InterPro domain: IPR007685

This entry includes the catalytic domains of Escherichia coli ppGpp synthetase (RelA), ppGpp synthetase/hydrolase (SpoT), and related proteins. The functions of Escherichia coli RelA and SpoT differ somewhat. RelA ( 2.7.6.5 ) produces pppGpp (or ppGpp) from ATP and GTP (or GDP) in response to amino-acid starvation and in association with ribosomes [ 1 ]. SpoT ( 3.1.7.2 ) degrades ppGpp, but may also act as a secondary ppGpp synthetase under carbon limitation in a ribosome-independent manner [ 2 , 3 ]. Gram-negative bacteria have two enzymes involved in (p)ppGpp metabolism while most Gram-positive organisms have a single Rel-Spo enzyme (Rel), which both synthesizes and degrades (p)ppGpp [ 4 , 5 ]. The Arabidopsis thaliana Rel-Spo proteins, At-RSH1, At-RSH2, and At-RSH3 appear to regulate a rapid (p)ppGpp-mediated response to pathogens and other stresses [ 6 ]. This catalytic domain is found in association with an N-terminal HD domain and a C-terminal metal dependent phosphohydrolase domain (TGS). Some Rel-Spo proteins also have a C-terminal regulatory ACT domain. This subgroup belongs to the Pol beta-like NT superfamily [ 7 , 8 ].

(p)ppGpp is a regulatory metabolite of the stringent response [ 9 ], but appears also to be involved in antibiotic biosynthesis in some species [ 10 ].

In the Pol beta-like NT superfamily [ 11 , 11 ], the majority of enzymes have two carboxylates, Dx[D/E], together with a third more distal carboxylate, which coordinate two divalent metal cations involved in a two-metal ion mechanism of nucleotide addition. These carboxylate residues are fairly well conserved in this family.

1. The nucleotide sequence and characterization of the relA gene of Escherichia coli. J. Biol. Chem. 263, 15699-704
2. Mutational analysis of the Escherichia coli spoT gene identifies distinct but overlapping regions involved in ppGpp synthesis and degradation. Mol. Microbiol. 19, 1373-84
3. Control of spoT-dependent ppGpp synthesis and degradation in Escherichia coli. J. Mol. Biol. 259, 41-57
4. Intramolecular regulation of the opposing (p)ppGpp catalytic activities of Rel(Seq), the Rel/Spo enzyme from Streptococcus equisimilis. J. Bacteriol. 184, 2878-88
5. Functional analysis of a relA/spoT gene homolog from Streptococcus equisimilis. J. Bacteriol. 178, 1401-11
6. Arabidopsis RelA/SpoT homologs implicate (p)ppGpp in plant signaling. Proc. Natl. Acad. Sci. U.S.A. 97, 3747-52
7. DNA polymerase beta-like nucleotidyltransferase superfamily: identification of three new families, classification and evolutionary history. Nucleic Acids Res. 27, 1609-18
8. DNA polymerase beta belongs to an ancient nucleotidyltransferase superfamily. Trends Biochem. Sci. 20, 345-7
9. ppGpp: stringent response and survival. J. Microbiol. 44, 1-10
10. The guanosine nucleotide (p)ppGpp initiates development and A-factor production in myxococcus xanthus. Genes Dev. 12, 1022-35