{"doi":"10.1021/acschembio.1c00598","title":"How <i>cis</i>-Acyltransferase Assembly-Line Ketosynthases Gatekeep for Processed Polyketide Intermediates","abstract":null,"journal":"ACS Chemical Biology","year":2021,"id":639173,"datarank":0.5709993734655481,"base_score":3.8066624897703196,"endowment":3.8066624897703196,"self_citation_contribution":0.5709993734655481,"citation_network_contribution":0.0,"self_endowment_contribution":0.5709993734655481,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":44,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":572886,"name":"Brendan J. Fitzgerald","orcid":"0000-0002-3921-911X","position":1,"is_corresponding":false},{"id":313746,"name":"Adrian T. Keatinge‐Clay","orcid":"0000-0002-4358-7628","position":2,"is_corresponding":false},{"id":313744,"name":"Melissa Hirsch","orcid":"0000-0002-8959-4532","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"How <i>cis</i>-Acyltransferase Assembly-Line Ketosynthases Gatekeep for Processed Polyketide Intermediates","abstract":"With the redefinition of polyketide synthase (PKS) modules, a new appreciation of their most downstream domain, the ketosynthase (KS), is emerging. In addition to performing its well-established role of generating a carbon–carbon bond between an acyl-CoA building block and a growing polyketide, it may gatekeep against incompletely processed intermediates. Here, we investigate 739 KSs from 92 primarily actinomycete, cis -acyltransferase assembly lines. When KSs were separated into 16 families based on the chemistries at the α- and β-carbons of their polyketide substrates, a comparison of 32 substrate tunnel residues revealed unique sequence fingerprints. Surprisingly, additional fingerprints were detected when the chemistry at the γ-carbon was considered. Representative KSs were modeled bound to their natural polyketide substrates to better understand observed patterns, such as the substitution of a tryptophan by a smaller residue to accommodate an l -α-methyl group or the substitution of four smaller residues by larger ones to make better contact with a primer unit or diketide. Mutagenesis of a conserved glutamine in a KS within a model triketide synthase indicates that the substrate tunnel is sensitive to alteration and that engineering this KS to accept unnatural substrates may require several mutations.","is_dataset_classified":null,"base_score":3.8066624897703196,"endowment":3.8066624897703196,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"34590822","pmcid":"PMC9879353","openalex_id":"https://openalex.org/W3201668219","authors":[],"funders":[{"funder_name":"Welch Foundation","grant_id":"F-1712","title":null},{"funder_name":"National Institute of General Medical Sciences","grant_id":"GM106112","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"R01 GM106112","title":null},{"funder_name":"National Institutes of Health","grant_id":"5R01GM106112-07","title":"Determining the Architectures and Activities of Polyketide Synthase Modules"}],"total_grants":4,"fwci":2.8681,"citation_percentile":0.90520067,"influential_citations":0,"citation_trend":[{"year":2022,"count":2},{"year":2023,"count":9},{"year":2024,"count":8},{"year":2025,"count":15},{"year":2026,"count":10}],"oa_status":"green","license":"STM Policy #29","oa_locations":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/9879353","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/9879353","host_type":"repository"},{"url":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.1c00598","host_type":"publisher"},{"url":"https://doi.org/10.1021/acschembio.1c00598","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/34590822","host_type":"repository"},{"url":"https://dx.doi.org/10.1021/acschembio.1c00598","host_type":""}],"fields_of_study":["Microbial Natural Products and Biosynthesis","Fungal and yeast genetics research","Biofuel production and bioconversion","0301 basic medicine","0303 health sciences","03 medical and health sciences"],"mesh_terms":["Acyltransferases","Ligases","Catalytic Domain","Polyketides"],"keywords":["Polyketide","Polyketide synthase","Acyltransferase","Stereochemistry","Chemistry","Mutagenesis","Residue (chemistry)","Biochemistry","Enzyme","Biosynthesis","Mutant","Gene","Ligases","Catalytic Domain","Polyketides","Acyltransferases"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"pdb"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-06T22:47:07.999897Z","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":[]}