{"doi":"10.1101/2021.01.25.428124","title":"Nickel-Sulfonate Mode of Substrate Binding for Forward and Reverse Reactions of Methyl-SCoM Reductase Suggest a Radical Mechanism Involving Long Range Electron Transfer","abstract":"ABSTRACT Methyl-coenzyme M reductase (MCR) catalyzes both synthesis and anaerobic oxidation of methane (AOM). Its catalytic site contains Ni at the core of Cofactor F 430 . The Ni ion, in its low-valent Ni(I) state lights the fuse leading to homolysis of the C-S bond of methyl-coenzyme M (methyl-SCoM) to generate a methyl radical, which abstracts a hydrogen atom from Coenzyme B (HSCoB) to generate methane and the mixed disulfide CoMSSCoB. Direct reversal of this reaction activates methane to initiate anaerobic methane oxidation. Based on crystal structures, which reveal a Ni-thiol interaction between Ni(II)-MCR and inhibitor CoMSH, a Ni(I)-thioether complex with substrate methyl-SCoM has been transposed to canonical MCR mechanisms. Similarly, a Ni(I)-disulfide with CoMSSCoB is proposed for the reverse reaction. However, this Ni(I)-sulfur interaction poses a conundrum for the proposed hydrogen atom abstraction reaction because the >6 Å distance between the thiol group of SCoB and the thiol of SCoM observed in the structures appears too long for such a reaction. Spectroscopic, kinetic, structural and computational studies described here establish that both methyl-SCoM and CoMSSCoB bind to the active Ni(I) state of MCR through their sulfonate groups, forming a hexacoordinate Ni(I)-N/O complex, not Ni(I)-S. These studies rule out direct Ni(I)-sulfur interactions in both substrate-bound states. As a solution to the mechanistic conundrum, we propose that both forward and reverse MCR reactions emanate through long-range electron transfer from Ni(I)-sulfonate complexes with methyl-SCoM or CoMSSCoB, respectively.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":222969,"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":0.957,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":780547,"name":"Ritimukta Sarangi","orcid":"0000-0002-2764-2279","position":1,"is_corresponding":false},{"id":750886,"name":"Bojana Ginovska","orcid":"0000-0003-0165-8202","position":2,"is_corresponding":false},{"id":498834,"name":"Simone Raugei","orcid":"0000-0001-9118-8480","position":3,"is_corresponding":false},{"id":328499,"name":"Stephen W. Ragsdale","orcid":"0000-0003-3938-8906","position":4,"is_corresponding":false},{"id":824168,"name":"Anjali Patwardhan","orcid":"0000-0002-9479-220X","position":0,"is_corresponding":true}],"reference_count":61,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:54:07.287704Z","pmid":null,"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":[]}