{"doi":"10.1021/acschembio.4c00204","title":"Characterization, Structure, and Inhibition of the Human Succinyl-CoA:glutarate-CoA Transferase, a Putative Genetic Modifier of Glutaric Aciduria Type 1","abstract":"Glutaric Aciduria Type 1 (GA1) is a serious inborn error of metabolism with no pharmacological treatments. A novel strategy to treat this disease is to divert the toxic biochemical intermediates to less toxic or nontoxic metabolites. Here, we report a putative novel target, succinyl-CoA:glutarate-CoA transferase (SUGCT), which we hypothesize suppresses the GA1 metabolic phenotype through decreasing glutaryl-CoA and the derived 3-hydroxyglutaric acid. SUGCT is a type III CoA transferase that uses succinyl-CoA and glutaric acid as substrates. We report the structure of SUGCT, develop enzyme- and cell-based assays, and identify valsartan and losartan carboxylic acid as inhibitors of the enzyme in a high-throughput screen of FDA-approved compounds. The cocrystal structure of SUGCT with losartan carboxylic acid revealed a novel pocket in the active site and further validated the high-throughput screening approach. These results may form the basis for the future development of new pharmacological intervention to treat GA1.","journal":"ACS Chemical Biology","year":2024,"id":459710,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.955,"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":570377,"name":"Susmita Khamrui","orcid":null,"position":1,"is_corresponding":false},{"id":470524,"name":"Tetyana Dodatko","orcid":null,"position":2,"is_corresponding":false},{"id":447174,"name":"João Leandro","orcid":"0000-0002-0163-3235","position":3,"is_corresponding":false},{"id":1152370,"name":"Amanda Sabovic","orcid":null,"position":4,"is_corresponding":false},{"id":218457,"name":"Sara Violante","orcid":"0000-0003-2124-5712","position":5,"is_corresponding":false},{"id":218459,"name":"Justin R. Cross","orcid":"0000-0002-6356-057X","position":6,"is_corresponding":false},{"id":363618,"name":"Eric S. Marsan","orcid":"0000-0003-3862-7485","position":7,"is_corresponding":false},{"id":678131,"name":"Kunal Kumar","orcid":"0000-0002-1184-4837","position":8,"is_corresponding":false},{"id":469443,"name":"Robert J. DeVita","orcid":"0000-0002-2671-8497","position":9,"is_corresponding":false},{"id":447175,"name":"Michael B. Lazarus","orcid":"0000-0002-6738-2563","position":10,"is_corresponding":false},{"id":266343,"name":"Sander M. Houten","orcid":"0000-0002-6167-9147","position":11,"is_corresponding":false},{"id":1197668,"name":"Ruoxi Wu","orcid":null,"position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-19T02:03:59.428859Z","pmid":"38915184","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":[]}