Make and break the alarmone: regulation of (p)ppGpp synthetase/hydrolase enzymes in bacteria

Abranches, 2009, The molecular alarmone (p)ppGpp mediates stress responses, vancomycin tolerance, and virulence in Enterococcus faecalis, J Bacteriol, 191, 2248, 10.1128/JB.01726-08

Agirrezabala, 2013, The ribosome triggers the stringent response by RelA via a highly distorted tRNA, EMBO Rep, 14, 811, 10.1038/embor.2013.106

Al-Rabiee, 1996, The mechanism of velocity modulated allosteric regulation in D-3-phosphoglycerate dehydrogenase. Site-directed mutagenesis of effector binding site residues, J Biol Chem, 271, 23235, 10.1074/jbc.271.38.23235

Aravind, 1998, The HD domain defines a new superfamily of metal-dependent phosphohydrolases, Trends Biochem Sci, 23, 469, 10.1016/S0968-0004(98)01293-6

Arenz, 2016, The stringent factor RelA adopts an open conformation on the ribosome to stimulate ppGpp synthesis, Nucleic Acids Res, 44, 6471, 10.1093/nar/gkw470

Atkinson, 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, 10.1371/journal.pone.0023479

Avarbock, 2000, Differential regulation of opposing RelMtb activities by the aminoacylation state of a tRNA.ribosome.mRNA.RelMtb complex, Biochemistry, 39, 11640, 10.1021/bi001256k

Balaban, 2004, Bacterial persistence as a phenotypic switch, Science, 305, 1622, 10.1126/science.1099390

Battesti, 2006, Acyl carrier protein/SpoT interaction, the switch linking SpoT-dependent stress response to fatty acid metabolism, Mol Microbiol, 62, 1048, 10.1111/j.1365-2958.2006.05442.x

Battesti, 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, 10.1128/JB.01195-08

Belitsky, 1982, Absence of accumulation of ppGpp and RNA during amino acid starvation in Rhizobium meliloti, J Biol Chem, 257, 4677, 10.1016/S0021-9258(18)34574-5

Beljantseva, 2017, Negative allosteric regulation of Enterococcus faecalis small alarmone synthetase RelQ by single-stranded RNA, Proc Natl Acad Sci USA, 114, 3726, 10.1073/pnas.1617868114

Boutte, 2011, The complex logic of stringent response regulation in Caulobacter crescentus: starvation signalling in an oligotrophic environment, Mol Microbiol, 80, 695, 10.1111/j.1365-2958.2011.07602.x

Brown, 2016, Ribosome-dependent activation of stringent control, Nature, 534, 277, 10.1038/nature17675

Brown, 2019, Nitrogen starvation induces persister cell formation in Escherichia coli, J Bacteriol, 201, e00622, 10.1128/JB.00622-18

Brown, 2014, Nitrogen stress response and stringent response are coupled in Escherichia coli, Nat Commun, 5, 4115, 10.1038/ncomms5115

Cao, 2002, Defining the Bacillus subtilis sigma(W) regulon: a comparative analysis of promoter consensus search, run-off transcription/macroarray analysis (ROMA), and transcriptional profiling approaches, J Mol Biol, 316, 443, 10.1006/jmbi.2001.5372

Cashel, 1969, Two compounds implicated in the function of the RC gene of Escherichia coli, Nature, 221, 838, 10.1038/221838a0

Chipman, 2001, The ACT domain family, Curr Opin Struct Biol, 11, 694, 10.1016/S0959-440X(01)00272-X

D'Elia, 2009, Probing teichoic acid genetics with bioactive molecules reveals new interactions among diverse processes in bacterial cell wall biogenesis, Chem Biol, 16, 548, 10.1016/j.chembiol.2009.04.009

Dalebroux, 2010, ppGpp conjures bacterial virulence, Microbiol Mol Biol Rev, 74, 171, 10.1128/MMBR.00046-09

Das, 2008, Molecular characterization of Vibrio cholerae ΔrelA ΔspoT double mutants, Arch Microbiol, 189, 227, 10.1007/s00203-007-0312-z

Das, 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, 10.1111/j.1365-2958.2009.06653.x

De Nisco, 2014, Global analysis of cell cycle gene expression of the legume symbiont Sinorhizobium meliloti, Proc Natl Acad Sci USA, 111, 3217, 10.1073/pnas.1400421111

Deutscher, 2006, How phosphotransferase system-related protein phosphorylation regulates carbohydrate metabolism in bacteria, Microbiol Mol Biol Rev, 70, 939, 10.1128/MMBR.00024-06

Deutscher, 2014, The bacterial phosphoenolpyruvate:carbohydrate phosphotransferase system: regulation by protein phosphorylation and phosphorylation-dependent protein-protein interactions, Microbiol Mol Biol Rev, 78, 231, 10.1128/MMBR.00001-14

Dozot, 2006, The stringent response mediator Rsh is required for Brucella melitensis and Brucella suis virulence, and for expression of the type IV secretion system virB, Cell Microbiol, 8, 1791, 10.1111/j.1462-5822.2006.00749.x

Eisenstein, 1995, An expanded two-state model accounts for homotropic cooperativity in biosynthetic threonine deaminase from Escherichia coli, Biochemistry, 34, 9403, 10.1021/bi00029a016

Fang, 2018, Regulation of stringent factor by branched-chain amino acids, Proc Natl Acad Sci USA, 115, 6446, 10.1073/pnas.1803220115

Feng, 2014, Structural and functional insights into the mode of action of a universally conserved Obg GTPase, PLoS Biol, 12, e1001866, 10.1371/journal.pbio.1001866

Gaca, 2013, Basal levels of (p)ppGpp in Enterococcus faecalis: the magic beyond the stringent response, MBio, 4, e00646, 10.1128/mBio.00646-13

Gallant, 1977, Anomalous synthesis of ppGpp in growing cells, Cell, 11, 181, 10.1016/0092-8674(77)90329-4

Geiger, 2014, Two small (p)ppGpp synthases in Staphylococcus aureus mediate tolerance against cell envelope stress conditions, J Bacteriol, 196, 894, 10.1128/JB.01201-13

Geiger, 2010, Role of the (p)ppGpp synthase RSH, a RelA/SpoT homolog, in stringent response and virulence of Staphylococcus aureus, Infect Immun, 78, 1873, 10.1128/IAI.01439-09

Geiger, 2012, The stringent response of Staphylococcus aureus and its impact on survival after phagocytosis through the induction of intracellular PSMs expression, PLoS Pathog, 8, e1003016, 10.1371/journal.ppat.1003016

Germain, 2013, Molecular mechanism of bacterial persistence by HipA, Mol Cell, 52, 248, 10.1016/j.molcel.2013.08.045

Glass, 1979, Synthesis of guanosine tetra- and pentaphosphates by the obligately anaerobic bacterium Bacteroides thetaiotaomicron in response to molecular oxygen, J Bacteriol, 137, 956, 10.1128/JB.137.2.956-962.1979

Gonzalez, 2014, Effects of (p)ppGpp on the progression of the cell cycle of Caulobacter crescentus, J Bacteriol, 196, 2514, 10.1128/JB.01575-14

Goodwin, 2014, Biochemical characterization of a nitrogen-type phosphotransferase system reveals that enzyme EI(Ntr) integrates carbon and nitrogen signaling in Sinorhizobium meliloti, J Bacteriol, 196, 1901, 10.1128/JB.01489-14

Gratani, 2018, Regulation of the opposing (p)ppGpp synthetase and hydrolase activities in a bifunctional RelA/SpoT homologue from Staphylococcus aureus, PLoS Genet, 14, e1007514, 10.1371/journal.pgen.1007514

Gropp, 2001, Regulation of Escherichia coli RelA requires oligomerization of the C-terminal domain, J Bacteriol, 183, 570, 10.1128/JB.183.2.570-579.2001

Hallez, 2017, Hit the right spots: cell cycle control by phosphorylated guanosines in alphaproteobacteria, Nat Rev Microbiol, 15, 137, 10.1038/nrmicro.2016.183

Haseltine, 1973, Synthesis of guanosine tetra- and pentaphosphate requires the presence of a codon-specific, uncharged transfer ribonucleic acid in the acceptor site of ribosomes, Proc Natl Acad Sci USA, 70, 1564, 10.1073/pnas.70.5.1564

Hauryliuk, 2015, Recent functional insights into the role of (p)ppGpp in bacterial physiology, Nat Rev Microbiol, 13, 298, 10.1038/nrmicro3448

Hogg, 2004, Conformational antagonism between opposing active sites in a bifunctional RelA/SpoT homolog modulates (p)ppGpp metabolism during the stringent response, Cell, 117, 57, 10.1016/S0092-8674(04)00260-0

Honsa, 2017, RelA mutant Enterococcus faecium with multiantibiotic tolerance arising in an immunocompromised host, MBio, 8, e02124, 10.1128/mBio.02124-16

Hood, 2016, The stringent response regulates adaptation to darkness in the cyanobacterium Synechococcus elongatus, Proc Natl Acad Sci USA, 113, E4867, 10.1073/pnas.1524915113

Jain, 2006, Molecular dissection of the mycobacterial stringent response protein Rel, Protein Sci, 15, 1449, 10.1110/ps.062117006

Jiang, 2007, G-protein control of the ribosome-associated stress response protein SpoT, J Bacteriol, 189, 6140, 10.1128/JB.00315-07

Karstens, 2014, Phosphotransferase protein EIIANtr interacts with SpoT, a key enzyme of the stringent response, in Ralstonia eutropha H16, Microbiology, 160, 711, 10.1099/mic.0.075226-0

Kaspy, 2013, HipA-mediated antibiotic persistence via phosphorylation of the glutamyl-tRNA-synthetase, Nat Commun, 4, 3001, 10.1038/ncomms4001

Keasling, 1993, Guanosine pentaphosphate phosphohydrolase of Escherichia coli is a long-chain exopolyphosphatase, Proc Natl Acad Sci USA, 90, 7029, 10.1073/pnas.90.15.7029

Krasny, 2004, An alternative strategy for bacterial ribosome synthesis: Bacillus subtilis rRNA transcription regulation, EMBO J, 23, 4473, 10.1038/sj.emboj.7600423

Kriel, 2012, Direct regulation of GTP homeostasis by (p)ppGpp: a critical component of viability and stress resistance, Mol Cell, 48, 231, 10.1016/j.molcel.2012.08.009

Krol, 2011, ppGpp in Sinorhizobium meliloti biosynthesis in response to sudden nutritional downshifts and modulation of the transcriptome, Mol Microbiol, 81, 1233, 10.1111/j.1365-2958.2011.07752.x

Kudrin, 2018, The ribosomal A-site finger is crucial for binding and activation of the stringent factor RelA, Nucleic Acids Res, 46, 1973, 10.1093/nar/gky023

Kuroda, 1997, Guanosine tetra- and pentaphosphate promote accumulation of inorganic polyphosphate in Escherichia coli, J Biol Chem, 272, 21240, 10.1074/jbc.272.34.21240

Lee, 2018, Rsd balances (p)ppGpp level by stimulating the hydrolase activity of SpoT during carbon source downshift in Escherichia coli, Proc Natl Acad Sci USA, 115, E6845, 10.1073/pnas.1722514115

Leigh, 2007, Nitrogen regulation in bacteria and archaea, Annu Rev Microbiol, 61, 349, 10.1146/annurev.micro.61.080706.093409

Lemos, 2007, Three gene products govern (p)ppGpp production by Streptococcus mutans, Mol Microbiol, 65, 1568, 10.1111/j.1365-2958.2007.05897.x

Liu, 2015, Diversity in (p)ppGpp metabolism and effectors, Curr Opin Microbiol, 24, 72, 10.1016/j.mib.2015.01.012

Liu, 2015, Molecular mechanism and evolution of guanylate kinase regulation by (p)ppGpp, Mol Cell, 57, 735, 10.1016/j.molcel.2014.12.037

Loveland, 2016, Ribosome*RelA structures reveal the mechanism of stringent response activation, Elife, 5, e17029, 10.7554/eLife.17029

Manav, 2018, Structural basis for (p)ppGpp synthesis by the Staphylococcus aureus small alarmone synthetase RelP, J Biol Chem, 293, 3254, 10.1074/jbc.RA117.001374

Mechold, 2002, Intramolecular regulation of the opposing (p)ppGpp catalytic activities of Rel(Seq), the Rel/Spo enzyme from Streptococcus equisimilis, J Bacteriol, 184, 2878, 10.1128/JB.184.11.2878-2888.2002

Metzger, 1989, Characterization of the relA1 mutation and a comparison of relA1 with new relA null alleles in Escherichia coli, J Biol Chem, 264, 21146, 10.1016/S0021-9258(19)30059-6

Mitchell, 2007, The Escherichia coli regulator of sigma 70 protein, Rsd, can up-regulate some stress-dependent promoters by sequestering sigma 70, J Bacteriol, 189, 3489, 10.1128/JB.00019-07

Mittenhuber, 2001, Comparative genomics and evolution of genes encoding bacterial (p)ppGpp synthetases/hydrolases (the Rel, RelA and SpoT proteins), J Mol Microbiol Biotechnol, 3, 585

Nakagawa, 2006, Identification and characterization of a second, inducible promoter of relA in Escherichia coli, Genes Genet Syst, 81, 299, 10.1266/ggs.81.299

Nanamiya, 2008, Identification and functional analysis of novel (p)ppGpp synthetase genes in Bacillus subtilis, Mol Microbiol, 67, 291, 10.1111/j.1365-2958.2007.06018.x

Ochi, 1981, Initiation of Bacillus subtilis sporulation by the stringent response to partial amino acid deprivation, J Biol Chem, 256, 6866, 10.1016/S0021-9258(19)69072-1

Ooga, 2009, Degradation of ppGpp by nudix pyrophosphatase modulates the transition of growth phase in the bacterium Thermus thermophilus, J Biol Chem, 284, 15549, 10.1074/jbc.M900582200

Pando, 2017, Ethanol-induced stress response of Staphylococcus aureus, Can J Microbiol, 63, 745, 10.1139/cjm-2017-0221

Park, 2013, HPr antagonizes the anti-sigma70 activity of Rsd in Escherichia coli, Proc Natl Acad Sci USA, 110, 21142, 10.1073/pnas.1316629111

Persky, 2009, The ObgE/CgtA GTPase influences the stringent response to amino acid starvation in Escherichia coli, Mol Microbiol, 73, 253, 10.1111/j.1365-2958.2009.06767.x

Poole, 2012, Bacterial stress responses as determinants of antimicrobial resistance, J Antimicrob Chemother, 67, 2069, 10.1093/jac/dks196

Potrykus, 2008, (p)ppGpp: still magical?, Annu Rev Microbiol, 62, 35, 10.1146/annurev.micro.62.081307.162903

Raskin, 2007, Regulation of the stringent response is the essential function of the conserved bacterial G protein CgtA in Vibrio cholerae, Proc Natl Acad Sci USA, 104, 4636, 10.1073/pnas.0611650104

Reitzer, 2003, Nitrogen assimilation and global regulation in Escherichia coli, Annu Rev Microbiol, 57, 155, 10.1146/annurev.micro.57.030502.090820

Ronneau, 2016, Phosphotransferase-dependent accumulation of (p)ppGpp in response to glutamine deprivation in Caulobacter crescentus, Nat Commun, 7, 11423, 10.1038/ncomms11423

Ronneau, 2019, Regulation of (p)ppGpp hydrolysis by a conserved archetypal regulatory domain, Nucleic Acids Res, 47, 843, 10.1093/nar/gky1201

Ross, 2013, The magic spot: a ppGpp binding site on E. coli RNA polymerase responsible for regulation of transcription initiation, Mol Cell, 50, 420, 10.1016/j.molcel.2013.03.021

Ross, 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, 10.1016/j.molcel.2016.04.029

Sanselicio, 2015, Convergence of alarmone and cell cycle signaling from trans-encoded sensory domains, MBio, 6, e01415, 10.1128/mBio.01415-15

Schofield, 2018, The stringent response determines the ability of a commensal bacterium to survive starvation and to persist in the gut, Cell Host Microbe, 24, 120, 10.1016/j.chom.2018.06.002

Schreiber, 1991, Overexpression of the relA gene in Escherichia coli, J Biol Chem, 266, 3760, 10.1016/S0021-9258(19)67860-9

Schuller, 1995, The allosteric ligand site in the Vmax-type cooperative enzyme phosphoglycerate dehydrogenase, Nat Struct Biol, 2, 69, 10.1038/nsb0195-69

Seyfzadeh, 1993, SpoT-dependent accumulation of guanosine tetraphosphate in response to fatty acid starvation in Escherichia coli, Proc Natl Acad Sci USA, 90, 11004, 10.1073/pnas.90.23.11004

Steinchen, 2016, The magic dance of the alarmones (p)ppGpp, Mol Microbiol, 101, 531, 10.1111/mmi.13412

Steinchen, 2018, Structural and mechanistic divergence of the small (p)ppGpp synthetases RelP and RelQ, Sci Rep, 8, 2195, 10.1038/s41598-018-20634-4

Steinchen, 2015, Catalytic mechanism and allosteric regulation of an oligomeric (p)ppGpp synthetase by an alarmone, Proc Natl Acad Sci USA, 112, 13348, 10.1073/pnas.1505271112

Syal, 2017, Synthetic (p)ppGpp analogue is an inhibitor of stringent response in mycobacteria, Antimicrob Agents Chemother, 61, e00443, 10.1128/AAC.00443-17

Tan, 2002, Overexpression of two different GTPases rescues a null mutation in a heat-induced rRNA methyltransferase, J Bacteriol, 184, 2692, 10.1128/JB.184.10.2692-2698.2002

Thompson, 2005, Vmax regulation through domain and subunit changes. The active form of phosphoglycerate dehydrogenase, Biochemistry, 44, 5763, 10.1021/bi047944b

Villadsen, 1977, Regulation of PRPP and nucleoside tri and tetraphosphate pools in Escherichia coli under conditions of nitrogen starvation, J Bacteriol, 130, 136, 10.1128/JB.130.1.136-143.1977

Wang, 2007, Nutritional control of elongation of DNA replication by (p)ppGpp, Cell, 128, 865, 10.1016/j.cell.2006.12.043

Weinrick, 2004, Effect of mild acid on gene expression in Staphylococcus aureus, J Bacteriol, 186, 8407, 10.1128/JB.186.24.8407-8423.2004

Wells, 2006, Helicobacter pylori initiates the stringent response upon nutrient and pH downshift, J Bacteriol, 188, 3726, 10.1128/JB.188.10.3726-3729.2006

Wessel, 2000, Evidence for two distinct effector-binding sites in threonine deaminase by site-directed mutagenesis, kinetic, and binding experiments, Biochemistry, 39, 15136, 10.1021/bi001625c

Wexselblatt, 2010, ppGpp analogues inhibit synthetase activity of Rel proteins from Gram-negative and Gram-positive bacteria, Bioorg Med Chem, 18, 4485, 10.1016/j.bmc.2010.04.064

Winther, 2018, Activation of the stringent response by loading of RelA-tRNA complexes at the ribosomal A-site, Mol Cell, 70, 95, 10.1016/j.molcel.2018.02.033

Wout, 2004, The Escherichia coli GTPase CgtAE cofractionates with the 50S ribosomal subunit and interacts with SpoT, a ppGpp synthetase/hydrolase, J Bacteriol, 186, 5249, 10.1128/JB.186.16.5249-5257.2004

Zhang, 2018, Novel (p)ppGpp binding and metabolizing proteins of Escherichia coli, MBio, 9, e02188, 10.1128/mBio.02188-17