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Gene Review

relA  -  GDP/GTP pyrophosphokinase

Escherichia coli O157:H7 str. EDL933

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Disease relevance of relA


High impact information on relA

  • We find that rRNA synthesized from plasmids does exhibit a relA-dependent, stringent response [6].
  • Cyclic AMP can replace the relA-dependent requirement for derepression of acetohydroxy acid synthase in E. coli K-12 [7].
  • Mutations in a nonessential viral gene permit bacteriophage T4 to form plaques on Escherichia coli valS ts relA [8].
  • Ectopic increase in the intracellular concentration of (p)ppGpp was achieved in M. xanthus by introducing a copy of the E. coli relA gene, whose product catalyzes pyrophosphate transfer from ATP- to GTP-forming pppGpp [9].
  • Many of these changes depend on the regulatory nucleotide ppGpp (guanosine tetraphosphate) synthesized by RelA (ppGpp synthetase I), the relA-encoded protein [10].

Chemical compound and disease context of relA


Biological context of relA

  • The genome of Borrelia burgdorferi encodes a single chromosomal rel gene (BB0198) (B. burgdorferi rel [rel(Bbu)]) homologous to relA and spoT of E. coli [1].
  • Induction of a relA gene deletion mutant in pSM11 containing 455 amino-terminal amino acids results in much lower levels of expression of a metabolically unstable 55-kDa protein and elevated ppGpp levels that are almost equivalent to induced pSM10 and are relC-independent [15].
  • It is also demonstrated that relA knock-outs diminish the high persistent phenotype in hipA7 mutants and that relA spoT knock-outs eliminate high persistence altogether, suggesting that hipA7 facilitates the establishment of the persister state by inducing (p)ppGpp synthesis [16].
  • We have previously reported that mazEF, the first regulatable chromosomal 'addiction module' located on the Escherichia coli chromosome, downstream from the relA gene, plays a crucial role in the programmed cell death in bacteria under stressful conditions [17].
  • Mutation in the relA gene of Vibrio cholerae affects in vitro and in vivo expression of virulence factors [18].

Anatomical context of relA

  • In amino acid-rich media, isopropyl-1-thio-beta-D-galactopyranoside induction of transcription of the wild type relA gene in pSM10 yields about a 100-fold overexpression of a metabolically stable, full length (743 amino acid) RelA protein to levels approximating the number of cellular ribosomes [15].
  • Studies of stringent controlled Escherichia coli CP78 (relA+) and relaxed controlled E. coli CP79 (relA-) were carried out to test whether these strains differ in the appearance of their cytoplasmic membranes after induction of stringent and relaxed response [19].
  • The effects of amino acid starvation on the metabolic behavior of polysomes and the size distribution of proteins have been studied in an otherwise isogenic pair of stringent (relA+) and relaxed (relA) strains of Escherichia coli [20].

Associations of relA with chemical compounds

  • Intracellular levels of guanosine 3',5'-bispyrophosphate (ppGpp) governed by the relA gene are normally regulated by aminoacyl-tRNA availability for protein synthesis [15].
  • This results in a slow but significant accumulation of this regulatory nucleotide in a relA mutant during serine starvation [21].
  • Both relA1 and relA null strains accumulate ppGpp during glucose starvation and do not accumulate ppGpp during the stringent response [22].
  • The most widely studied "relaxed" mutant of the relA locus, the relA1 allele, is shown here to consist of an IS2 insertion between the 85th and 86th codons of the otherwise wild-type relA structural gene, which normally encodes a 743-amino acid (84 kDa) protein [22].
  • Nutrient starvation experiments and the use of relA spoT mutant strains, IPTG-regulated overproduction of ppGpp and lacZ fusions revealed that the stringent response alarmone guanosine 3',5'-bispyrophosphate (ppGpp) is the main positive effector of Cka synthesis [23].

Regulatory relationships of relA

  • We found that overexpression of relA activated the expression of rpoS in P. aeruginosa and led to premature, cell density-independent LasB elastase production [24].
  • Interestingly, the cfa promoter expression is repressed in a L. lactis relA* mutant which accumulates (p)ppGpp, whereas its induction by acidity appeared independent of (p)ppGpp in L. lactis and in Escherichia coli [25].

Other interactions of relA

  • The activation was dependent on relA and spoT, which encode enzymes for the synthesis and degradation of ppGpp, and on dksA, which encodes an RNA polymerase accessory protein required for the stringent response [26].

Analytical, diagnostic and therapeutic context of relA


  1. Borrelia burgdorferi rel is responsible for generation of guanosine-3'-diphosphate-5'-triphosphate and growth control. Bugrysheva, J.V., Bryksin, A.V., Godfrey, H.P., Cabello, F.C. Infect. Immun. (2005) [Pubmed]
  2. The guanosine nucleotide (p)ppGpp initiates development and A-factor production in myxococcus xanthus. Harris, B.Z., Kaiser, D., Singer, M. Genes Dev. (1998) [Pubmed]
  3. Stringent control during carbon starvation of marine Vibrio sp. strain S14: molecular cloning, nucleotide sequence, and deletion of the relA gene. Flärdh, K., Axberg, T., Albertson, N.H., Kjelleberg, S. J. Bacteriol. (1994) [Pubmed]
  4. Characterization of the relA gene of Porphyromonas gingivalis. Sen, K., Hayashi, J., Kuramitsu, H.K. J. Bacteriol. (2000) [Pubmed]
  5. Temperature sensitivity of the penicillin-induced autolysis mechanism in nongrowing cultures of Escherichia coli. Kusser, W., Ishiguro, E.E. J. Bacteriol. (1987) [Pubmed]
  6. Regions of DNA involved in the stringent control of plasmid-encoded rRNA in vivo. Gourse, R.L., Stark, M.J., Dahlberg, A.E. Cell (1983) [Pubmed]
  7. Cyclic AMP can replace the relA-dependent requirement for derepression of acetohydroxy acid synthase in E. coli K-12. Freundlich, M. Cell (1977) [Pubmed]
  8. Mutations in a nonessential viral gene permit bacteriophage T4 to form plaques on Escherichia coli valS ts relA. Marchin, G.L. Science (1980) [Pubmed]
  9. Ectopic production of guanosine penta- and tetraphosphate can initiate early developmental gene expression in Myxococcus xanthus. Singer, M., Kaiser, D. Genes Dev. (1995) [Pubmed]
  10. RelE, a global inhibitor of translation, is activated during nutritional stress. Christensen, S.K., Mikkelsen, M., Pedersen, K., Gerdes, K. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  11. Role of the spoT gene product and manganese ion in the metabolism of guanosine 5'-diphosphate 3'-diphosphate in Escherichia coli. Johnson, G.S., Adler, C.R., Collins, J.J., Court, D. J. Biol. Chem. (1979) [Pubmed]
  12. Roles of the relA(+) gene and of 4-thiouridine in near-ultraviolet (344 nm) radiation inhibition of induced synthesis of tryptophanase in Escherichia coli B/r. Sharma, R.C., Wingo, R.J., Jagger, J. Photochem. Photobiol. (1981) [Pubmed]
  13. The relA gene is not required for glycogen accumulation during NH4+ starvation of Escherichia coli. Leckie, M.P., Tieber, V.L., Porter, S.E., Dietzler, D.N. Biochem. Biophys. Res. Commun. (1980) [Pubmed]
  14. The effect of intracellular ppGpp levels on glutamate and lysine overproduction in Escherichia coli. Imaizumi, A., Kojima, H., Matsui, K. J. Biotechnol. (2006) [Pubmed]
  15. Overexpression of the relA gene in Escherichia coli. Schreiber, G., Metzger, S., Aizenman, E., Roza, S., Cashel, M., Glaser, G. J. Biol. Chem. (1991) [Pubmed]
  16. Characterization of the hipA7 allele of Escherichia coli and evidence that high persistence is governed by (p)ppGpp synthesis. Korch, S.B., Henderson, T.A., Hill, T.M. Mol. Microbiol. (2003) [Pubmed]
  17. MazG -- a regulator of programmed cell death in Escherichia coli. Gross, M., Marianovsky, I., Glaser, G. Mol. Microbiol. (2006) [Pubmed]
  18. Mutation in the relA gene of Vibrio cholerae affects in vitro and in vivo expression of virulence factors. Haralalka, S., Nandi, S., Bhadra, R.K. J. Bacteriol. (2003) [Pubmed]
  19. The appearance of cytoplasmic membranes of Escherichia coli cells in freeze-fracture electron microscopy after stringent and relaxed response. Gitter, B., Richter, W., Riesenberg, D., Meyer, H.W. FEMS Microbiol. Lett. (1995) [Pubmed]
  20. Functional aspects of bacterial polysomes during limited protein synthesis. Marchal, J., Cortay, J.C., Cozzone, A.J. Biochim. Biophys. Acta (1983) [Pubmed]
  21. Accumulation of ppGpp in a relA mutant of Escherichia coli during amino acid starvation. Török, I., Kari, C. J. Biol. Chem. (1980) [Pubmed]
  22. Characterization of the relA1 mutation and a comparison of relA1 with new relA null alleles in Escherichia coli. Metzger, S., Schreiber, G., Aizenman, E., Cashel, M., Glaser, G. J. Biol. Chem. (1989) [Pubmed]
  23. Codon-usage based regulation of colicin K synthesis by the stress alarmone ppGpp. Kuhar, I., van Putten, J.P., Zgur-Bertok, D., Gaastra, W., Jordi, B.J. Mol. Microbiol. (2001) [Pubmed]
  24. Stringent response activates quorum sensing and modulates cell density-dependent gene expression in Pseudomonas aeruginosa. van Delden, C., Comte, R., Bally, A.M. J. Bacteriol. (2001) [Pubmed]
  25. Transcriptional analysis of the cyclopropane fatty acid synthase gene of Lactococcus lactis MG1363 at low pH. Budin-Verneuil, A., Maguin, E., Auffray, Y., Ehrlich, S.D., Pichereau, V. FEMS Microbiol. Lett. (2005) [Pubmed]
  26. ppGpp with DksA controls gene expression in the locus of enterocyte effacement (LEE) pathogenicity island of enterohaemorrhagic Escherichia coli through activation of two virulence regulatory genes. Nakanishi, N., Abe, H., Ogura, Y., Hayashi, T., Tashiro, K., Kuhara, S., Sugimoto, N., Tobe, T. Mol. Microbiol. (2006) [Pubmed]
  27. Cloning and characterization of a relA/spoT homologue from Bacillus subtilis. Wendrich, T.M., Marahiel, M.A. Mol. Microbiol. (1997) [Pubmed]
  28. The stringent response genes relA and spoT are important for Escherichia coil biofilms under slow-growth conditions. Balzer, G.J., McLean, R.J. Can. J. Microbiol. (2002) [Pubmed]
  29. Escherichia coli K12 relA strains as safe hosts for expression of recombinant DNA. Schweder, T., Hofmann, K., Hecker, M. Appl. Microbiol. Biotechnol. (1995) [Pubmed]
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