{"doi":"10.1101/2022.02.28.482149","title":"Orthogonal synthetases for polyketide precursors","abstract":"Abstract The absence of orthogonal aminoacyl-tRNA synthetases that accept non-L-α-amino acids is the primary bottleneck hindering the in vivo translation of sequence-defined hetero-oligomers. Here we report PylRS enzymes that accept α-hydroxy acids, α-thio acids, N -formyl-L-α-amino acids, and α-carboxyl acid monomers (malonic acids) that are formally precursors to polyketide natural products. These monomers are all accommodated and accepted by the translation apparatus in vitro . High-resolution structural analysis of the complex between one such PylRS enzyme and a meta -substituted 2-benzylmalonate derivative reveals an active site that discriminates pro -chiral carboxylates and accommodates the large size and distinct electrostatics of an α-carboxyl acid substituent. This work emphasizes the potential of PylRS-derived enzymes for acylating tRNA with monomers whose α-substituent diverges significantly from the α-amine embodied in proteinogenic amino acids. These enzymes could act in synergy with natural or evolved ribosomes to generate diverse sequence-defined non-protein hetero-oligomers.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":300975,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9457,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":991859,"name":"Cameron V. Swenson","orcid":"0000-0002-9896-3539","position":1,"is_corresponding":false},{"id":991860,"name":"Leah T. Roe","orcid":"0000-0002-2487-5587","position":2,"is_corresponding":false},{"id":991861,"name":"Noah X. Hamlish","orcid":"0000-0003-4318-8675","position":3,"is_corresponding":false},{"id":239100,"name":"Omer Ad","orcid":null,"position":4,"is_corresponding":false},{"id":991862,"name":"Sarah Smaga","orcid":"0000-0003-3469-2642","position":5,"is_corresponding":false},{"id":344885,"name":"Christine L. Gee","orcid":"0000-0002-2632-6418","position":6,"is_corresponding":false},{"id":237245,"name":"Alanna Schepartz","orcid":"0000-0003-2127-3932","position":7,"is_corresponding":false},{"id":991858,"name":"Riley Fricke","orcid":"0000-0001-9463-6314","position":0,"is_corresponding":true}],"reference_count":79,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:31:57.812980Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}