Tryptophanyl-tRNA Synthetase

Tryptophanyl-tRNA synthetase (TrpRS) is an enzyme that plays a crucial role in protein synthesis by catalyzing the attachment of tryptophan to its cognate tRNA: $ \text{Trp} + \text{tRNA}^\text{TrpRS} + \text{ATP} \xrightarrow{\text{TrpRS}} \text{Trp-tRNA}^\text{TrpRS} + \text{AMP} + \text{PP}_i $ TrpRS shares a number of similarities with its close homolog [TyrRS](/class1/tyr), which constitute subclass Ic. TyrRS and TrpRS are homodimeric, in contrast to many Class I synthetases, which operate as monomers (Gomez and Ibba, 2020). Moreover, the two amino acids may have been among the last amino acids to emerge in the metabolism (Trifonov 2000), and are chemically similar (aromatic side chains), consistent with the hypotheses of the two AARS sharing a common ancestor with either dual specificity, or one synthetase spawning off the other (Doublié et al. 1995, Fournier et al. 2015). Conserved aspartate side chains in the specificity determining helix (SDH) allow the respective enzymes to discriminate between tyrosine and tryptophan (Doublié et al. 1995). Lastly, while most Class I synthetases approach the tRNA acceptor stem from the minor groove side, TyrRS and TrpRS alike instead approach the acceptor stem directly (de Pouplana and Schimmel 2001). TrpRS from prokaryotic and archaeal/eukaryotic organisms form quite distinct groups, with respect to their sequences, allosteries, and domain architectures (Carter 2005). The archaeal-like TrpRS contains an additional N-terminal domain known as the eukaryote-specific-extension, ESE (Yang et al. 2007). Both the ESE and the C-terminal [anticodon binding domain](/superfamily/class1/Anticodon_binding_domain_WY) undergo vast conformational changes upon substrate binding, making the archaeal-like form quite complex (Shen et al. 2008). However, despite the intricate allostery displayed by TrpRS, the catalytic domain itself is less elaborate than other Class I synthetases, making it a useful target for investigating ancestral models, such as protozymes (Onodera et al. 2021) and urzymes (Pham et al. 2010), which display activation and aminoacylation activity respectively. The connecting peptide 1 (CP1) domains in TrpRS and TyrRS occur in their simplest forms. Some eukaryotes contain an additional domain upstream of the ESE. In humans, TrpRS contains the WHEP domain, which plays a role in the primary defense system against infection (Ahn et al. 2017). In certain parasites, TrpRS possesses an N-terminal domain homologous to the editing domain of [ThrRS](/class2/thr) and [AlaRS](/class2/ala) (Merritt et al. 2011).

References

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