{"doi":"10.1021/jacs.3c07941","title":"Cobalt–Sulfur Coordination Chemistry Drives B<sub>12</sub> Loading onto Methionine Synthase","abstract":") is an essential cobalt-containing organometallic cofactor in mammals and is escorted via an intricate network of chaperones to a single cytoplasmic target, methionine synthase. In this study, we report that the human cobalamin trafficking protein, MMADHC, exploits the chemical lability of Co-S coordination for cofactor off-loading onto methionine synthase. Cys-261 on MMADHC serves as the β-axial ligand to cobalamin. Complex formation between MMADHC and methionine synthase is signaled by loss of the lower axial nitrogen ligand, leading to five-coordinate thiolato-cobalamin. Nucleophilic displacement by the vicinal thiolate, Cys-262, completes cofactor transfer to methionine synthase and release of a cysteine disulfide-containing MMADHC. The physiological relevance of this mechanism is supported by clinical variants of MMADHC, which impair cofactor binding and off-loading, explaining the molecular basis of the associated homocystinuria.","journal":"Journal of the American Chemical Society","year":2023,"id":387659,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9596,"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":647270,"name":"Arkajit Guha","orcid":null,"position":1,"is_corresponding":false},{"id":286482,"name":"Zhu Li","orcid":"0000-0003-1536-9401","position":2,"is_corresponding":false},{"id":495543,"name":"Markus Ruetz","orcid":"0000-0001-9540-7310","position":3,"is_corresponding":false},{"id":580288,"name":"Sojin An","orcid":"0000-0003-4783-4400","position":4,"is_corresponding":false},{"id":350209,"name":"Javier Seravalli","orcid":"0000-0001-5619-9424","position":5,"is_corresponding":false},{"id":265994,"name":"Ruma Banerjee","orcid":"0000-0001-8332-3275","position":6,"is_corresponding":false},{"id":495542,"name":"Romila Mascarenhas","orcid":"0000-0002-5099-3528","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-19T01:18:08.845494Z","pmid":"37916782","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":[]}