1932

Abstract

Under stressful growth conditions and nutrient starvation, bacteria adapt by synthesizing signaling molecules that profoundly reprogram cellular physiology. At the onset of this process, called the stringent response, members of the RelA/SpoT homolog (RSH) protein superfamily are activated by specific stress stimuli to produce several hyperphosphorylated forms of guanine nucleotides, commonly referred to as (p)ppGpp. Some bifunctional RSH enzymes also harbor domains that allow for degradation of (p)ppGpp by hydrolysis. (p)ppGpp synthesis or hydrolysis may further be executed by single-domain alarmone synthetases or hydrolases, respectively. The downstream effects of (p)ppGpp rely mainly on direct interaction with specific intracellular effectors, which are widely used throughout most cellular processes. The growing number of identified (p)ppGpp targets allows us to deduce both common features of and differences between gram-negative and gram-positive bacteria. In this review, we give an overview of (p)ppGpp metabolism with a focus on the functional and structural aspects of the enzymes involved and discuss recent findings on alarmone-regulated cellular effectors.

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2021-10-08
2024-06-22
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Literature Cited

  1. 1. 
    Abduljalil JM. 2018. Bacterial riboswitches and RNA thermometers: nature and contributions to pathogenesis. Noncod. RNA Res. 3:54–63
    [Google Scholar]
  2. 2. 
    Anderson BW, Hao A, Satyshur KA, Keck JL, Wang JD. 2020. Molecular mechanism of regulation of the purine salvage enzyme XPRT by the alarmones pppGpp, ppGpp, and pGpp. J. Mol. Biol. 432:4108–26
    [Google Scholar]
  3. 3. 
    Anderson BW, Liu K, Wolak C, Dubiel K, She F et al. 2019. Evolution of (p)ppGpp-HPRT regulation through diversification of an allosteric oligomeric interaction. eLife8:e47534
    [Google Scholar]
  4. 4. 
    Arai K-I, Kawakita M, Kaziro Y. 1972. Studies on polypeptide elongation factors from Escherichia coli: II. Purification of factors Tu-Guanosine diphosphate, Ts, and Tu-Ts, and crystallization of Tu-Guanosine diphosphate and Tu-Ts. J. Biol. Chem. 247:7029–37
    [Google Scholar]
  5. 5. 
    Arenz S, Abdelshahid M, Sohmen D, Payoe R, Starosta AL et al. 2016. The stringent factor RelA adopts an open conformation on the ribosome to stimulate ppGpp synthesis. Nucleic Acids Res 44:6471–81
    [Google Scholar]
  6. 6. 
    Atkinson GC, Tenson T, Hauryliuk V. 2011. The RelA/SpoT homolog (RSH) superfamily: distribution and functional evolution of ppGpp synthetases and hydrolases across the tree of life. PLOS ONE 6:e23479
    [Google Scholar]
  7. 7. 
    Avarbock A, Avarbock D, Teh JS, Buckstein M, Wang ZM, Rubin H. 2005. Functional regulation of the opposing (p)ppGpp synthetase/hydrolase activities of RelMtb from Mycobacterium tuberculosis. Biochemistry 44:9913–23
    [Google Scholar]
  8. 8. 
    Bakkouri ME, Gutsche I, Kanjee U, Zhao B, Yu M et al. 2010. Structure of RacA MoxR AAA+ protein reveals the design principles of a molecular cage modulating the inducible lysine decarboxylase activity. PNAS 107:22499–504
    [Google Scholar]
  9. 9. 
    Bange G, Bedrunka P. 2020. Physiology of guanosine-based second messenger signaling in Bacillus subtilis. Biol. Chem. 401:1307–22
    [Google Scholar]
  10. 10. 
    Basu A, Yap M-NF. 2017. Disassembly of the Staphylococcus aureus hibernating 100S ribosome by an evolutionarily conserved GTPase. PNAS 114:E8165–73
    [Google Scholar]
  11. 11. 
    Battesti A, Bouveret E. 2006. Acyl carrier protein/SpoT interaction, the switch linking SpoT-dependent stress response to fatty acid metabolism. Mol. Microbiol. 62:1048–63
    [Google Scholar]
  12. 12. 
    Battesti A, Bouveret E. 2009. Bacteria possessing two RelA/SpoT-like proteins have evolved a specific stringent response involving the acyl carrier protein-SpoT interaction. J. Bacteriol. 191:616–24
    [Google Scholar]
  13. 13. 
    Beckert B, Abdelshahid M, Schäfer H, Steinchen W, Arenz S et al. 2017. Structure of the Bacillus subtilis hibernating 100S ribosome reveals the basis for 70S dimerization. EMBO J 36:2061–72
    [Google Scholar]
  14. 14. 
    Beljantseva J, Kudrin P, Andresen L, Shingler V, Atkinson GC et al. 2017. Negative allosteric regulation of Enterococcus faecalis small alarmone synthetase RelQ by single-stranded RNA. PNAS 114:3726–31
    [Google Scholar]
  15. 15. 
    Bennison DJ, Irving SE, Corrigan RM. 2019. The impact of the stringent response on TRAFAC GTPases and prokaryotic ribosome assembly. Cells 8:1313
    [Google Scholar]
  16. 16. 
    Berens C, Groher F, Suess B. 2015. RNA aptamers as genetic control devices: the potential of riboswitches as synthetic elements for regulating gene expression. Biotechnol. J. 10:246–57
    [Google Scholar]
  17. 17. 
    Bittner AN, Kriel A, Wang JD. 2014. Lowering GTP level increases survival of amino acid starvation but slows growth rate for Bacillus subtilis cells lacking (p)ppGpp. J. Bacteriol. 196:2067–76
    [Google Scholar]
  18. 18. 
    Blumenthal T, Landers TA, Weber K. 1972. Bacteriophage Qβ replicase contains the protein biosynthesis elongation factors EF Tu and EF Ts. PNAS 69:1313–17
    [Google Scholar]
  19. 19. 
    Brown A, Fernández IS, Gordiyenko Y, Ramakrishnan V. 2016. Ribosome-dependent activation of stringent control. Nature 534:277–80
    [Google Scholar]
  20. 20. 
    Buglino J, Shen V, Hakimian P, Lima CD. 2002. Structural and biochemical analysis of the Obg GTP binding protein. Structure 10:1581–92
    [Google Scholar]
  21. 21. 
    Caban K, Pavlov M, Ehrenberg M, Gonzalez RL. 2017. A conformational switch in initiation factor 2 controls the fidelity of translation initiation in bacteria. Nat. Commun. 8:1475
    [Google Scholar]
  22. 22. 
    Caserta E, Tomšic J, Spurio R, La Teana A, Pon CL, Gualerzi CO 2006. Translation initiation factor IF2 interacts with the 30 S ribosomal subunit via two separate binding sites. J. Mol. Biol. 362:787–99
    [Google Scholar]
  23. 23. 
    Cashel M, Gentry DR, Hernandez VJ, Vinella D 1996. The stringent response. Escherichia coli and Salmonella: Cellular and Molecular Biology FC Neidhardt, R Curtiss III, JL Ingraham, ECC Lin, KB Low, et al. 1458–95 Washington, DC: ASM, 2nd ed..
    [Google Scholar]
  24. 24. 
    Cashel M, Gallant J. 1969. Two compounds implicated in the function of the RC gene of Escherichia coli. Nature 221:838–41
    [Google Scholar]
  25. 25. 
    Chen C, Cui X, Beausang JF, Zhang H, Farrell I et al. 2016. Elongation factor G initiates translocation through a power stroke. PNAS 113:7515–20
    [Google Scholar]
  26. 26. 
    Chen Y, Kaji A, Kaji H, Cooperman BS. 2017. The kinetic mechanism of bacterial ribosome recycling. Nucleic Acids Res 45:10168–77
    [Google Scholar]
  27. 27. 
    Coatham ML, Brandon HE, Fischer JJ, Schümmer T, Wieden H-J. 2016. The conserved GTPase HflX is a ribosome splitting factor that binds to the E-site of the bacterial ribosome. Nucleic Acids Res 44:1952–61
    [Google Scholar]
  28. 28. 
    Corrigan RM, Bellows LE, Wood A, Gründling A. 2016. ppGpp negatively impacts ribosome assembly affecting growth and antimicrobial tolerance in Gram-positive bacteria. PNAS 113:E1710–19
    [Google Scholar]
  29. 29. 
    Cuthbert BJ, Ross W, Rohlfing AE, Dove SL, Gourse RL et al. 2017. Dissection of the molecular circuitry controlling virulence in Francisella tularensis. Genes Dev 31:1549–60
    [Google Scholar]
  30. 30. 
    Dalebroux ZD, Swanson MS. 2012. ppGpp: magic beyond RNA polymerase. Nat. Rev. Microbiol. 10:203–12
    [Google Scholar]
  31. 31. 
    Das B, Pal RR, Bag S, Bhadra RK. 2009. Stringent response in Vibrio cholerae: genetic analysis of spoT gene function and identification of a novel (p)ppGpp synthetase gene. Mol. Microbiol. 72:380–98
    [Google Scholar]
  32. 32. 
    Dasgupta S, Basu P, Pal RR, Bag S, Bhadra RK. 2014. Genetic and mutational characterization of the small alarmone synthetase gene relV of Vibrio cholerae. Microbiology 160:1855–66
    [Google Scholar]
  33. 33. 
    Dedrick RM, Jacobs-Sera D, Bustamante CA, Garlena RA, Mavrich TN et al. 2017. Prophage-mediated defence against viral attack and viral counter-defence. Nat. Microbiol. 2:16251
    [Google Scholar]
  34. 34. 
    Diez S, Ryu J, Caban K, Gonzalez RL Jr., Dworkin J. 2020. The alarmones (p)ppGpp directly regulate translation initiation during entry into quiescence. PNAS 117:15565–72
    [Google Scholar]
  35. 35. 
    Faxén M, Isaksson LA. 1994. Functional interactions between translation, transcription and ppGpp in growing Escherichia coli. Biochim. Biophys. Acta Gene Struct. Expression 1219:425–34
    [Google Scholar]
  36. 36. 
    Feng B, Mandava CS, Guo Q, Wang J, Cao W et al. 2014. Structural and functional insights into the mode of action of a universally conserved Obg GTPase. PLOS Biol 12:e1001866
    [Google Scholar]
  37. 37. 
    Fung DK, Yang J, Stevenson DM, Amador-Noguez D, Wang JD. 2020. Small alarmone synthetase SasA expression leads to concomitant accumulation of pGpp, ppApp, and AppppA in Bacillus subtilis. Front. Microbiol. 11:2083
    [Google Scholar]
  38. 38. 
    Gaca AO, Kudrin P, Colomer-Winter C, Beljantseva J, Liu K et al. 2015. From (p)ppGpp to (pp)pGpp: characterization of regulatory effects of pGpp synthesized by the small alarmone synthetase of Enterococcus faecalis. J. Bacteriol. 197:2908–19
    [Google Scholar]
  39. 39. 
    Gao A, Vasilyev N, Kaushik A, Duan W, Serganov A. 2020. Principles of RNA and nucleotide discrimination by the RNA processing enzyme RppH. Nucleic Acids Res 48:3776–88
    [Google Scholar]
  40. 40. 
    Gao N, Zavialov AV, Li W, Sengupta J, Valle M et al. 2005. Mechanism for the disassembly of the posttermination complex inferred from cryo-EM studies. Mol. Cell 18:663–74
    [Google Scholar]
  41. 41. 
    Geiger T, Kastle B, Gratani FL, Goerke C, Wolz C. 2014. Two small (p)ppGpp synthases in Staphylococcus aureus mediate tolerance against cell envelope stress conditions. J. Bacteriol. 196:894–902
    [Google Scholar]
  42. 42. 
    Gentry DR, Cashel M. 1996. Mutational analysis of the Escherichia coli spoT gene identifies distinct but overlapping regions involved in ppGpp synthesis and degradation. Mol. Microbiol. 19:1373–84
    [Google Scholar]
  43. 43. 
    Gohara DW, Yap M-NF. 2018. Survival of the drowsiest: the hibernating 100S ribosome in bacterial stress management. Curr. Genet. 64:753–60
    [Google Scholar]
  44. 44. 
    Goyal A, Belardinelli R, Maracci C, Milón P, Rodnina MV. 2015. Directional transition from initiation to elongation in bacterial translation. Nucleic Acids Res 43:10700–12
    [Google Scholar]
  45. 45. 
    Gualerzi CO, Pon CL. 2015. Initiation of mRNA translation in bacteria: structural and dynamic aspects. Cell. Mol. Life Sci. 72:4341–67
    [Google Scholar]
  46. 46. 
    Hamel E, Cashel M. 1973. Role of guanine nucleotides in protein synthesis: elongation factor G and guanosine 5′-triphosphate, 3′-diphosphate. PNAS 70:3250–54
    [Google Scholar]
  47. 47. 
    Hauryliuk V, Atkinson GC, Murakami KS, Tenson T, Gerdes K. 2015. Recent functional insights into the role of (p)ppGpp in bacterial physiology. Nat. Rev. Microbiol. 13:298–309
    [Google Scholar]
  48. 48. 
    Hogg T, Mechold U, Malke H, Cashel M, Hilgenfeld R. 2004. Conformational antagonism between opposing active sites in a bifunctional RelA/SpoT homolog modulates (p)ppGpp metabolism during the stringent response [corrected]. Cell 117:57–68 Erratum 2004. Cell 117:415
    [Google Scholar]
  49. 49. 
    Holtkamp W, Cunha CE, Peske F, Konevega AL, Wintermeyer W, Rodnina MV. 2014. GTP hydrolysis by EF-G synchronizes tRNA movement on small and large ribosomal subunits. EMBO J 33:1073–85
    [Google Scholar]
  50. 50. 
    Ito D, Kato T, Maruta T, Tamoi M, Yoshimura K, Shigeoka S. 2012. Enzymatic and molecular characterization of Arabidopsis ppGpp pyrophosphohydrolase, AtNUDX26. Biosci. Biotechnol. Biochem. 76:2236–41
    [Google Scholar]
  51. 51. 
    Izutsu K, Wada C, Komine Y, Sako T, Ueguchi C et al. 2001. Escherichia coli ribosome-associated protein SRA, whose copy number increases during stationary phase. J. Bacteriol. 183:2765–73
    [Google Scholar]
  52. 52. 
    Jiang M, Sullivan SM, Wout PK, Maddock JR. 2007. G-protein control of the ribosome-associated stress response protein SpoT. J. Bacteriol. 189:6140–47
    [Google Scholar]
  53. 53. 
    Kanjee U, Gutsche I, Alexopoulos E, Zhao B, El Bakkouri M et al. 2011. Linkage between the bacterial acid stress and stringent responses: the structure of the inducible lysine decarboxylase. EMBO J 30:931–44
    [Google Scholar]
  54. 54. 
    Kanjee U, Gutsche I, Ramachandran S, Houry WA. 2011. The enzymatic activities of the Escherichia coli basic aliphatic amino acid decarboxylases exhibit a pH zone of inhibition. Biochemistry 50:9388–98
    [Google Scholar]
  55. 55. 
    Kato T, Yoshida H, Miyata T, Maki Y, Wada A, Namba K. 2010. Structure of the 100S ribosome in the hibernation stage revealed by electron cryomicroscopy. Structure 18:719–24
    [Google Scholar]
  56. 56. 
    Kiel MC, Kaji H, Kaji A. 2007. Ribosome recycling: an essential process of protein synthesis. Biochem. Mol. Biol. Educ. 35:40–44
    [Google Scholar]
  57. 57. 
    Kihira K, Shimizu Y, Shomura Y, Shibata N, Kitamura M et al. 2012. Crystal structure analysis of the translation factor RF3 (release factor 3). FEBS Lett 586:3705–9
    [Google Scholar]
  58. 58. 
    Kriel A, Brinsmade SR, Tse JL, Tehranchi AK, Bittner AN et al. 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
    [Google Scholar]
  59. 59. 
    Krishnan S, Petchiappan A, Singh A, Bhatt A, Chatterji D. 2016. R-loop induced stress response by second (p)ppGpp synthetase in Mycobacterium smegmatis: functional and domain interdependence. Mol. Microbiol. 102:168–82
    [Google Scholar]
  60. 60. 
    Kristensen O, Laurberg M, Liljas A, Kastrup JS, Gajhede M. 2004. Structural characterization of the stringent response related exopolyphosphatase/guanosine pentaphosphate phosphohydrolase protein family. Biochemistry 43:8894–900
    [Google Scholar]
  61. 61. 
    Kristensen O, Ross B, Gajhede M. 2008. Structure of the PPX/GPPA phosphatase from Aquifex aeolicus in complex with the alarmone ppGpp. J. Mol. Biol. 375:1469–76
    [Google Scholar]
  62. 62. 
    Kudrin P, Dzhygyr I, Ishiguro K, Beljantseva J, Maksimova E et al. 2018. The ribosomal A-site finger is crucial for binding and activation of the stringent factor RelA. Nucleic Acids Res 46:1973–83
    [Google Scholar]
  63. 63. 
    Kushwaha GS, Bange G, Bhavesh NS. 2019. Interaction studies on bacterial stringent response protein RelA with uncharged tRNA provide evidence for its prerequisite complex for ribosome binding. Curr. Genet. 65:1173–84
    [Google Scholar]
  64. 64. 
    Lecompte O, Ripp R, Thierry JC, Moras D, Poch O. 2002. Comparative analysis of ribosomal proteins in complete genomes: an example of reductive evolution at the domain scale. Nucleic Acids Res 30:5382–90
    [Google Scholar]
  65. 65. 
    Lee JW, Park YH, Seok YJ. 2018. Rsd balances (p)ppGpp level by stimulating the hydrolase activity of SpoT during carbon source downshift in Escherichia coli. PNAS 115:E6845–54
    [Google Scholar]
  66. 66. 
    Legault L, Jeantet C, Gros F. 1972. Inhibition of in vitro protein synthesis by ppGpp. FEBS Lett 27:71–75
    [Google Scholar]
  67. 67. 
    Lemos JA, Lin VK, Nascimento MM, Abranches J, Burne RA. 2007. Three gene products govern (p)ppGpp production by Streptococcus mutans. Mol. Microbiol. 65:1568–81
    [Google Scholar]
  68. 68. 
    Liu K, Bittner AN, Wang JD. 2015. Diversity in (p)ppGpp metabolism and effectors. Curr. Opin. Microbiol. 24:72–79
    [Google Scholar]
  69. 69. 
    Liu K, Myers AR, Pisithkul T, Claas KR, Satyshur KA et al. 2015. Molecular mechanism and evolution of guanylate kinase regulation by (p)ppGpp. Mol. Cell 57:735–49
    [Google Scholar]
  70. 70. 
    Loveland AB, Bah E, Madireddy R, Zhang Y, Brilot AF et al. 2016. Ribosome⋅RelA structures reveal the mechanism of stringent response activation. eLife 5:e17029
    [Google Scholar]
  71. 71. 
    Manav MC, Beljantseva J, Bojer MS, Tenson T, Ingmer H et al. 2018. Structural basis for (p)ppGpp synthesis by the Staphylococcus aureus small alarmone synthetase RelP. J. Biol. Chem. 293:3254–64
    [Google Scholar]
  72. 72. 
    Matzov D, Bashan A, Yap MNF, Yonath A. 2019. Stress response as implemented by hibernating ribosomes: a structural overview. FEBS J 286:3558–65
    [Google Scholar]
  73. 73. 
    McCown PJ, Corbino KA, Stav S, Sherlock ME, Breaker RR. 2017. Riboswitch diversity and distribution. RNA 23:995–1011
    [Google Scholar]
  74. 74. 
    Miller DL. 1972. Elongation factors EF Tu and EF G interact at related sites on ribosomes. PNAS 69:752–55
    [Google Scholar]
  75. 75. 
    Miller DL, Cashel M, Weissbach H. 1973. The interaction of guanosine 5′-diphosphate, 2′(3′)-diphosphate with the bacterial elongation factor Tu. Arch. Biochem. Biophys. 154:675–82
    [Google Scholar]
  76. 76. 
    Milon P, Carotti M, Konevega AL, Wintermeyer W, Rodnina MV, Gualerzi CO. 2010. The ribosome-bound initiation factor 2 recruits initiator tRNA to the 30S initiation complex. EMBO Rep 11:312–16
    [Google Scholar]
  77. 77. 
    Milón P, Maracci C, Filonava L, Gualerzi CO, Rodnina MV. 2012. Real-time assembly landscape of bacterial 30S translation initiation complex. Nat. Struct. Mol. Biol. 19:609
    [Google Scholar]
  78. 78. 
    Milón P, Rodnina MV. 2012. Kinetic control of translation initiation in bacteria. Crit. Rev. Biochem. Mol. Biol. 47:334–48
    [Google Scholar]
  79. 79. 
    Milon P, Tischenko E, Tomšic J, Caserta E, Folkers G et al. 2006. The nucleotide-binding site of bacterial translation initiation factor 2 (IF2) as a metabolic sensor. PNAS 103:13962–67
    [Google Scholar]
  80. 80. 
    Mitkevich VA, Ermakov A, Kulikova AA, Tankov S, Shyp V et al. 2010. Thermodynamic characterization of ppGpp binding to EF-G or IF2 and of initiator tRNA binding to free IF2 in the presence of GDP, GTP, or ppGpp. J. Mol. Biol. 402:838–46
    [Google Scholar]
  81. 81. 
    Molodtsov V, Sineva E, Zhang L, Huang X, Cashel M et al. 2018. Allosteric effector ppGpp potentiates the inhibition of transcript initiation by DksA. Mol. Cell 69:828–39.e5
    [Google Scholar]
  82. 82. 
    Muchmore CR, Krahn JM, Kim JH, Zalkin H, Smith JL. 1998. Crystal structure of glutamine phosphoribosylpyrophosphate amidotransferase from Escherichia coli. Protein Sci 1:39–51
    [Google Scholar]
  83. 83. 
    Nanamiya H, Kasai K, Nozawa A, Yun CS, Narisawa T et al. 2008. Identification and functional analysis of novel (p)ppGpp synthetase genes in Bacillus subtilis. Mol. Microbiol. 67:291–304
    [Google Scholar]
  84. 84. 
    Nelson JW, Atilho RM, Sherlock ME, Stockbridge RB, Breaker RR. 2017. Metabolism of free guanidine in bacteria is regulated by a widespread riboswitch class. Mol. Cell 65:220–230
    [Google Scholar]
  85. 85. 
    Nierhaus KH, Lafontaine DL. 2004. Ribosome assembly. In Protein Synthesis and Ribosome Structure: Translating the Genome.
    [Google Scholar]
  86. 86. 
    Nissen P, Kjeldgaard M, Thirup S, Clark B, Nyborg J 1996. The ternary complex of aminoacylated tRNA and EF-Tu-GTP: recognition of a bond and a fold. Biochimie 78:921–33
    [Google Scholar]
  87. 87. 
    Ogilvie A, Wiebauer K, Kersten W. 1975. Stringent control of ribonucleic acid synthesis in Bacillus subtilis treated with granaticin. Biochem. J. 152:517–22
    [Google Scholar]
  88. 88. 
    Oh YT, Lee KM, Bari W, Raskin DM, Yoon SS. 2015. (p)ppGpp, a small nucleotide regulator, directs the metabolic fate of glucose in Vibrio cholerae. J. Biol. Chem. 290:13178–90
    [Google Scholar]
  89. 89. 
    Ooga T, Ohashi Y, Kuramitsu S, Koyama Y, Tomita M et al. 2009. Degradation of ppGpp by Nudix pyrophosphatase modulates the transition of growth phase in the bacterium Thermus thermophilus. J. Biol. Chem. 284:15549–56
    [Google Scholar]
  90. 90. 
    Ortiz JO, Brandt F, Matias VR, Sennels L, Rappsilber J et al. 2010. Structure of hibernating ribosomes studied by cryoelectron tomography in vitro and in situ. J. Cell Biol. 190:613–21
    [Google Scholar]
  91. 91. 
    Park YH, Lee CR, Choe M, Seok YJ. 2013. HPr antagonizes the anti-σ70 activity of Rsd in Escherichia coli. PNAS 110:21142–47
    [Google Scholar]
  92. 92. 
    Pausch P, Abdelshahid M, Steinchen W, Schafer H, Gratani FL et al. 2020. Structural basis for regulation of the opposing (p)ppGpp synthetase and hydrolase within the stringent response orchestrator Rel. Cell Rep 32:108157
    [Google Scholar]
  93. 93. 
    Pausch P, Steinchen W, Wieland M, Klaus T, Freibert SA et al. 2018. Structural basis for (p)ppGpp-mediated inhibition of the GTPase RbgA. J. Biol. Chem. 293:19699–709
    [Google Scholar]
  94. 94. 
    Pech M, Karim Z, Yamamoto H, Kitakawa M, Qin Y, Nierhaus KH. 2011. Elongation factor 4 (EF4/LepA) accelerates protein synthesis at increased Mg2+ concentrations. PNAS 108:3199–203
    [Google Scholar]
  95. 95. 
    Peselis A, Serganov A. 2018. ykkC riboswitches employ an add-on helix to adjust specificity for polyanionic ligands. Nat. Chem. Biol. 14:887–94
    [Google Scholar]
  96. 96. 
    Petchiappan A, Naik SY, Chatterji D. 2020. RelZ-mediated stress response in Mycobacterium smegmatis: pGpp synthesis and its regulation. J. Bacteriol. 202:e00444-19
    [Google Scholar]
  97. 97. 
    Prossliner T, Skovbo Winther K, Sørensen MA, Gerdes K 2018. Ribosome hibernation. Annu. Rev. Genet. 52:321–48
    [Google Scholar]
  98. 98. 
    Raskin DM, Judson N, Mekalanos JJ. 2007. Regulation of the stringent response is the essential function of the conserved bacterial G protein CgtA in Vibrio cholerae. PNAS 104:4636–41
    [Google Scholar]
  99. 99. 
    Rhaese HJ, Dichtelmuller H, Grade R. 1975. Studies on the control of development: accumulation of guanosine tetraphosphate and pentaphosphate in response to inhibition of protein synthesis in Bacillus subtilis. Eur. J. Biochem. 56:385–92
    [Google Scholar]
  100. 100. 
    Rodnina MV. 2018. Translation in prokaryotes. Cold Spring Harb. Perspect. Biol. 10:a032664
    [Google Scholar]
  101. 101. 
    Rodnina MV, Beringer M, Wintermeyer W. 2007. How ribosomes make peptide bonds. Trends Biochem. Sci. 32:20–26
    [Google Scholar]
  102. 102. 
    Rodnina MV, Wintermeyer W. 1995. GTP consumption of elongation factor Tu during translation of heteropolymeric mRNAs. PNAS 92:1945–49
    [Google Scholar]
  103. 103. 
    Rojas A-M, Ehrenberg M, Andersson SG, Kurland C. 1984. ppGpp inhibition of elongation factors Tu, G and Ts during polypeptide synthesis. Mol. Gen. Genet. 197:36–45
    [Google Scholar]
  104. 104. 
    Ronneau S, Hallez R. 2019. Make and break the alarmone: regulation of (p)ppGpp synthetase/hydrolase enzymes in bacteria. FEMS Microbiol. Rev. 43:389–400
    [Google Scholar]
  105. 105. 
    Ross W, Sanchez-Vazquez P, Chen AY, Lee JH, Burgos HL, Gourse RL. 2016. ppGpp binding to a site at the RNAP-DksA interface accounts for its dramatic effects on transcription initiation during the stringent response. Mol. Cell 62:811–23
    [Google Scholar]
  106. 106. 
    Roth A, Breaker RR. 2009. The structural and functional diversity of metabolite-binding riboswitches. Annu. Rev. Biochem. 78:305–34
    [Google Scholar]
  107. 107. 
    Serganov A, Nudler E. 2013. A decade of riboswitches. Cell 152:17–24
    [Google Scholar]
  108. 108. 
    Serganov A, Yuan YR, Pikovskaya O, Polonskaia A, Malinina L et al. 2004. Structural basis for discriminative regulation of gene expression by adenine- and guanine-sensing mRNAs. Chem. Biol. 11:1729–41
    [Google Scholar]
  109. 109. 
    Setlow P. 1974. Percent charging of transfer ribonucleic acid and levels of ppGpp and pppGpp in dormant and germinated spores of Bacillus megaterium. J. Bacteriol. 118:1067–74
    [Google Scholar]
  110. 110. 
    Sherlock ME, Breaker RR. 2020. Former orphan riboswitches reveal unexplored areas of bacterial metabolism, signaling, and gene control processes. RNA 26:675–93
    [Google Scholar]
  111. 111. 
    Sherlock ME, Sadeeshkumar H, Breaker RR. 2019. Variant bacterial riboswitches associated with nucleotide hydrolase genes sense nucleoside diphosphates. Biochemistry 58:401–10
    [Google Scholar]
  112. 112. 
    Sherlock ME, Sudarsan N, Breaker RR. 2018. Riboswitches for the alarmone ppGpp expand the collection of RNA-based signaling systems. PNAS 115:6052–57
    [Google Scholar]
  113. 113. 
    Sherlock ME, Sudarsan N, Stav S, Breaker RR. 2018. Tandem riboswitches form a natural Boolean logic gate to control purine metabolism in bacteria. eLife 7:e33908
    [Google Scholar]
  114. 114. 
    Shyp V, Tankov S, Ermakov A, Kudrin P, English BP et al. 2012. Positive allosteric feedback regulation of the stringent response enzyme RelA by its product. EMBO Rep 13:835–39
    [Google Scholar]
  115. 115. 
    Singal B, Balakrishna AM, Nartey W, Manimekalai MSS, Jeyakanthan J, Gruber G. 2017. Crystallographic and solution structure of the N-terminal domain of the Rel protein from Mycobacterium tuberculosis. FEBS Lett 591:2323–37
    [Google Scholar]
  116. 116. 
    Sprinzl M, Richter D. 1976. Free 3′-OH group of the terminal adenosine of the tRNA molecule is essential for the synthesis in vitro of guanosine tetraphosphate and pentaphosphate in a ribosomal system from Escherichia coli. Eur. J. Biochem. 71:171–76
    [Google Scholar]
  117. 117. 
    Steinchen W, Bange G. 2016. The magic dance of the alarmones (p)ppGpp. Mol. Microbiol. 101:531–44
    [Google Scholar]
  118. 118. 
    Steinchen W, Schuhmacher JS, Altegoer F, Fage CD, Srinivasan V et al. 2015. Catalytic mechanism and allosteric regulation of an oligomeric (p)ppGpp synthetase by an alarmone. PNAS 112:13348–53
    [Google Scholar]
  119. 119. 
    Steinchen W, Vogt MS, Altegoer F, Giammarinaro PI, Horvatek P et al. 2018. Structural and mechanistic divergence of the small (p)ppGpp synthetases RelP and RelQ. Sci. Rep. 8: 2195.
    [Google Scholar]
  120. 120. 
    Steinchen W, Zegarra V, Bange G. 2020. (p)ppGpp: magic modulators of bacterial physiology and metabolism. Front. Microbiol. 11: 2072.
    [Google Scholar]
  121. 121. 
    Sun D, Lee G, Lee JH, Kim HY, Rhee HW et al. 2010. A metazoan ortholog of SpoT hydrolyzes ppGpp and functions in starvation responses. Nat. Struct. Mol. Biol. 17:1188–94
    [Google Scholar]
  122. 122. 
    Sy J, Lipmann F. 1973. Identification of the synthesis of guanosine tetraphosphate (MS I) as insertion of a pyrophosphoryl group into the 3′-position in guanosine 5′-diphosphate. PNAS 70:306–9
    [Google Scholar]
  123. 123. 
    Tagami K, Nanamiya H, Kazo Y, Maehashi M, Suzuki S et al. 2012. Expression of a small (p) ppGpp synthetase, YwaC, in the (p) ppGpp0 mutant of Bacillus subtilis triggers YvyD‐dependent dimerization of ribosome. Microbiol. Open 1:115–34
    [Google Scholar]
  124. 124. 
    Tamman H, Van Nerom K, Takada H, Vandenberk N, Scholl D et al. 2020. A nucleotide-switch mechanism mediates opposing catalytic activities of Rel enzymes. Nat. Chem. Biol. 16:834–40
    [Google Scholar]
  125. 125. 
    Vinogradova DS, Zegarra V, Maksimova E, Nakamoto JA, Kasatsky P et al. 2020. How the initiating ribosome copes with ppGpp to translate mRNAs. PLOS Biol 18:e3000593
    [Google Scholar]
  126. 126. 
    Wada A. 1998. Growth phase coupled modulation of Escherichia coli ribosomes. Genes Cells 3:203–8
    [Google Scholar]
  127. 127. 
    Wada A, Yamazaki Y, Fujita N, Ishihama A. 1990. Structure and probable genetic location of a “ribosome modulation factor” associated with 100S ribosomes in stationary-phase Escherichia coli cells. PNAS 87:2657–61
    [Google Scholar]
  128. 128. 
    Wang B, Dai P, Ding D, Del Rosario A, Grant RA et al. 2019. Affinity-based capture and identification of protein effectors of the growth regulator ppGpp. Nat. Chem. Biol. 15:141–50
    [Google Scholar]
  129. 129. 
    Wang B, Grant RA, Laub MT. 2020. ppGpp coordinates nucleotide and amino-acid synthesis in E. coli during starvation. Mol. Cell 180:29–42.e10
    [Google Scholar]
  130. 130. 
    Wendrich TM, Blaha G, Wilson DN, Marahiel MA, Nierhaus KH. 2002. Dissection of the mechanism for the stringent factor RelA. Mol. Cell 10:779–88
    [Google Scholar]
  131. 131. 
    Winther KS, Roghanian M, Gerdes K. 2018. Activation of the stringent response by loading of RelA-tRNA complexes at the ribosomal A-site. Mol. Cell 70:95–105.e4
    [Google Scholar]
  132. 132. 
    Yang J, Anderson BW, Turdiev A, Turdiev H, Stevenson DM et al. 2020. The nucleotide pGpp acts as a third alarmone in Bacillus, with functions distinct from those of (p)ppGpp. Nat. Commun. 11: 5388.
    [Google Scholar]
  133. 133. 
    Yoshida H, Maki Y, Kato H, Fujisawa H, Izutsu K et al. 2002. The ribosome modulation factor (RMF) binding site on the 100S ribosome of Escherichia coli. J. Biochem. 132:983–89
    [Google Scholar]
  134. 134. 
    Zhang Y, Mandava CS, Cao W, Li X, Zhang D et al. 2015. HflX is a ribosome-splitting factor rescuing stalled ribosomes under stress conditions. Nat. Struct. Mol. Biol. 22:906
    [Google Scholar]
  135. 135. 
    Zhang Y, Zborníková E, Rejman D, Gerdes K. 2018. Novel (p) ppGpp binding and metabolizing proteins of Escherichia coli. mBio 9:e02188-17
    [Google Scholar]
  136. 136. 
    Zhang YE, Baerentsen RL, Fuhrer T, Sauer U, Gerdes K, Brodersen DE. 2019. (p)ppGpp regulates a bacterial nucleosidase by an allosteric two-domain switch. Mol. Cell 74:1239–49.e4
    [Google Scholar]
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