{"doi":"10.3389/fmolb.2022.923042","title":"Allosteric regulation of substrate channeling: Salmonella typhimurium tryptophan synthase","abstract":"The regulation of the synthesis of L-tryptophan (L-Trp) in enteric bacteria begins at the level of gene expression where the cellular concentration of L-Trp tightly controls expression of the five enzymes of the Trp operon responsible for the synthesis of L-Trp. Two of these enzymes, trpA and trpB, form an αββα bienzyme complex, designated as tryptophan synthase (TS). TS carries out the last two enzymatic processes comprising the synthesis of L-Trp. The TS α-subunits catalyze the cleavage of 3-indole D-glyceraldehyde 3'-phosphate to indole and D-glyceraldehyde 3-phosphate; the pyridoxal phosphate-requiring β-subunits catalyze a nine-step reaction sequence to replace the L-Ser hydroxyl by indole giving L-Trp and a water molecule. Within αβ dimeric units of the αββα bienzyme complex, the common intermediate indole is channeled from the α site to the β site via an interconnecting 25 Å-long tunnel. The TS system provides an unusual example of allosteric control wherein the structures of the nine different covalent intermediates along the β-reaction catalytic path and substrate binding to the α-site provide the allosteric triggers for switching the αββα system between the open (T) and closed (R) allosteric states. This triggering provides a linkage that couples the allosteric conformational coordinate to the covalent chemical reaction coordinates at the α- and β-sites. This coupling drives the α- and β-sites between T and R conformations to achieve regulation of substrate binding and/or product release, modulation of the α- and β-site catalytic activities, prevention of indole escape from the confines of the active sites and the interconnecting tunnel, and synchronization of the α- and β-site catalytic activities. Here we review recent advances in the understanding of the relationships between structure, function, and allosteric regulation of the complex found in","journal":"Frontiers in Molecular Biosciences","year":2022,"id":272098,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9642,"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":390583,"name":"E. Hilario","orcid":"0000-0002-9187-8892","position":1,"is_corresponding":false},{"id":327109,"name":"Chia‐en A. Chang","orcid":"0000-0002-6504-8529","position":2,"is_corresponding":false},{"id":454378,"name":"Leonard J. Mueller","orcid":"0000-0002-2607-9875","position":3,"is_corresponding":false},{"id":454377,"name":"Michael F. Dunn","orcid":"0000-0002-8657-0375","position":4,"is_corresponding":false},{"id":755297,"name":"Rittik K. Ghosh","orcid":null,"position":0,"is_corresponding":true}],"reference_count":127,"raw_metadata":null,"created_at":"2026-07-19T00:27:43.806977Z","pmid":"36172042","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":[]}