relA

RelA is a ribosome-associated enzyme in many bacteria that synthesizes alarmone nucleotides as part of the stringent response. It is encoded by the relA gene and belongs to the RelA/SpoT homolog (RSH) family, which regulates intracellular levels of the signaling nucleotides (p)ppGpp. In most bacteria, RelA acts primarily as a synthetase, producing (p)ppGpp, and operates in concert with the hydrolase SpoT to balance alarmone pools.

During amino acid scarcity, uncharged tRNA binds to the ribosomal A site, triggering RelA activation. The enzyme catalyzes the production of ppGpp and pppGpp from GDP or GTP and ATP. The resulting alarmones bind RNA polymerase and, often with cofactors such as DksA, reprogram transcription: downregulating ribosomal RNA and tRNA synthesis while upregulating stress response, amino acid biosynthesis, and maintenance pathways. These changes slow growth and help the cell adapt to nutrient limitation. RelA's activity and alarmone levels are tightly coordinated with SpoT, which primarily hydrolyzes (p)ppGpp but can also synthesize under certain conditions.

RelA contains an N-terminal catalytic region responsible for (p)ppGpp synthesis and a C-terminal regulatory region that contacts the ribosome and senses deacylated tRNA; the exact architecture varies among species. In addition to its bacterial roles, RelA-like proteins are found in other branches of life, including chloroplasts in plants, reflecting a conserved function in stress signaling.