{"doi":"10.1016/j.jbc.2024.108074","title":"Mammalian hydroxylation of microbiome-derived obesogen, delta-valerobetaine, to homocarnitine, a 5-carbon carnitine analog","abstract":"The recently discovered microbiome-generated obesogen, δ-valerobetaine (5-(trimethylammonio)pentanoate), is a 5-carbon structural analog of the carnitine precursor, γ-butyrobetaine. Here, we report that δ-valerobetaine is enzymatically hydroxylated by mammalian γ-butyrobetaine dioxygenase (BBOX) to form 3-hydroxy-5-(trimethylammonio)pentanoate, a 5-carbon analog of carnitine, which we term homocarnitine. Homocarnitine production by human liver extracts depends upon the required BBOX cofactors, 2-oxoglutarate, Fe 2+ , and ascorbate. Molecular dynamics simulations show successful docking of δ-valerobetaine and homocarnitine to BBOX, pharmacological inhibition of BBOX prevents homocarnitine production, and transfection of a liver cell line with BBOX substantially increases production. Furthermore, an in vivo isotope tracer study shows the conversion of 13 C 3 -trimethyllysine to 13 C 3 -δ-valerobetaine then 13 C 3 -homocarnitine in mice, confirming the in vivo production of homocarnitine. Functional assays show that carnitine palmitoyltransferase acylates homocarnitine to acyl-homocarnitine, analogous to the reactions for the carnitine shuttle. Studies of mouse tissues and human plasma show widespread distribution of homocarnitine and fatty acyl-homocarnitines. The respective structural similarities of homocarnitine and acyl-homocarnitines to carnitine and acyl-carnitines indicate that homocarnitine could impact multiple sites of carnitine distribution and activity, potentially mediating microbiome-associated obesity and metabolic disorders.","journal":"Journal of Biological Chemistry","year":2024,"id":460567,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9542,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":246041,"name":"Ken Liu","orcid":"0000-0002-9736-5828","position":1,"is_corresponding":false},{"id":436665,"name":"Choon‐Myung Lee","orcid":null,"position":2,"is_corresponding":false},{"id":454773,"name":"William J. Crandall","orcid":"0000-0002-2537-2033","position":3,"is_corresponding":false},{"id":852626,"name":"André Cuevas","orcid":"0000-0002-9103-5908","position":4,"is_corresponding":false},{"id":649122,"name":"Samuel Druzak","orcid":null,"position":5,"is_corresponding":false},{"id":435351,"name":"Edward T. Morgan","orcid":"0000-0003-4273-2261","position":6,"is_corresponding":false},{"id":300622,"name":"Zachery Jarrell","orcid":"0000-0003-4670-1497","position":7,"is_corresponding":false},{"id":74596,"name":"Eric A. Ortlund","orcid":"0000-0001-8855-3029","position":8,"is_corresponding":false},{"id":24174,"name":"Greg S. Martin","orcid":"0000-0002-9684-7593","position":9,"is_corresponding":false},{"id":668553,"name":"Grant Singer","orcid":null,"position":10,"is_corresponding":false},{"id":1060951,"name":"Frederick H. Strobel","orcid":null,"position":11,"is_corresponding":false},{"id":300625,"name":"Young‐Mi Go","orcid":"0000-0003-3353-0844","position":12,"is_corresponding":false},{"id":231483,"name":"Dean P. Jones","orcid":"0000-0002-2090-0677","position":13,"is_corresponding":false},{"id":875333,"name":"Jaclyn Weinberg","orcid":"0000-0002-1855-3338","position":0,"is_corresponding":true}],"reference_count":87,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:04:07.925246Z","pmid":"39675709","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":[]}