2007. Transcriptional profiling of Bacillus anthracis during infection of host macrophages. Infect Immun 75:3434–3444. [PubMed][CrossRef]
22. Chatterjee SS, Hossain H, Otten S, Kuenne C, Kuchmina K, Machata S, Domann E, Chakraborty T, Hain T. 2006. Intracellular gene expression profile of Listeria monocytogenes. Infect Immun 74:1323–1338. [PubMed][CrossRef]
23. Fleury B, Kelley WL, Lew D, Gotz F, Proctor RA, Vaudaux P. 2009. Transcriptomic and metabolic responses of Staphylococcus aureus exposed to supra-physiological temperatures. BMC Microbiol 9:76. [PubMed][CrossRef]
24. Weigoldt M, Meens J, Bange FC, Pich A, Gerlach GF, Goethe R. 2013. Metabolic adaptation of Mycobacterium avium subsp. paratuberculosis to the gut environment. Microbiol 159:380–391. [PubMed][CrossRef]
25. delCardayre SB, Stock KP, Newton GL, Fahey RC, Davies JE. 1998. Coenzyme A disulfide reductase, the primary low molecular weight disulfide reductase from Staphylococcus aureus. Purification and characterization of the native enzyme. J Biol Chem 273:5744–5751. [PubMed][CrossRef]
26. Helmann JD. 2011. Bacillithiol, a new player in bacterial redox homeostasis. Antioxid Redox Signal 15:123–133. [PubMed][CrossRef]
27. Newton GL, Fahey RC, Rawat M. 2012. Detoxification of toxins by bacillithiol in Staphylococcus aureus. Microbiol 158:1117–1126. [PubMed][CrossRef]
28. Spies HS, Steenkamp DJ. 1994. Thiols of intracellular pathogens. Identification of ovothiol A in Leishmania donovani and structural analysis of a novel thiol from Mycobacterium bovis. Eur J Biochem 224:203–213. [PubMed][CrossRef]
29. Holmgren A. 1985. Thioredoxin. Annu Rev Biochem 54:237–271. [PubMed][CrossRef]
30. Moore EC, Reichard P, Thelander L. 1964. Enzymatic synthesis of deoxyribonucleotides. V. Purification and properties of thioredoxin reductase from Escherichia coli B. J Biol Chem 239:3445–3452. [PubMed]
31. Gustafsson TN, Sahlin M, Lu J, Sjoberg BM, Holmgren A. 2012. Bacillus anthracis thioredoxin systems, characterization and role as electron donors for ribonucleotide reductase. J Biol Chem 287:39686–39697. [PubMed][CrossRef]
32. Newton GL, Buchmeier N, Fahey RC. 2008. Biosynthesis and functions of mycothiol, the unique protective thiol of Actinobacteria. Microbiol Mol Biol Rev 72:471–494. [PubMed][CrossRef]
33. Eisenreich W, Slaghuis J, Laupitz R, Bussemer J, Stritzker J, Schwarz C, Schwarz R, Dandekar T, Goebel W, Bacher A. 2006. 13C isotopologue perturbation studies of Listeria monocytogenes carbon metabolism and its modulation by the virulence regulator PrfA. Proc Natl Acad Sci U S A 103:2040–2045. [PubMed][CrossRef]
34. Pfefferkorn ER, Rebhun S, Eckel M. 1986. Characterization of an indoleamine 2,3-dioxygenase induced by gamma-interferon in cultured human fibroblasts. J Interferon Res 6:267–279. [PubMed][CrossRef]
35. Daubener W, MacKenzie CR. 1999. IFN-gamma activated indoleamine 2,3-dioxygenase activity in human cells is an antiparasitic and an antibacterial effector mechanism. Adv Exp Med Biol 467:517–524. [PubMed]
36. Mraheil MA, Billion A, Mohamed W, Rawool D, Hain T, Chakraborty T. 2011. Adaptation of Listeria monocytogenes to oxidative and nitrosative stress in IFN-gamma-activated macrophages. Int J Med Microbiol 301:547–555. [PubMed][CrossRef]
37. Hucke C, MacKenzie CR, Adjogble KD, Takikawa O, Daubener W. 2004. Nitric oxide-mediated regulation of gamma interferon-induced bacteriostasis: inhibition and degradation of human indoleamine 2,3-dioxygenase. Infect Immun 72:2723–2730. [PubMed][CrossRef]
38. MacKenzie CR, Hadding U, Daubener W. 1998. Interferon-gamma-induced activation of indoleamine 2,3-dioxygenase in cord blood monocyte-derived macrophages inhibits the growth of group B streptococci. J Infect Dis 178:875–878. [PubMed][CrossRef]
39. Huynen MA, Dandekar T, Bork P. 1999. Variation and evolution of the citric-acid cycle: a genomic perspective. Trends Microbiol 7:281–291. [PubMed][CrossRef]
40. Srinivasan V, Morowitz HJ. 2006. Ancient genes in contemporary persistent microbial pathogens. Biol Bull 210:1–9. [PubMed][CrossRef]
41. Sonenshein AL. 2002. The Krebs citric acid cycle, p. 151–162. In Sonenshein AL, Hoch JA, Losick R (ed), Bacillus subtilis and its closest relatives: From genes to cells. ASM Press, Washington, D.C. [CrossRef]
42. Bondi A, Kornblum J, De St Phalle M. 1954. The amino acid requirements of penicillin resistant and penicillin sensitive strains of Micrococcus pyogenes. J Bacteriol 68:617–621. [PubMed]
43. Murray BE, Singh KV, Ross RP, Heath JD, Dunny GM, Weinstock GM. 1993. Generation of restriction map of Enterococcus faecalis OG1 and investigation of growth requirements and regions encoding biosynthetic function. J Bacteriol 175:5216–5223. [PubMed]
44. Tourtellotte ME, Morowitz HJ, Kasimer P. 1964. Defined medium for Mycoplasma laidlawii. J Bacteriol 88:11–15. [PubMed]
45. Melendez-Hevia E, Waddell TG, Cascante M. 1996. The puzzle of the Krebs citric acid cycle: assembling the pieces of chemically feasible reactions, and opportunism in the design of metabolic pathways during evolution. J Mol Evol 43:293–303. [PubMed][CrossRef]
46. Kim HJ, Mittal M, Sonenshein AL. 2006. CcpC-dependent regulation of citB and lmo0847 in Listeria monocytogenes. J Bacteriol 188:179–190. [PubMed][CrossRef]
47. Cerdeno-Tarraga AM, Efstratiou A, Dover LG, Holden MT, Pallen M, Bentley SD, Besra GS, Churcher C, James KD, De Zoysa A, Chillingworth T, Cronin A, Dowd L, Feltwell T, Hamlin N, Holroyd S, Jagels K, Moule S, Quail MA, Rabbinowitsch E, Rutherford KM, Thomson NR, Unwin L, Whitehead S, Barrell BG, Parkhill J. 2003. The complete genome sequence and analysis of Corynebacterium diphtheriae NCTC13129. Nucleic Acids Res 31:6516–6523. [PubMed][CrossRef]
48. Nakano MM, Zuber P, Sonenshein AL. 1998. Anaerobic regulation of Bacillus subtilis Krebs cycle genes. J Bacteriol 180:3304–3311. [PubMed]
49. Eoh H, Rhee KY. 2013. Multifunctional essentiality of succinate metabolism in adaptation to hypoxia in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 110:6554–6559. [PubMed][CrossRef]
50. Somerville GA, Chaussee MS, Morgan CI, Fitzgerald JR, Dorward DW, Reitzer LJ, Musser JM. 2002. Staphylococcus aureus aconitase inactivation unexpectedly inhibits post-exponential-phase growth and enhances stationary-phase survival. Infect Immun 70:6373–6382. [PubMed][CrossRef]
51. Mei JM, Nourbakhsh F, Ford CW, Holden DW. 1997. Identification of Staphylococcus aureus virulence genes in a murine model of bacteraemia using signature-tagged mutagenesis. Mol Microbiol 26:399–407. [PubMed][CrossRef]
52. Kornberg HL, Krebs HA. 1957. Synthesis of cell constiuents from C 2-units by a modified tricarboxylic acid cycle. Nature 179:988–991. [PubMed][CrossRef]
53. Beaman BL, Beaman L. 1994. Nocardia species: host-parasite relationships. Clin Microbiol Rev 7:213–264. [PubMed]
54. Muscatello G. 2012. Rhodococcus equi pneumonia in the foal--part 1: pathogenesis and epidemiology. Vet J 192:20–26. [PubMed][CrossRef]
55. Lorenz MC, Fink GR. 2002. Life and death in a macrophage: role of the glyoxylate cycle in virulence. Eukaryot. Cell 1:657–662. [CrossRef]
56. Titgemeyer F, Hillen W. 2002. Global control of sugar metabolism: a gram-positive solution. Antonie Van Leeuwenhoek 82:59–71. [PubMed][CrossRef]
57. Warner JB, Lolkema JS. 2003. CcpA-dependent carbon catabolite repression in bacteria. Microbiol Mol Biol Rev 67:475–490. [CrossRef]
58. Pimentel-Schmitt EF, Thomae AW, Amon J, Klieber MA, Roth HM, Muller YA, Jahreis K, Burkovski A, Titgemeyer F. 2007. A glucose kinase from Mycobacterium smegmatis. J Mol Microbiol Biotechnol 12:75–81. [PubMed][CrossRef]
59. Bowles JA, Segal W. 1965. Kinetics of utilization of organic compounds in the growth of Mycobacterium tuberculosis. J Bacteriol 90:157–163. [PubMed]
60. Collins FM, Lascelles J. 1962. The effect of growth conditions on oxidative and dehydrogenase activity in Staphylococcus aureus. J Gen Microbiol 29:531–535. [PubMed][CrossRef]
61. Hanson RS, Srinivasan VR, Halvorson HO. 1963. Biochemistry of sporulation. I. Metabolism of acetate by vegetative and sporulating cells. J Bacteriol 85:451–460. [PubMed]
62. Hanson RS, Blicharska J, Arnaud M, Szulmajster J. 1964. Observation on the regulation of the synthesis of the tricarboxylic acid cycle enzymes in Bacillus subtilis, Marburg. Biochem Biophys Res Commun 17:690–695. [CrossRef]
63. Holmgren NB, Millman I, Youmans GP. 1954. Studies on the metabolism of Mycobacterium tuberculosis. VI. The effect of Krebs' tricarboxylic acid cycle intermediates and precursors on the growth and respiration of Mycobacterium tuberculosis. J Bacteriol 68:405–410. [PubMed]
64. Somerville GA, Saïd-Salim B, Wickman JM, Raffel SJ, Kreiswirth BN, Musser JM. 2003. Correlation of acetate catabolism and growth yield in Staphylococcus aureus: Implications for host-pathogen interactions. Infect Immun 71:4724–4732. [PubMed][CrossRef]
65. Somerville GA, Cockayne A, Dürr M, Peschel A, Otto M, Musser JM. 2003. Synthesis and deformylation of Staphylococcus aureus delta-toxin are linked to tricarboxylic acid cycle activity. J Bacteriol 185:6686–6694. [PubMed][CrossRef]
66. Vuong C, Kidder JB, Jacobson ER, Otto M, Proctor RA, Somerville GA. 2005. Staphylococcus epidermidis polysaccharide intercellular adhesin production significantly increases during tricarboxylic acid cycle stress. J Bacteriol 187:2967–2973. [PubMed][CrossRef]
67. Varghese S, Tang Y, Imlay JA. 2003. Contrasting sensitivities of Escherichia coli aconitases A and B to oxidation and iron depletion. J Bacteriol 185:221–230. [PubMed][CrossRef]
68. Jaeger T, Mayer C. 2008. The transcriptional factors MurR and catabolite activator protein regulate N-acetylmuramic acid catabolism in Escherichia coli. J Bacteriol 190:6598–6608. [PubMed][CrossRef]
69. Shivers RP, Sonenshein AL. 2004. Activation of the Bacillus subtilis global regulator CodY by direct interaction with branched-chain amino acids. Mol Microbiol 53:599–611. [PubMed][CrossRef]
70. Romling U, Galperin MY, Gomelsky M. 2013. Cyclic di-GMP: the first 25 years of a universal bacterial second messenger. Microbiol Mol Biol Rev 77:1–52. [PubMed][CrossRef]
71. Ernst JF, Bennett RL, Rothfield LI. 1978. Constitutive expression of the iron-enterochelin and ferrichrome uptake systems in a mutant strain of Salmonella typhimurium. J Bacteriol 135:928–934. [PubMed]
72. Somerville GA, Proctor RA. 2009. At the crossroads of bacterial metabolism and virulence factor synthesis in staphylococci. Microbiol Mol Biol Rev 73:233–248. [PubMed][CrossRef]
73. Reitzer L. 2003. Nitrogen assimilation and global regulation in Escherichia coli. Annu Rev Microbiol 57:155–176. [PubMed][CrossRef]
74. Fisher SH. 1999. Regulation of nitrogen metabolism in Bacillus subtilis: vive la difference! Mol Microbiol 32:223–232. [PubMed][CrossRef]
75. Tempest DW, Meers JL, Brown CM. 1970. Synthesis of glutamate in Aerobacter aerogenes by a hitherto unknown route. Biochem J 117:405–407. [PubMed]
76. Slack FJ, Serror P, Joyce E, Sonenshein AL. 1995. A gene required for nutritional repression of the Bacillus subtilis dipeptide permease operon. Mol Microbiol 15:689–702. [PubMed][CrossRef]
77. Armstrong FB, Wagner RP. 1961. Biosynthesis of valine and isoleucine. IV. alpha-hydroxy-beta-keto acid reductoisomerase of Salmonella. J Biol Chem 236:2027–2032. [PubMed]
78. Myers JW. 1961. Dihydroxy acid dehydrase: an enzyme involved in the biosynthesis of isoleucine and valine. J Biol Chem 236:1414–1418. [PubMed]
79. Leitzmann C, Bernlohr RW. 1968. Threonine dehydratase of Bacillus licheniformis. I. Purification and properties. Biochim Biophys Acta 151:449–460. [PubMed][CrossRef]
80. Nobre LS, Saraiva LM. 2013. Effect of combined oxidative and nitrosative stresses on Staphylococcus aureus transcriptome. Appl Microbiol Biotechnol 97:2563–2573. [PubMed][CrossRef]
81. Thorsing M, Klitgaard JK, Atilano ML, Skov MN, Kolmos HJ, Filipe SR, Kallipolitis BH. 2013. Thioridazine induces major changes in global gene expression and cell wall composition in methicillin-resistant Staphylococcus aureus USA300. PloS One 8:e64518. [PubMed][CrossRef]
82. Moreno MS, Schneider BL, Maile RR, Weyler W, Saier MH, Jr. 2001. Catabolite repression mediated by the CcpA protein in Bacillus subtilis: novel modes of regulation revealed by whole-genome analyses. Mol Microbiol 39:1366–1381. [PubMed][CrossRef]
83. Yoshida K, Kobayashi K, Miwa Y, Kang CM, Matsunaga M, Yamaguchi H, Tojo S, Yamamoto M, Nishi R, Ogasawara N, Nakayama T, Fujita Y. 2001. Combined transcriptome and proteome analysis as a powerful approach to study genes under glucose repression in Bacillus subtilis. Nucleic Acids Res 29:683–692. [PubMed][CrossRef]
84. Antunes A, Camiade E, Monot M, Courtois E, Barbut F, Sernova NV, Rodionov DA, Martin-Verstraete I, Dupuy B. 2012. Global transcriptional control by glucose and carbon regulator CcpA in Clostridium difficile. Nucleic Acids Res 40:10701–10718. [PubMed][CrossRef]
85. Ren C, Gu Y, Wu Y, Zhang W, Yang C, Yang S, Jiang W. 2012. Pleiotropic functions of catabolite control protein CcpA in Butanol-producing Clostridium acetobutylicum. BMC Genomics 13:349. [PubMed][CrossRef]
86. Jankovic I, Egeter O, Bruckner R. 2001. Analysis of catabolite control protein A-dependent repression in Staphylococcus xylosus by a genomic reporter gene system. J Bacteriol 183:580–586. [PubMed][CrossRef]
87. Seidl K, Muller S, Francois P, Kriebitzsch C, Schrenzel J, Engelmann S, Bischoff M, Berger-Bachi B. 2009. Effect of a glucose impulse on the CcpA regulon in Staphylococcus aureus. BMC Microbiol 9:95. [PubMed][CrossRef]
88. Zeng L, Choi SC, Danko CG, Siepel A, Stanhope MJ, Burne RA. 2013. Gene regulation by CcpA and catabolite repression explored by RNA-Seq in Streptococcus mutans. PloS One 8:e60465. [PubMed][CrossRef]
89. Willenborg J, Fulde M, de Greeff A, Rohde M, Smith HE, Valentin-Weigand P, Goethe R. 2011. Role of glucose and CcpA in capsule expression and virulence of Streptococcus suis. Microbiology 157:1823–1833. [PubMed][CrossRef]
90. Carvalho SM, Kloosterman TG, Kuipers OP, Neves AR. 2011. CcpA ensures optimal metabolic fitness of Streptococcus pneumoniae. PloS One 6:e26707. [PubMed][CrossRef]
91. Kinkel TL, McIver KS. 2008. CcpA-mediated repression of streptolysin S expression and virulence in the group A streptococcus. Infect Immun 76:3451–3463. [PubMed][CrossRef]
92. Zomer AL, Buist G, Larsen R, Kok J, Kuipers OP. 2007. Time-resolved determination of the CcpA regulon of Lactococcus lactis subsp. cremoris MG1363. J Bacteriol 189:1366–1381. [PubMed][CrossRef]
93. Leboeuf C, Leblanc L, Auffray Y, Hartke A. 2000. Characterization of the ccpA gene of Enterococcus faecalis: identification of starvation-inducible proteins regulated by CcpA. J Bacteriol 182:5799–5806. [PubMed][CrossRef]
94. Asanuma N, Yoshii T, Hino T. 2004. Molecular characterization of CcpA and involvement of this protein in transcriptional regulation of lactate dehydrogenase and pyruvate formate-lyase in the ruminal bacterium Streptococcus bovis. Appl Environ Microbiol 70:5244–5251. [PubMed][CrossRef]
95. Fujita Y. 2009. Carbon catabolite control of the metabolic network in Bacillus subtilis. Biosci Biotechnol Biochem 73:245–259. [PubMed][CrossRef]
96. Dahl MK. 2002. CcpA-independent carbon catabolite repression in Bacillus subtilis. J Mol Microbiol Biotechnol 4:315–321. [PubMed]
97. Deutscher J, Herro R, Bourand A, Mijakovic I, Poncet S. 2005. P-Ser-HPr--a link between carbon metabolism and the virulence of some pathogenic bacteria. Biochim Biophys Acta 1754:118–125. [PubMed][CrossRef]
98. Luesink EJ, Beumer CM, Kuipers OP, De Vos WM. 1999. Molecular characterization of the Lactococcus lactis ptsHI operon and analysis of the regulatory role of HPr. J Bacteriol 181:764–771. [PubMed]
99. Zeng L, Burne RA. 2010. Seryl-phosphorylated HPr regulates CcpA-independent carbon catabolite repression in conjunction with PTS permeases in Streptococcus mutans. Mol Microbiol 75:1145–1158. [PubMed][CrossRef]
100. Antunes A, Martin-Verstraete I, Dupuy B. 2011. CcpA-mediated repression of Clostridium difficile toxin gene expression. Mol Microbiol 79:882–899. [PubMed][CrossRef]
101. Leiba J, Hartmann T, Cluzel ME, Cohen-Gonsaud M, Delolme F, Bischoff M, Molle V. 2012. A novel mode of regulation of the Staphylococcus aureus catabolite control protein A (CcpA) mediated by Stk1 protein phosphorylation. J Biol Chem 287:43607–43619. [PubMed][CrossRef]
102. Bayer AS, Coulter SN, Stover CK, Schwan WR. 1999. Impact of the high-affinity proline permease gene ( putP) on the virulence of Staphylococcus aureus in experimental endocarditis. Infect Immun 67:740–744. [PubMed]
103. Schwan WR, Wetzel KJ, Gomez TS, Stiles MA, Beitlich BD, Grunwald S. 2004. Low-proline environments impair growth, proline transport and in vivo survival of Staphylococcus aureus strain-specific putP mutants. Microbiology 150:1055–1061. [PubMed][CrossRef]
104. Li C, Sun F, Cho H, Yelavarthi V, Sohn C, He C, Schneewind O, Bae T. 2010. CcpA mediates proline auxotrophy and is required for Staphylococcus aureus pathogenesis. J Bacteriol 192:3883–3892. [PubMed][CrossRef]
105. Giammarinaro P, Paton JC. 2002. Role of RegM, a homologue of the catabolite repressor protein CcpA, in the virulence of Streptococcus pneumoniae. Infect Immun 70:5454–5461. [PubMed][CrossRef]
106. Iyer R, Baliga NS, Camilli A. 2005. Catabolite control protein A (CcpA) contributes to virulence and regulation of sugar metabolism in Streptococcus pneumoniae. J Bacteriol 187:8340–8349. [PubMed][CrossRef]
107. Zhang A, Chen B, Yuan Z, Li R, Liu C, Zhou H, Chen H, Jin M. 2012. HP0197 contributes to CPS synthesis and the virulence of Streptococcus suis via CcpA. PloS One 7:e50987. [PubMed][CrossRef]
108. Abranches J, Nascimento MM, Zeng L, Browngardt CM, Wen ZT, Rivera MF, Burne RA. 2008. CcpA regulates central metabolism and virulence gene expression in Streptococcus mutans. J Bacteriol 190:2340–2349. [PubMed][CrossRef]
109. Zheng L, Itzek A, Chen Z, Kreth J. 2011. Environmental influences on competitive hydrogen peroxide production in Streptococcus gordonii. Appl Environ Microbiol 77:4318–4328. [PubMed][CrossRef]
110. Zheng L, Chen Z, Itzek A, Ashby M, Kreth J. 2011. Catabolite control protein A controls hydrogen peroxide production and cell death in Streptococcus sanguinis. J Bacteriol 193:516–526. [PubMed][CrossRef]
111. Ahn SJ, Rice KC, Oleas J, Bayles KW, Burne RA. 2010. The Streptococcus mutans Cid and Lrg systems modulate virulence traits in response to multiple environmental signals. Microbiology 156:3136–3147. [PubMed][CrossRef]
112. Almengor AC, Kinkel TL, Day SJ, McIver KS. 2007. The catabolite control protein CcpA binds to P mga and influences expression of the virulence regulator Mga in the Group A Streptococcus. J Bacteriol 189:8405–8416. [PubMed][CrossRef]
113. Dupuy B, Sonenshein AL. 1998. Regulated transcription of Clostridium difficile toxin genes. Mol Microbiol 27:107–120. [PubMed][CrossRef]
114. Karlsson S, Burman LG, Akerlund T. 1999. Suppression of toxin production in Clostridium difficile VPI 10463 by amino acids. Microbiology 145:1683–1693. [PubMed][CrossRef]
115. Mendez MB, Goni A, Ramirez W, Grau RR. 2012. Sugar inhibits the production of the toxins that trigger clostridial gas gangrene. Microb Pathog 52:85–91. [PubMed][CrossRef]
116. Mendez M, Huang IH, Ohtani K, Grau R, Shimizu T, Sarker MR. 2008. Carbon catabolite repression of type IV pilus-dependent gliding motility in the anaerobic pathogen Clostridium perfringens. J Bacteriol 190:48–60. [PubMed][CrossRef]
117. Varga JJ, Therit B, Melville SB. 2008. Type IV pili and the CcpA protein are needed for maximal biofilm formation by the gram-positive anaerobic pathogen Clostridium perfringens. Infect Immun 76:4944–4951. [PubMed][CrossRef]
118. Varga J, Stirewalt VL, Melville SB. 2004. The CcpA protein is necessary for efficient sporulation and enterotoxin gene (cpe) regulation in Clostridium perfringens. J Bacteriol 186:5221–5229. [PubMed][CrossRef]
119. Mackey-Lawrence NM, Jefferson KK. 2013. Regulation of Staphylococcus aureus immunodominant antigen B (IsaB). Microbiol Res 168:113–118. [PubMed][CrossRef]
120. Seidl K, Goerke C, Wolz C, Mack D, Berger-Bachi B, Bischoff M. 2008. Staphylococcus aureus CcpA affects biofilm formation. Infect Immun 76:2044–2050. [PubMed][CrossRef]
121. Seidl K, Stucki M, Ruegg M, Goerke C, Wolz C, Harris L, Berger-Bachi B, Bischoff M. 2006. Staphylococcus aureus CcpA affects virulence determinant production and antibiotic resistance. Antimicrob Agents Chemother 50:1183–1194. [PubMed][CrossRef]
122. Seidl K, Bischoff M, Berger-Bachi B. 2008. CcpA mediates the catabolite repression of tst in Staphylococcus aureus. Infect Immun 76:5093–5099. [PubMed][CrossRef]
123. Chiang C, Bongiorni C, Perego M. 2011. Glucose-dependent activation of Bacillus anthracis toxin gene expression and virulence requires the carbon catabolite protein CcpA. J Bacteriol 193:52–62. [PubMed][CrossRef]
124. Gao P, Pinkston KL, Bourgogne A, Cruz MR, Garsin DA, Murray BE, Harvey BR. 2013. Library screen identifies Enterococcus faecalis CcpA, the catabolite control protein A, as an effector of Ace, a collagen adhesion protein linked to virulence. J Bacteriol 195:4761–4768. [PubMed][CrossRef]
125. Herro R, Poncet S, Cossart P, Buchrieser C, Gouin E, Glaser P, Deutscher J. 2005. How seryl-phosphorylated HPr inhibits PrfA, a transcription activator of Listeria monocytogenes virulence genes. J Mol Microbiol Biotechnol 9:224–234. [PubMed][CrossRef]
126. Mertins S, Joseph B, Goetz M, Ecke R, Seidel G, Sprehe M, Hillen W, Goebel W, Muller-Altrock S. 2007. Interference of components of the phosphoenolpyruvate phosphotransferase system with the central virulence gene regulator PrfA of Listeria monocytogenes. J Bacteriol 189:473–490. [PubMed][CrossRef]
127. Molle V, Nakaura Y, Shivers RP, Yamaguchi H, Losick R, Fujita Y, Sonenshein AL. 2003. Additional targets of the Bacillus subtilis global regulator CodY identified by chromatin immunoprecipitation and genome-wide transcript analysis. J Bacteriol 185:1911–1922. [PubMed][CrossRef]
128. Dineen SS, McBride SM, Sonenshein AL. 2010. Integration of metabolism and virulence by Clostridium difficile CodY. J Bacteriol 192:5350–5362. [PubMed][CrossRef]
129. Majerczyk CD, Dunman PM, Luong TT, Lee CY, Sadykov MR, Somerville GA, Bodi K, Sonenshein AL. 2010. Direct targets of CodY in Staphylococcus aureus. J Bacteriol 192:2861–2877. [PubMed][CrossRef]
130. Pohl K, Francois P, Stenz L, Schlink F, Geiger T, Herbert S, Goerke C, Schrenzel J, Wolz C. 2009. CodY in Staphylococcus aureus: a regulatory link between metabolism and virulence gene expression. J Bacteriol 191:2953–2963. [PubMed][CrossRef]
131. Malke H, Ferretti JJ. 2007. CodY-affected transcriptional gene expression of Streptococcus pyogenes during growth in human blood. J Med Microbiol 56:707–714. [PubMed][CrossRef]
132. Kreth J, Chen Z, Ferretti J, Malke H. 2011. Counteractive balancing of transcriptome expression involving CodY and CovRS in Streptococcus pyogenes. J Bacteriol 193:4153–4165. [PubMed][CrossRef]
133. Guedon E, Serror P, Ehrlich SD, Renault P, Delorme C. 2001. Pleiotropic transcriptional repressor CodY senses the intracellular pool of branched-chain amino acids in Lactococcus lactis. Mol Microbiol 40:1227–1239. [PubMed][CrossRef]
134. Bennett HJ, Pearce DM, Glenn S, Taylor CM, Kuhn M, Sonenshein AL, Andrew PW, Roberts IS. 2007. Characterization of relA and codY mutants of Listeria monocytogenes: identification of the CodY regulon and its role in virulence. Mol Microbiol 63:1453–1467. [PubMed][CrossRef]
135. Brinsmade SR, Kleijn RJ, Sauer U, Sonenshein AL. 2010. Regulation of CodY activity through modulation of intracellular branched-chain amino acid pools. J Bacteriol 192:6357–6368. [PubMed][CrossRef]
136. Ratnayake-Lecamwasam M, Serror P, Wong KW, Sonenshein AL. 2001. Bacillus subtilis CodY represses early-stationary-phase genes by sensing GTP levels. Genes Dev 15:1093–1103. [PubMed][CrossRef]
137. Handke LD, Shivers RP, Sonenshein AL. 2008. Interaction of Bacillus subtilis CodY with GTP. J Bacteriol 190:798–806. [PubMed][CrossRef]
138. Brinsmade SR, Sonenshein AL. 2011. Dissecting complex metabolic integration provides direct genetic evidence for CodY activation by guanine nucleotides. J Bacteriol 193:5637–5648. [PubMed][CrossRef]
139. Hendriksen WT, Bootsma HJ, Estevao S, Hoogenboezem T, de Jong A, de Groot R, Kuipers OP, Hermans PW. 2008. CodY of Streptococcus pneumoniae: link between nutritional gene regulation and colonization. J Bacteriol 190:590–601. [PubMed][CrossRef]
140. Petranovic D, Guedon E, Sperandio B, Delorme C, Ehrlich D, Renault P. 2004. Intracellular effectors regulating the activity of the Lactococcus lactis CodY pleiotropic transcription regulator. Mol Microbiol 53:613–621. [CrossRef]
141. Levdikov VM, Blagova E, Colledge VL, Lebedev AA, Williamson DC, Sonenshein AL, Wilkinson AJ. 2009. Structural rearrangement accompanying ligand binding in the GAF domain of CodY from Bacillus subtilis. J Mol Biol 390:1007–1018. [PubMed][CrossRef]
142. Kriel A, Bittner AN, Kim SH, Liu K, Tehranchi AK, Zou WY, Rendon S, Chen R, Tu BP, Wang JD. 2012. Direct regulation of GTP homeostasis by (p)ppGpp: a critical component of viability and stress resistance. Mol Cell 48:231–241. [PubMed][CrossRef]
143. Kriel A, Brinsmade SR, Tse JL, Tehranchi A, Bittner A, Sonenshein AL, Wang JD. 2014. GTP dysregulation in Bacillus subtilis cells lacking (p)ppGpp results in phenotypic amino acid auxotrophy and failure to adapt to nutrient downshift and regulate biosynthesis genes. J Bacteriol 196:189–201. [PubMed][CrossRef]
144. Geiger T, Goerke C, Fritz M, Schafer T, Ohlsen K, Liebeke M, Lalk M, Wolz C. 2010. Role of the (p)ppGpp synthase RSH, a RelA/SpoT homolog, in stringent response and virulence of Staphylococcus aureus. Infect Immun 78:1873–1883. [PubMed][CrossRef]
145. Guedon E, Sperandio B, Pons N, Ehrlich SD, Renault P. 2005. Overall control of nitrogen metabolism in Lactococcus lactis by CodY, and possible models for CodY regulation in Firmicutes. Microbiology 151:3895–3909. [PubMed][CrossRef]
146. Belitsky BR, Sonenshein AL. 2008. Genetic and biochemical analysis of CodY-binding sites in Bacillus subtilis. J Bacteriol 190:1224–1236. [PubMed][CrossRef]
147. Belitsky BR, Sonenshein AL. 2011. Contributions of multiple binding sites and effector-independent binding to CodY-mediated regulation in Bacillus subtilis. J Bacteriol 193:473–484. [PubMed][CrossRef]
148. Wray LV, Jr., Fisher SH. 2011. Bacillus subtilis CodY operators contain overlapping CodY binding sites. J Bacteriol 193:4841–4848. [PubMed][CrossRef]
149. Belitsky BR, Sonenshein AL. 2013. Genome-wide identification of Bacillus subtilis CodY-binding sites at single-nucleotide resolution. Proc Natl Acad Sci U S A 110:7026–7031. [PubMed][CrossRef]
150. Shivers RP, Dineen SS, Sonenshein AL. 2006. Positive regulation of Bacillus subtilis ackA by CodY and CcpA: establishing a potential hierarchy in carbon flow. Mol Microbiol 62:811–822. [PubMed][CrossRef]
151. Belitsky BR, Sonenshein AL. 2011. Roadblock repression of transcription by Bacillus subtilis CodY. J Mol Biol 411:729–743. [PubMed][CrossRef]
152. Belitsky BR. 2011. Indirect repression by Bacillus subtilis CodY via displacement of the activator of the proline utilization operon. J Mol Biol 413:321–336. [PubMed][CrossRef]
153. Karlsson S, Lindberg A, Norin E, Burman LG, Akerlund T. 2000. Toxins, butyric acid, and other short-chain fatty acids are coordinately expressed and down-regulated by cysteine in Clostridium difficile. Infect Immun 68:5881–5888. [PubMed][CrossRef]
154. Dineen SS, Villapakkam AC, Nordman JT, Sonenshein AL. 2007. Repression of Clostridium difficile toxin gene expression by CodY. Mol Microbiol 66:206–219. [PubMed][CrossRef]
155. Li J, Ma M, Sarker MR, McClane BA. 2013. CodY is a global regulator of virulence-associated properties for Clostridium perfringens type D strain CN3718. mBio 4:e00770–00713. [PubMed][CrossRef]
156. Montgomery CP, Boyle-Vavra S, Roux A, Ebine K, Sonenshein AL, Daum RS. 2012. CodY deletion enhances in vivo virulence of community-associated methicillin-resistant Staphylococcus aureus clone USA300. Infect Immun 80:2382–2389. [PubMed][CrossRef]
157. Rivera FE, Miller HK, Kolar SL, Stevens SM, Jr., Shaw LN. 2012. The impact of CodY on virulence determinant production in community-associated methicillin-resistant Staphylococcus aureus. Proteomics 12:263–268. [PubMed][CrossRef]
158. Majerczyk CD, Sadykov MR, Luong TT, Lee C, Somerville GA, Sonenshein AL. 2008. Staphylococcus aureus CodY negatively regulates virulence gene expression. J Bacteriol 190:2257–2265. [PubMed][CrossRef]
159. Novick RP. 2003. Autoinduction and signal transduction in the regulation of staphylococcal virulence. Mol Microbiol 48:1429–1449. [PubMed][CrossRef]
160. Batzilla CF, Rachid S, Engelmann S, Hecker M, Hacker J, Ziebuhr W. 2006. Impact of the accessory gene regulatory system (Agr) on extracellular proteins, codY expression and amino acid metabolism in Staphylococcus epidermidis. Proteomics 6:3602–3613. [PubMed][CrossRef]
161. Reiss S, Pane-Farre J, Fuchs S, Francois P, Liebeke M, Schrenzel J, Lindequist U, Lalk M, Wolz C, Hecker M, Engelmann S. 2012. Global analysis of the Staphylococcus aureus response to mupirocin. Antimicrob Agents Chemother 56:787–804. [PubMed][CrossRef]
162. Tu Quoc PH, Genevaux P, Pajunen M, Savilahti H, Georgopoulos C, Schrenzel J, Kelley WL. 2007. Isolation and characterization of biofilm formation-defective mutants of Staphylococcus aureus. Infect Immun 75:1079–1088. [PubMed][CrossRef]
163. van Schaik W, Chateau A, Dillies MA, Coppee JY, Sonenshein AL, Fouet A. 2009. The global regulator CodY regulates toxin gene expression in Bacillus anthracis and is required for full virulence. Infect Immun 77:4437–4445. [PubMed][CrossRef]
164. Chateau A, van Schaik W, Six A, Aucher W, Fouet A. 2011. CodY regulation is required for full virulence and heme iron acquisition in Bacillus anthracis. FASEB J 25:4445–4456. [PubMed][CrossRef]
165. Frenzel E, Doll V, Pauthner M, Lucking G, Scherer S, Ehling-Schulz M. 2012. CodY orchestrates the expression of virulence determinants in emetic Bacillus cereus by impacting key regulatory circuits. Mol Microbiol 85:67–88. [PubMed][CrossRef]
166. Lindback T, Mols M, Basset C, Granum PE, Kuipers OP, Kovacs AT. 2012. CodY, a pleiotropic regulator, influences multicellular behaviour and efficient production of virulence factors in Bacillus cereus. Environ Microbiol 14:2233–2246. [PubMed][CrossRef]
167. Hsueh YH, Somers EB, Wong AC. 2008. Characterization of the codY gene and its influence on biofilm formation in Bacillus cereus. Arch Microbiol 189:557–568. [PubMed][CrossRef]
168. Lobel L, Sigal N, Borovok I, Ruppin E, Herskovits AA. 2012. Integrative genomic analysis identifies isoleucine and CodY as regulators of Listeria monocytogenes virulence. PLoS Genet 8:e1002887. [PubMed][CrossRef]
169. Malke H, Steiner K, McShan WM, Ferretti JJ. 2006. Linking the nutritional status of Streptococcus pyogenes to alteration of transcriptional gene expression: the action of CodY and RelA. Int J Med Microbiol 296:259–275. [PubMed][CrossRef]
170. Caymaris S, Bootsma HJ, Martin B, Hermans PW, Prudhomme M, Claverys JP. 2010. The global nutritional regulator CodY is an essential protein in the human pathogen Streptococcus pneumoniae. Mol Microbiol 78:344–360. [PubMed][CrossRef]
171. Bouillaut L, Self WT, Sonenshein AL. 2013. Proline-dependent regulation of Clostridium difficile Stickland metabolism. J Bacteriol 195:844–854. [PubMed][CrossRef]
172. Stickland LH. 1935. Studies in the metabolism of the strict anaerobes (Genus Clostridium): The reduction of proline by Cl. sporogenes. Biochem J 29:288–290. [PubMed]
173. Jackson S, Calos M, Myers A, Self WT. 2006. Analysis of proline reduction in the nosocomial pathogen Clostridium difficile. J Bacteriol 188:8487–8495. [PubMed][CrossRef]
174. Brekasis D, Paget MS. 2003. A novel sensor of NADH/NAD+ redox poise in Streptomyces coelicolor A3(2). EMBO J 22:4856–4865. [PubMed][CrossRef]
175. Schau M, Chen Y, Hulett FM. 2004. Bacillus subtilis YdiH is a direct negative regulator of the cydABCD operon. J Bacteriol 186:4585–4595. [PubMed][CrossRef]
176. Larsson JT, Rogstam A, von Wachenfeldt C. 2005. Coordinated patterns of cytochrome bd and lactate dehydrogenase expression in Bacillus subtilis. Microbiology 151:3323–3335. [PubMed][CrossRef]
177. Gyan S, Shiohira Y, Sato I, Takeuchi M, Sato T. 2006. Regulatory loop between redox sensing of the NADH/NAD(+) ratio by Rex (YdiH) and oxidation of NADH by NADH dehydrogenase Ndh in Bacillus subtilis. J Bacteriol 188:7062–7071. [PubMed][CrossRef]
178. Pagels M, Fuchs S, Pane-Farre J, Kohler C, Menschner L, Hecker M, McNamarra PJ, Bauer MC, von Wachenfeldt C, Liebeke M, Lalk M, Sander G, von Eiff C, Proctor RA, Engelmann S. 2010. Redox sensing by a Rex-family repressor is involved in the regulation of anaerobic gene expression in Staphylococcus aureus. Mol Microbiol 76:1142–1161. [PubMed][CrossRef]
179. Mehmeti I, Jonsson M, Fergestad EM, Mathiesen G, Nes IF, Holo H. 2011. Transcriptome, proteome, and metabolite analyses of a lactate dehydrogenase-negative mutant of Enterococcus faecalis V583. Appl Environ Microbiol 77:2406–2413. [PubMed][CrossRef]
180. Wietzke M, Bahl H. 2012. The redox-sensing protein Rex, a transcriptional regulator of solventogenesis in Clostridium acetobutylicum. Appl Microbiol Biotechnol 96:749–761. [PubMed][CrossRef]
181. Sickmier EA, Brekasis D, Paranawithana S, Bonanno JB, Paget MS, Burley SK, Kielkopf CL. 2005. X-ray structure of a Rex-family repressor/NADH complex insights into the mechanism of redox sensing. Structure 13:43–54. [PubMed][CrossRef]
182. Richardson AR, Libby SJ, Fang FC. 2008. A nitric oxide-inducible lactate dehydrogenase enables Staphylococcus aureus to resist innate immunity. Science 319:1672–1676. [PubMed][CrossRef]
183. Aboulnaga el H, Pinkenburg O, Schiffels J, El-Refai A, Buckel W, Selmer T. 2013. Effect of an oxygen-tolerant bifurcating butyryl coenzyme A dehydrogenase/electron-transferring flavoprotein complex from Clostridium difficile on butyrate production in Escherichia coli. J Bacteriol 195:3704–3713. [PubMed][CrossRef]
184. Sohling B, Gottschalk G. 1996. Molecular analysis of the anaerobic succinate degradation pathway in Clostridium kluyveri. J Bacteriol 178:871–880. [PubMed]
185. Sorensen KI, Hove-Jensen B. 1996. Ribose catabolism of Escherichia coli: characterization of the rpiB gene encoding ribose phosphate isomerase B and of the rpiR gene, which is involved in regulation of rpiB expression. J Bacteriol 178:1003–1011. [PubMed]
186. Daddaoua A, Krell T, Ramos JL. 2009. Regulation of glucose metabolism in Pseudomonas: the phosphorylative branch and Entner-Doudoroff enzymes are regulated by a repressor containing a sugar isomerase domain. J Biol Chem 284:21360–21368. [PubMed][CrossRef]
187. Kohler PR, Choong EL, Rossbach S. 2011. The RpiR-like repressor IolR regulates inositol catabolism in Sinorhizobium meliloti. J Bacteriol 193:5155–5163. [PubMed][CrossRef]
188. Yamamoto H, Serizawa M, Thompson J, Sekiguchi J. 2001. Regulation of the glv operon in Bacillus subtilis: YfiA (GlvR) is a positive regulator of the operon that is repressed through CcpA and cre. J Bacteriol 183:5110–5121. [PubMed][CrossRef]
189. Zhu Y, Nandakumar R, Sadykov MR, Madayiputhiya N, Luong TT, Gaupp R, Lee CY, Somerville GA. 2011. RpiR homologues may link Staphylococcus aureus RNAIII synthesis and pentose phosphate pathway regulation. J Bacteriol 193:6187–6196. [PubMed][CrossRef]
190. Tojo S, Satomura T, Morisaki K, Yoshida K, Hirooka K, Fujita Y. 2004. Negative transcriptional regulation of the ilv- leu operon for biosynthesis of branched-chain amino acids through the Bacillus subtilis global regulator TnrA. J Bacteriol 186:7971–7979. [PubMed][CrossRef]
191. Shivers RP, Sonenshein AL. 2005. Bacillus subtilis ilvB operon: an intersection of global regulons. Mol Microbiol 56:1549–1559. [PubMed][CrossRef]
192. Tojo S, Satomura T, Morisaki K, Deutscher J, Hirooka K, Fujita Y. 2005. Elaborate transcription regulation of the Bacillus subtilis ilv- leu operon involved in the biosynthesis of branched-chain amino acids through global regulators of CcpA, CodY and TnrA. Mol Microbiol 56:1560–1573. [PubMed][CrossRef]
193. Grandoni JA, Fulmer SB, Brizzio V, Zahler SA, Calvo JM. 1993. Regions of the Bacillus subtilis ilv- leu operon involved in regulation by leucine. J Bacteriol 175:7581–7593. [PubMed]
194. Tojo S, Kumamoto K, Hirooka K, Fujita Y. 2010. Heavy involvement of stringent transcription control depending on the adenine or guanine species of the transcription initiation site in glucose and pyruvate metabolism in Bacillus subtilis. J Bacteriol 192:1573–1585. [PubMed][CrossRef]
195. Jourlin-Castelli C, Mani N, Nakano MM, Sonenshein AL. 2000. CcpC, a novel regulator of the LysR family required for glucose repression of the citB gene in Bacillus subtilis. J Mol Biol 295:865–878. [PubMed][CrossRef]
196. Mittal M, Pechter KB, Picossi S, Kim HJ, Kerstein KO, Sonenshein AL. 2013. Dual role of CcpC protein in regulation of aconitase gene expression in Listeria monocytogenes and Bacillus subtilis. Microbiology 159:68–76. [PubMed][CrossRef]
197. Hartmann T, Zhang B, Baronian G, Schulthess B, Homerova D, Grubmuller S, Kutzner E, Gaupp R, Bertram R, Powers R, Eisenreich W, Kormanec J, Herrmann M, Molle V, Somerville GA, Bischoff M. 2013. Catabolite control protein E (CcpE) is a LysR-type transcriptional regulator of TCA cycle activity in Staphylococcus aureus. J Biol Chem 288:36116–361128. [PubMed][CrossRef]
198. Crooke AK, Fuller JR, Obrist MW, Tomkovich SE, Vitko NP, Richardson AR. 2013. CcpA-independent glucose regulation of lactate dehydrogenase 1 in Staphylococcus aureus. PloS One 8:e54293. [PubMed][CrossRef]
199. Ravcheev DA, Li X, Latif H, Zengler K, Leyn SA, Korostelev YD, Kazakov AE, Novichkov PS, Osterman AL, Rodionov DA. 2012. Transcriptional regulation of central carbon and energy metabolism in bacteria by redox-responsive repressor Rex. J Bacteriol 194:1145–1157. [PubMed][CrossRef]
200. Larson TJ, Ehrmann M, Boos W. 1983. Periplasmic glycerophosphodiester phosphodiesterase of Escherichia coli, a new enzyme of the glp regulon. J Biol Chem 258:5428–5432. [PubMed]
201. Pitts AC, Tuck LR, Faulds-Pain A, Lewis RJ, Marles-Wright J. 2012. Structural insight into the Clostridium difficile ethanolamine utilisation microcompartment. PloS One 7:e48360. [PubMed][CrossRef]
202. Garsin DA. 2010. Ethanolamine utilization in bacterial pathogens: roles and regulation. Nat Rev Microbiol 8:290–295. [PubMed][CrossRef]
203. Joseph B, Przybilla K, Stuhler C, Schauer K, Slaghuis J, Fuchs TM, Goebel W. 2006. Identification of Listeria monocytogenes genes contributing to intracellular replication by expression profiling and mutant screening. J Bacteriol 188:556–568. [PubMed][CrossRef]
204. Maadani A, Fox KA, Mylonakis E, Garsin DA. 2007. Enterococcus faecalis mutations affecting virulence in the Caenorhabditis elegans model host. Infect Immun 75:2634–2637. [PubMed][CrossRef]
205. Newsholme P, Curi R, Gordon S, Newsholme EA. 1986. Metabolism of glucose, glutamine, long-chain fatty acids and ketone bodies by murine macrophages. Biochem J 239:121–125. [PubMed]
206. Gordon S, Martinez FO. 2010. Alternative activation of macrophages: mechanism and functions. Immunity 32:593–604. [PubMed][CrossRef]
207. Tugal D, Liao X, Jain MK. 2013. Transcriptional control of macrophage polarization. Arterioscler Thromb Vasc Biol 33:1135–1144. [PubMed][CrossRef]
208. Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M. 2013. Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol 229:176–185. [PubMed][CrossRef]
209. Mahdavian Delavary B, van der Veer WM, van Egmond M, Niessen FB, Beelen RH. 2011. Macrophages in skin injury and repair. Immunobiology 216:753–762. [PubMed][CrossRef]
210. Nizet V, Johnson RS. 2009. Interdependence of hypoxic and innate immune responses. Nat Rev Immunol 9:609–617. [PubMed][CrossRef]
211. Palsson-McDermott EM, O'Neill LA. 2013. The Warburg effect then and now: from cancer to inflammatory diseases. Bioessays 35:965–973. [PubMed][CrossRef]
212. Newsholme P, Gordon S, Newsholme EA. 1987. Rates of utilization and fates of glucose, glutamine, pyruvate, fatty acids and ketone bodies by mouse macrophages. Biochem J 242:631–636. [PubMed]
213. Cramer T, Yamanishi Y, Clausen BE, Forster I, Pawlinski R, Mackman N, Haase VH, Jaenisch R, Corr M, Nizet V, Firestein GS, Gerber HP, Ferrara N, Johnson RS. 2003. HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell 112:645–657. [PubMed][CrossRef]
214. Hothersall JS, Gordge M, Noronha-Dutra AA. 1998. Inhibition of NADPH supply by 6-aminonicotinamide: effect on glutathione, nitric oxide and superoxide in J774 cells. FEBS Lett 434:97–100. [PubMed][CrossRef]
215. Vats D, Mukundan L, Odegaard JI, Zhang L, Smith KL, Morel CR, Wagner RA, Greaves DR, Murray PJ, Chawla A. 2006. Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation. Cell Metab 4:13–24. [PubMed][CrossRef]
216. Wu G, Bazer FW, Davis TA, Kim SW, Li P, Marc Rhoads J, Carey Satterfield M, Smith SB, Spencer TE, Yin Y. 2009. Arginine metabolism and nutrition in growth, health and disease. Amino Acids 37:153–168. [PubMed][CrossRef]
217. De Groote MA, Fang FC. 1995. NO inhibitions: antimicrobial properties of nitric oxide. Clin Infect Dis 21(Suppl 2) :S162–165. [PubMed][CrossRef]
218. Shay JE, Celeste Simon M. 2012. Hypoxia-inducible factors: crosstalk between inflammation and metabolism. Semin Cell Dev Biol 23:389–394. [PubMed][CrossRef]
219. Semenza GL. 2010. HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev 20:51–56. [PubMed][CrossRef]
220. Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, Mukundan L, Red Eagle A, Vats D, Brombacher F, Ferrante AW, Chawla A. 2007. Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature 447:1116–1120. [PubMed][CrossRef]
221. Lehrke M, Lazar MA. 2005. The many faces of PPARgamma. Cell 123:993–999. [PubMed][CrossRef]
222. Kiss M, Czimmerer Z, Nagy L. 2013. The role of lipid-activated nuclear receptors in shaping macrophage and dendritic cell function: From physiology to pathology. J Allergy Clin Immunol 132:264–286. [PubMed][CrossRef]
223. Mandard S, Patsouris D. 2013. Nuclear control of the inflammatory response in mammals by peroxisome proliferator-activated receptors. PPAR Res 2013:613864. [PubMed][CrossRef]
224. Bloch H, Segal W. 1956. Biochemical differentiation of Mycobacterium tuberculosis grown in vivo and in vitro. J Bacteriol 72:132–141. [PubMed]
225. Schnappinger D, Ehrt S, Voskuil MI, Liu Y, Mangan JA, Monahan IM, Dolganov G, Efron B, Butcher PD, Nathan C, Schoolnik GK. 2003. Transcriptional adaptation of Mycobacterium tuberculosis within macrophages: insights into the phagosomal environment. J Exp Med 198:693–704. [PubMed][CrossRef]
226. de Carvalho LP, Fischer SM, Marrero J, Nathan C, Ehrt S, Rhee KY. 2010. Metabolomics of Mycobacterium tuberculosis reveals compartmentalized co-catabolism of carbon substrates. Chem Biol 17:1122–1131. [PubMed][CrossRef]
227. Marrero J, Rhee KY, Schnappinger D, Pethe K, Ehrt S. 2010. Gluconeogenic carbon flow of tricarboxylic acid cycle intermediates is critical for Mycobacterium tuberculosis to establish and maintain infection. Proc Natl Acad Sci U S A 107:9819–9824. [PubMed][CrossRef]
228. Munoz-Elias EJ, McKinney JD. 2005. Mycobacterium tuberculosis isocitrate lyases 1 and 2 are jointly required for in vivo growth and virulence. Nat Med 11:638–644. [PubMed][CrossRef]
229. 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 61:940–947. [PubMed][CrossRef]
230. Brock M, Buckel W. 2004. On the mechanism of action of the antifungal agent propionate. Eur J Biochem 271:3227–3241. [PubMed][CrossRef]
231. Rocco CJ, Escalante-Semerena JC. 2010. In Salmonella enterica, 2-methylcitrate blocks gluconeogenesis. J Bacteriol 192:771–778. [PubMed][CrossRef]
232. Lee W, VanderVen BC, Fahey RJ, Russell DG. 2013. Intracellular Mycobacterium tuberculosis exploits host-derived fatty acids to limit metabolic stress. J Biol Chem 288:6788–6800. [PubMed][CrossRef]
233. Savvi S, Warner DF, Kana BD, McKinney JD, Mizrahi V, Dawes SS. 2008. Functional characterization of a vitamin B12-dependent methylmalonyl pathway in Mycobacterium tuberculosis: implications for propionate metabolism during growth on fatty acids. J Bacteriol 190:3886–3895. [PubMed][CrossRef]
234. Rajaram MV, Brooks MN, Morris JD, Torrelles JB, Azad AK, Schlesinger LS. 2010. Mycobacterium tuberculosis activates human macrophage peroxisome proliferator-activated receptor gamma linking mannose receptor recognition to regulation of immune responses. J Immunol 185:929–942. [PubMed][CrossRef]
235. Mahajan S, Dkhar HK, Chandra V, Dave S, Nanduri R, Janmeja AK, Agrewala JN, Gupta P. 2012. Mycobacterium tuberculosis modulates macrophage lipid-sensing nuclear receptors PPARgamma and TR4 for survival. J Immunol 188:5593–5603. [PubMed][CrossRef]
236. Almeida PE, Carneiro AB, Silva AR, Bozza PT. 2012. PPARgamma expression and function in mycobacterial infection: roles in lipid metabolism, immunity, and bacterial killing. PPAR Res 2012:383829. [PubMed][CrossRef]
237. Chatterjee SS, Hossain H, Otten S, Kuenne C, Kuchmina K, Machata S, Domann E, Chakraborty T, Hain T. 2006. Intracellular gene expression profile of Listeria monocytogenes. Infect Immun 74:1323–1338. [PubMed][CrossRef]
238. Joseph B, Przybilla K, Stuhler C, Schauer K, Slaghuis J, Fuchs TM, Goebel W. 2006. Identification of Listeria monocytogenes genes contributing to intracellular replication by expression profiling and mutant screening. J Bacteriol 188:556–568. [PubMed][CrossRef]
239. Chico-Calero I, Suarez M, Gonzalez-Zorn B, Scortti M, Slaghuis J, Goebel W, Vazquez-Boland JA. 2002. Hpt, a bacterial homolog of the microsomal glucose- 6-phosphate translocase, mediates rapid intracellular proliferation in Listeria. Proc Natl Acad Sci U S A 99:431–436. [PubMed][CrossRef]
240. Stoll R, Goebel W. 2010. The major PEP-phosphotransferase systems (PTSs) for glucose, mannose and cellobiose of Listeria monocytogenes, and their significance for extra- and intracellular growth. Microbiology 156:1069–1083. [PubMed][CrossRef]
241. Gillmaier N, Gotz A, Schulz A, Eisenreich W, Goebel W. 2012. Metabolic responses of primary and transformed cells to intracellular Listeria monocytogenes. PloS One 7:e52378. [PubMed][CrossRef]
242. Purves J, Cockayne A, Moody PC, Morrissey JA. 2010. Comparison of the regulation, metabolic functions, and roles in virulence of the glyceraldehyde-3-phosphate dehydrogenase homologues gapA and gapB in Staphylococcus aureus. Infect Immun 78:5223–5232. [PubMed][CrossRef]
243. Hochgrafe F, Wolf C, Fuchs S, Liebeke M, Lalk M, Engelmann S, Hecker M. 2008. Nitric oxide stress induces different responses but mediates comparable protein thiol protection in Bacillus subtilis and Staphylococcus aureus. J Bacteriol 190:4997–5008. [PubMed][CrossRef]
244. Richardson AR, Payne EC, Younger N, Karlinsey JE, Thomas VC, Becker LA, Navarre WW, Castor ME, Libby SJ, Fang FC. 2011. Multiple targets of nitric oxide in the tricarboxylic acid cycle of Salmonella enterica serovar typhimurium. Cell Host Microbe 10:33–43. [PubMed][CrossRef]
245. Richardson AR, Dunman PM, Fang FC. 2006. The nitrosative stress response of Staphylococcus aureus is required for resistance to innate immunity. Mol Microbiol 61:927–939. [PubMed][CrossRef]
246. Fuller JR, Vitko NP, Perkowski EF, Scott E, Khatri D, Spontak JS, Thurlow LR, Richardson AR. 2011. Identification of a lactate-quinone oxidoreductase in Staphylococcus aureus that is essential for virulence. Front Cell Infect Microbiol 1:19. [PubMed][CrossRef]
247. Weiner MA, Read TD, Hanna PC. 2003. Identification and characterization of the gerH operon of Bacillus anthracis endospores: a differential role for purine nucleosides in germination. J Bacteriol 185:1462–1464. [PubMed][CrossRef]
248. Sorg JA, Sonenshein AL. 2008. Bile salts and glycine as cogerminants for Clostridium difficile spores. J Bacteriol 190:2505–2512. [PubMed][CrossRef]
249. Janoir C, Deneve C, Bouttier S, Barbut F, Hoys S, Caleechum L, Chapeton-Montes D, Pereira FC, Henriques AO, Collignon A, Monot M, Dupuy B. 2013. Adaptive strategies and pathogenesis of Clostridium difficile from in vivo transcriptomics. Infect Immun 81:3757–3769. [PubMed][CrossRef]
250. Antunes LC, Han J, Ferreira RB, Lolic P, Borchers CH, Finlay BB. 2011. Effect of antibiotic treatment on the intestinal metabolome. Antimicrob Agents Chemother 55:1494–1503. [PubMed][CrossRef]
251. Ng KM, Ferreyra JA, Higginbottom SK, Lynch JB, Kashyap PC, Gopinath S, Naidu N, Choudhury B, Weimer BC, Monack DM, Sonnenburg JL. 2013. Microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens. Nature 502:96–99. [PubMed][CrossRef]
252. Roux A, Todd DA, Velázquez JV, Cech NB, Sonenshein AL. 2014. CodY-mediated regulation of the Staphylococcus aureus Agr system integrates nutritional and population density signals. J Bacteriol 196:1184–1196. [PubMed][CrossRef]
253. Vitko NP, Spahich NA, Richardson AR. 2015. Glycolytic dependency of high-level nitric oxide resistance and virulence in Staphylococcus aureus. MBio. 6(2) :0045–15. doi: 10.1128/mBio.00045-15. [CrossRef]
Loading

Article metrics loading...

/content/journal/microbiolspec/10.1128/microbiolspec.MBP-0004-2014
2015-06-11
2019-09-23

Abstract:

Pathogenic bacteria must contend with immune systems that actively restrict the availability of nutrients and cofactors, and create a hostile growth environment. To deal with these hostile environments, pathogenic bacteria have evolved or acquired virulence determinants that aid in the acquisition of nutrients. This connection between pathogenesis and nutrition may explain why regulators of metabolism in nonpathogenic bacteria are used by pathogenic bacteria to regulate both metabolism and virulence. Such coordinated regulation is presumably advantageous because it conserves carbon and energy by aligning synthesis of virulence determinants with the nutritional environment. In Gram-positive bacterial pathogens, at least three metabolite-responsive global regulators, CcpA, CodY, and Rex, have been shown to coordinate the expression of metabolism and virulence genes. In this chapter, we discuss how environmental challenges alter metabolism, the regulators that respond to this altered metabolism, and how these regulators influence the host-pathogen interaction.

Highlighted Text: Show | Hide
Loading full text...

Full text loading...

/deliver/fulltext/microbiolspec/3/3/MBP-0004-2014.html?itemId=/content/journal/microbiolspec/10.1128/microbiolspec.MBP-0004-2014&mimeType=html&fmt=ahah

Figures

Regulating the Intersection of Metabolism and Pathogenesis in Gram-positive Bacteria
[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/microbiolspec/10.1128/microbiolspec.MBP-0004-2014-1,webId=/content/author/microbiolspec/10.1128/microbiolspec.MBP-0004-2014-1,properties={foaf_givenname=Anthony R., foaf_name=Anthony R. Richardson†, foaf_surname=Richardson†, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/microbiolspec/10.1128/microbiolspec.MBP-0004-2014-aff1]]}], com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/microbiolspec/10.1128/microbiolspec.MBP-0004-2014-2,webId=/content/author/microbiolspec/10.1128/microbiolspec.MBP-0004-2014-2,properties={foaf_givenname=Greg A., foaf_name=Greg A. Somerville†, foaf_surname=Somerville†, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/microbiolspec/10.1128/microbiolspec.MBP-0004-2014-aff2]]}], com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/microbiolspec/10.1128/microbiolspec.MBP-0004-2014-3,webId=/content/author/microbiolspec/10.1128/microbiolspec.MBP-0004-2014-3,properties={foaf_givenname=Abraham L., foaf_name=Abraham L. Sonenshein†, foaf_surname=Sonenshein†, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/microbiolspec/10.1128/microbiolspec.MBP-0004-2014-aff3]]}]]
Citation: Richardson† A, Somerville† G, Sonenshein† A. 2015. Regulating the intersection of metabolism and pathogenesis in gram-positive bacteria. microbiolspec 3(3): doi:10.1128/microbiolspec.MBP-0004-2014
/content/microbiolspec/10.1128/microbiolspec.MBP-0004-2014.fig1
FIGURE 1
A simplified view of bacterial physiology. The 13 biosynthetic intermediates discussed in this chapter are all derived from the three metabolic pathways of central metabolism. Alterations in the availability of these biosynthetic intermediates always affect virulence factor synthesis.
microbiolspec/3/3/MBP-0004-2014-fig1_thmb.gif
microbiolspec/3/3/MBP-0004-2014-fig1.gif
Image of FIGURE 1

Click to view

FIGURE 1

A simplified view of bacterial physiology. The 13 biosynthetic intermediates discussed in this chapter are all derived from the three metabolic pathways of central metabolism. Alterations in the availability of these biosynthetic intermediates always affect virulence factor synthesis.

Source: microbiolspec June 2015 vol. 3 no. 3 doi:10.1128/microbiolspec.MBP-0004-2014
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/microbiolspec/10.1128/microbiolspec.MBP-0004-2014.fig2
FIGURE 2
Synergistic repression of toxin synthesis by CodY and CcpA. Responding independently to different nutritional signals, CcpA and CodY both bind to the regulatory region of the gene, repressing production of the alternative sigma factor necessary for high-level toxin gene ( and ) expression.
microbiolspec/3/3/MBP-0004-2014-fig2_thmb.gif
microbiolspec/3/3/MBP-0004-2014-fig2.gif
Image of FIGURE 2

Click to view

FIGURE 2

Synergistic repression of toxin synthesis by CodY and CcpA. Responding independently to different nutritional signals, CcpA and CodY both bind to the regulatory region of the gene, repressing production of the alternative sigma factor necessary for high-level toxin gene ( and ) expression.

Source: microbiolspec June 2015 vol. 3 no. 3 doi:10.1128/microbiolspec.MBP-0004-2014
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/microbiolspec/10.1128/microbiolspec.MBP-0004-2014.fig3
FIGURE 3
Examples of oxidative and reductive metabolic pathways in . NADH produced during glycolysis and other oxidative pathways is converted back to NAD by a series of reductive pathways. The proline pathway, catalyzed by proline reductase, appears to be the favored pathway. When proline is available, the other pathways shown are repressed by Rex. Repression by Rex is relieved when the ratio of NAD to NADH indicates the need for increased regeneration of NAD. Additional repression by CcpA and CodY restricts maximal expression of the alternative pathways to conditions in which CcpA and CodY are relatively inactive. The bottom three pathways (effectively, acetyl-CoA to butyrate) are encoded in a single eight-gene operon.
microbiolspec/3/3/MBP-0004-2014-fig3_thmb.gif
microbiolspec/3/3/MBP-0004-2014-fig3.gif
Image of FIGURE 3

Click to view

FIGURE 3

Examples of oxidative and reductive metabolic pathways in . NADH produced during glycolysis and other oxidative pathways is converted back to NAD by a series of reductive pathways. The proline pathway, catalyzed by proline reductase, appears to be the favored pathway. When proline is available, the other pathways shown are repressed by Rex. Repression by Rex is relieved when the ratio of NAD to NADH indicates the need for increased regeneration of NAD. Additional repression by CcpA and CodY restricts maximal expression of the alternative pathways to conditions in which CcpA and CodY are relatively inactive. The bottom three pathways (effectively, acetyl-CoA to butyrate) are encoded in a single eight-gene operon.

Source: microbiolspec June 2015 vol. 3 no. 3 doi:10.1128/microbiolspec.MBP-0004-2014
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/microbiolspec/10.1128/microbiolspec.MBP-0004-2014.fig4
FIGURE 4
Differences in M1- versus M2-macrophage fueling reactions. In response to inflammatory stimuli, M1-macrophages upregulate a pathway known as aerobic glycolysis. This involves the import of glucose through GLUT-1 and its phosphorylation by Hexokinase-1 (HK-1). The resulting glucose-6-phosphate (G6P) can be shuttled through the pentose phosphate pathway (PPP) for NADPH generation, which fuels immune radical production, including nitric oxide (NO). At the same time, G6P is also oxidized to pyruvate (PYR) for ATP synthesis, and this PYR is primarily reduced to lactate (LAC) to conserve redox balance. Very little PYR enters the Krebs cycle as acetyl-CoA (Ac-CoA) due to the phosphorylation and inactivation of pyruvate dehydrogenase (PDH). Genes activated/repressed by HIF-1α are depicted as green/red. Upon stimulation with anti-inflammatory stimuli, M2-macrophages adopt an oxidative metabolism involving the import of free fatty acids and low-density lipoprotein (LDL)-associated lipids (fatty acids and LDL) by CD36. These fatty acids are linked to carnitine and shuttled to the mitochondria for β-oxidation, yielding ATP. In addition, some of the Ac-CoA is reused to synthesize new fatty acids. Rather than using tissue arginine for NO-production, these cells use the amino acid for proline and polyamine production, the former of which is critical for collagen synthesis. Features activated/repressed by PPAR-γ are depicted in green/red.
microbiolspec/3/3/MBP-0004-2014-fig4_thmb.gif
microbiolspec/3/3/MBP-0004-2014-fig4.gif
Image of FIGURE 4

Click to view

FIGURE 4

Differences in M1- versus M2-macrophage fueling reactions. In response to inflammatory stimuli, M1-macrophages upregulate a pathway known as aerobic glycolysis. This involves the import of glucose through GLUT-1 and its phosphorylation by Hexokinase-1 (HK-1). The resulting glucose-6-phosphate (G6P) can be shuttled through the pentose phosphate pathway (PPP) for NADPH generation, which fuels immune radical production, including nitric oxide (NO). At the same time, G6P is also oxidized to pyruvate (PYR) for ATP synthesis, and this PYR is primarily reduced to lactate (LAC) to conserve redox balance. Very little PYR enters the Krebs cycle as acetyl-CoA (Ac-CoA) due to the phosphorylation and inactivation of pyruvate dehydrogenase (PDH). Genes activated/repressed by HIF-1α are depicted as green/red. Upon stimulation with anti-inflammatory stimuli, M2-macrophages adopt an oxidative metabolism involving the import of free fatty acids and low-density lipoprotein (LDL)-associated lipids (fatty acids and LDL) by CD36. These fatty acids are linked to carnitine and shuttled to the mitochondria for β-oxidation, yielding ATP. In addition, some of the Ac-CoA is reused to synthesize new fatty acids. Rather than using tissue arginine for NO-production, these cells use the amino acid for proline and polyamine production, the former of which is critical for collagen synthesis. Features activated/repressed by PPAR-γ are depicted in green/red.

Source: microbiolspec June 2015 vol. 3 no. 3 doi:10.1128/microbiolspec.MBP-0004-2014
Permissions and Reprints Request Permissions
Download as Powerpoint

Supplemental Material

No supplementary material available for this content.

Back to top
This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error