{"doi":"10.1101/2023.08.08.552419","title":"Crystal Structure of Histone Deacetylase 6 Complexed with ( <i>R</i> )-Lipoic Acid, an Essential Cofactor in Central Carbon Metabolism","abstract":"Abstract The enzyme cofactor ( R )-lipoic acid plays a critical role in central carbon metabolism due to its catalytic function in the generation of acetyl-CoA, which links glycolysis with the tricarboxylic acid cycle. This cofactor is also essential for the generation of succinyl CoA within the tricarboxylic acid cycle. However, the biological functions of ( R )-lipoic acid extend beyond metabolism owing to its facile redox chemistry. Most recently, the reduced form of ( R )-lipoic acid, ( R )-dihydrolipoic acid, has been shown to inhibit histone deacetylases (HDACs) with selectivity for the inhibition of HDAC6. Here, we report the 2.4 Å-resolution X-ray crystal structure of the HDAC6–( R )-dihydrolipoic acid complex, and we report a dissociation constant (K D ) of 350 nM for this complex as determined by isothermal titration calorimetry. The crystal structure illuminates key affinity determinants in the enzyme active site, including thiolate-Zn 2+ coordination and S-π interactions in the F583-F643 aromatic crevice. This study provides the first visualization of the connection between HDAC function and the biological response to oxidative stress: the dithiol moiety of ( R )-dihydrolipoic acid can serve as a redox-regulated pharmacophore capable of simultaneously targeting the catalytic Zn 2+ ion and the aromatic crevice in the active site of HDAC6.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":394939,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9551,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":974003,"name":"Juana Goulart Stollmaier","orcid":"0000-0002-5110-8818","position":1,"is_corresponding":false},{"id":63442,"name":"David W. Christianson","orcid":"0000-0002-0194-5212","position":2,"is_corresponding":false},{"id":452836,"name":"P. R. Watson","orcid":"0000-0002-6990-525X","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":null,"created_at":"2026-07-19T01:19:18.686170Z","pmid":"37609266","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":[]}