SpoT explained

Bifunctional (p)ppGpp synthase/hydrolase SpoT
Symbol:spoT
Uniprot:P0AG24
Organism:Escherichia coli (strain K12)

Bifunctional (p)ppGpp synthase/hydrolase SpoT or SpoT is a regulatory enzyme in the RelA/SpoT Homologue (RSH) protein family that synthesizes and hydrolyzes (p)ppGpp to regulate the bacterial stringent response to environmental stressors.[1] SpoT is considered a "long" form RSH protein and is found in many bacteria and plant chloroplasts.[2] SpoT and its homologues have been studied in bacterial model organism E.coli for their role in the production and degradation of (p)ppGpp in the stringent response pathway.

Role in Stringent Response Pathway

The stringent response regulated by SpoT, RelA, and their homologues can cause a bacterium to increase its persistence in stressful environments.[3] SpoT can act as both a hydrolase and a synthetase to (p)ppGpp alarmones in the stringent response pathway with Mn2+ as its cofactor.[4] When there are environmental stressors present, SpoT uses ATP and GDP to synthesize (p)ppGpp and catalyze the stringent response.[5] When stressors are removed and a stringent response is no longer necessary SpoT hydrolyzes (p)ppGpp, cleaving it into GTP and diphosphate. Environmental stressors including but not limited to amino acid starvation, carbon deficiencies,[6] phosphate deficiencies[7] and changes in temperature have been documented to cause the gene encoding SpoT to activate.

The acyl carrier protein (ACP) binds to the TGS domain of SpoT; this binding is probably influenced by the ratio of unacylated ACP to acylated ACP in the cell.[8]

Role as a Hydrolase

SpoT mainly serves as a hydrolase in systems similar to E.coli. SpoT's hydrolase activity is Mn2+-dependent with a conserved His-Asp (HD) motif.[9] Phosphate starvation is sensed by SpoT hydrolase to elevate (p)ppGpp, which induces IraP, a RssB antiadaptor that antagonizes RssB activation of RpoS turnover, thereby inducing RpoS.

SpoT in E. coli

In E. coli, the SpoT protein consists of 702 amino acids. E.coli uses RelA and SpoT as its two main (p)ppGpp regulating enzymes.[10] When the gene for encoding RelA is nonfunctional, E. coli can still regulate (p)ppGpp through SpoT as it has both HD and SYNTH domains.

Related Proteins and the RelA/SpoT Homologue Superfamily

SpoT and RelA have many homologous variations, forming the RelA/SpoT Homologue (RSH) protein family. These homologues serve similar functions to SpoT and RelA in stringent responses. Protein domains observed in members of the RSH protein family are separated by hydrolase (HD) functionality and synthetase (SYNTH) functionality (see Figure 2).

Further reading

Notes and References

  1. Pausch P, Abdelshahid M, Steinchen W, Schäfer H, Gratani FL, Freibert SA, Wolz C, Turgay K, Wilson DN, Bange G . 6 . Structural Basis for Regulation of the Opposing (p)ppGpp Synthetase and Hydrolase within the Stringent Response Orchestrator Rel . Cell Reports . 32 . 11 . 108157 . September 2020 . 32937119 . 10.1016/j.celrep.2020.108157 . 221770084 . free .
  2. Atkinson GC, Tenson T, Hauryliuk V . The RelA/SpoT homolog (RSH) superfamily: distribution and functional evolution of ppGpp synthetases and hydrolases across the tree of life . PLOS ONE . 6 . 8 . e23479 . 2011-08-09 . 21858139 . 3153485 . 10.1371/journal.pone.0023479 . free . 2011PLoSO...623479A .
  3. Balaban NQ, Helaine S, Lewis K, Ackermann M, Aldridge B, Andersson DI, Brynildsen MP, Bumann D, Camilli A, Collins JJ, Dehio C, Fortune S, Ghigo JM, Hardt WD, Harms A, Heinemann M, Hung DT, Jenal U, Levin BR, Michiels J, Storz G, Tan MW, Tenson T, Van Melderen L, Zinkernagel A . 6 . Definitions and guidelines for research on antibiotic persistence . Nature Reviews. Microbiology . 17 . 7 . 441–448 . July 2019 . 30980069 . 7136161 . 10.1038/s41579-019-0196-3 .
  4. Web site: spoT - Bifunctional (p)ppGpp synthase/hydrolase SpoT - Escherichia coli (strain K12) - spoT gene & protein . 2022-05-01 . www.uniprot.org . en.
  5. Ronneau S, Hallez R . Make and break the alarmone: regulation of (p)ppGpp synthetase/hydrolase enzymes in bacteria . FEMS Microbiology Reviews . 43 . 4 . 389–400 . July 2019 . 30980074 . 6606846 . 10.1093/femsre/fuz009 .
  6. Lesley JA, Shapiro L . SpoT regulates DnaA stability and initiation of DNA replication in carbon-starved Caulobacter crescentus . Journal of Bacteriology . 190 . 20 . 6867–6880 . October 2008 . 18723629 . 2566184 . 10.1128/JB.00700-08 .
  7. Spira B, Silberstein N, Yagil E . Guanosine 3',5'-bispyrophosphate (ppGpp) synthesis in cells of Escherichia coli starved for Pi . Journal of Bacteriology . 177 . 14 . 4053–4058 . July 1995 . 7608079 . 177136 . 10.1128/jb.177.14.4053-4058.1995 .
  8. Battesti A, Bouveret E . Acyl carrier protein/SpoT interaction, the switch linking SpoT-dependent stress response to fatty acid metabolism . Molecular Microbiology . 62 . 4 . 1048–1063 . November 2006 . 17078815 . 10.1111/j.1365-2958.2006.05442.x . 7857443 . free .
  9. Yakunin AF, Proudfoot M, Kuznetsova E, Savchenko A, Brown G, Arrowsmith CH, Edwards AM . The HD domain of the Escherichia coli tRNA nucleotidyltransferase has 2',3'-cyclic phosphodiesterase, 2'-nucleotidase, and phosphatase activities . The Journal of Biological Chemistry . 279 . 35 . 36819–36827 . August 2004 . 15210699 . 10.1074/jbc.M405120200 . free .
  10. Liu K, Bittner AN, Wang JD . Diversity in (p)ppGpp metabolism and effectors . Current Opinion in Microbiology . 24 . 72–79 . April 2015 . 25636134 . 4380541 . 10.1016/j.mib.2015.01.012 . Cell regulation .

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