Cyclodipeptide synthases recognize a minimalistic substrate to produce cyclic dipeptides in a tRNA-independent manner.

Correction for ‘Bypassing the requirement for aminoacyl-tRNA by a cyclodipeptide synthase enzyme’ by Christopher J. Harding et al., RSC Chem. Biol., 2021, 2, 230–240, DOI: 10.1039/D0CB00142B.

Ligand-activated nuclear receptors (NRs) including steroid receptors orchestrate development, growth, and reproduction across all animal lifeforms - the Metazoa - but how NRs evolved remains mysterious. Given the universality of terpenoids - including steroids and retinoids - as activating NR ligands, we asked if NRs might have evolved from enzymes that catalyze terpene synthesis and metabolism. We provide evidence suggesting that NRs are a sub-branch of the terpene synthase (TS) enzyme superfamily. Based on over ten thousand 3D structural comparisons, backed up by multiple primary sequence alignments and mapping of ligand-contacting residues, we report that the NR ligand-binding domain and TS enzymes share a conserved core of seven α-helical segments. Primary sequence comparisons reveal potential amino acid sequence similarities between NRs and the subfamily of cis-isoprene transferases, in particular dehydrodolichyl pyrophosphate synthase (DHDPPS) and its obligate partner, NUS1/NOGOB receptor. Our results suggest that a ligand-gated receptor may have arisen from an enzyme antecedent, and thus resolve the long-standing debate about whether the ancestral NR was unliganded. This would also explain aspects of NR ligand 'promiscuity', with implications for the development of pharmaceuticals targeting NRs and TS enzymes.

Ligand-activated nuclear receptors (NRs) orchestrate development, growth, and reproduction across all animal lifeforms – the Metazoa – but how NRs evolved remains mysterious. Given the NR ligands including steroids and retinoids are predominantly terpenoids, we asked whether NRs might have evolved from enzymes that catalyze terpene synthesis and metabolism. We provide evidence suggesting that NRs may be related to the terpene synthase (TS) enzyme superfamily. Based on over 10,000 3D structural comparisons, we report that the NR ligand-binding domain and TS enzymes share a conserved core of seven α-helical segments. In addition, the 3D locations of the major ligand-contacting residues are also conserved between the two protein classes. Primary sequence comparisons reveal suggestive similarities specifically between NRs and the subfamily of cis-isoprene transferases, notably with dehydrodolichyl pyrophosphate synthase (DHDPPS) and its obligate partner, NUS1/NOGOB receptor. Pharmacological overlaps between NRs and TS enzymes add weight to the contention that they share a distant evolutionary origin, and the combined data raise the possibility that a ligand-gated receptor may have arisen from an enzyme antecedent. However, our findings do not formally exclude other interpretations such as convergent evolution, and further analysis will be necessary to confirm the inferred relationship between the two protein classes.