{"doi":"10.1101/2025.10.07.680981","title":"PANK2-mediated <i>de novo</i> CoA synthesis is required for metabolic switching to fatty acid oxidation","abstract":"ABSTRACT Humans have 3 different PANK enzymes (PANK1-3) that catalyze the first step in the de novo synthesis of Coenzyme A (CoA). All PANKs are feedback inhibited by acyl-CoAs but only PANK2 can overcome this inhibition by binding palmitoyl-carnitine. Previous studies, conducted under glucose-replete conditions, have failed to detect a PANK2-mediated contribution to CoA synthesis. We found that exposure to BSA-conjugated palmitate (PAL-BSA) led to activation of fatty acid oxidation (FAO) and the accumulation of both palmitoyl-carnitine and palmitoyl-CoA in HEK293T cells, suggesting that PANK2 is active under these conditions. Isotope tracing experiments with 13 C 15 N-pantothenate showed that PANK2 uniquely sustains de novo CoA synthesis and high production of Acetyl-CoA in the presence of long-chain fatty acids, indicating that FAO is limited by CoA availability in these conditions. Consistent with this mechanism, fibroblasts from PKAN patients exhibited impaired oxidation of palmitoyl-carnitine, confirming the functional relevance of our results in a disease context.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":577184,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9583,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":580570,"name":"Robert J. Schafer","orcid":"0000-0002-0874-830X","position":1,"is_corresponding":false},{"id":261886,"name":"Adam J. Rauckhorst","orcid":"0000-0002-4101-0075","position":2,"is_corresponding":false},{"id":1486729,"name":"Ana M Santos-Exposito","orcid":null,"position":3,"is_corresponding":false},{"id":1486730,"name":"Andrés Prieto-Rodríguez","orcid":null,"position":4,"is_corresponding":false},{"id":679378,"name":"Bryce A. Wilson","orcid":null,"position":5,"is_corresponding":false},{"id":1486731,"name":"I. Antice Evans","orcid":null,"position":6,"is_corresponding":false},{"id":1486732,"name":"Una Hadziamehtovic","orcid":null,"position":7,"is_corresponding":false},{"id":1486733,"name":"Frances Nowlen","orcid":null,"position":8,"is_corresponding":false},{"id":1274903,"name":"Carlos Santos‐Ocaña","orcid":"0000-0002-2379-796X","position":9,"is_corresponding":false},{"id":261897,"name":"Eric B. Taylor","orcid":"0000-0003-4549-6567","position":10,"is_corresponding":false},{"id":326371,"name":"Michael C. Kruer","orcid":"0000-0002-1373-7891","position":11,"is_corresponding":false},{"id":123374,"name":"Sergio Lopez","orcid":"0000-0001-5952-3568","position":12,"is_corresponding":false},{"id":669733,"name":"Sandra M. Nordlie","orcid":"0000-0001-8095-2455","position":0,"is_corresponding":true}],"reference_count":32,"raw_metadata":null,"created_at":"2026-07-19T02:58:04.622308Z","pmid":"41279021","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":[]}