{"doi":"10.1021/acs.biochem.5c00316","title":"A Structurally Divergent Class Ia Ribonucleotide Reductase from a Tick-Borne Pathogen","abstract":"Ribonucleotide reductases (RNRs) generate 2′-deoxynucleotides for DNA biosynthesis, a reaction essential to all life. Class I RNRs have two subunits, α and β. α binds and reduces the substrate, whereas β oxidizes one of the cysteines in α to a C3′–H-bond-cleaving thiyl radical to begin the reaction. The α-Cys oxidant in β is variously a tyrosyl radical (Y • ) generated by a diiron or dimanganese cluster, a high-valent dimetal cluster [Mn(IV)/Fe(III) or Mn 2 (IV/III)], or a dihydroxylphenylalanine (DOPA) radical that operates without need of a transition metal. The metal (in)dependence of the Cys oxidant in β correlates loosely with sequence-similarity groupings. We show here that Francisella hispaniensis ( Fh ) β, which lies within an uncharacterized sequence cluster that contains orthologs from multiple human pathogens, harbors a Fe 2 (III/III)/Y • cofactor, as in class Ia RNRs from eukaryotes and Escherichia coli . Fh β has several unusual structural features that may reflect adaptation to the bacterium’s environment(s). In its apo form, an unwound helix everts a metal ligand toward solvent, and the radical-harboring Y points away from the diiron cluster. An additional aromatic residue (W194), conserved within the sequence cluster, is found close to the universally conserved W37, which is thought to mediate α-Cys oxidation in all class I enzymes. The Y • in resting β is remarkably resistant to reduction by hydroxyurea but becomes 8000 times more sensitive when β is engaged in turnover with α. These structural and functional distinctions could be counter measures against host redox defenses that would target the pathogen’s RNR and its cofactor.","journal":"Biochemistry","year":2025,"id":546458,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9512,"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":1218081,"name":"Gavin M. Palowitch","orcid":"0000-0003-0283-7894","position":1,"is_corresponding":false},{"id":1438588,"name":"John P. Gajewski","orcid":null,"position":2,"is_corresponding":false},{"id":582412,"name":"Kai Hu","orcid":"0000-0002-6555-2581","position":3,"is_corresponding":false},{"id":1438589,"name":"A. H. Wheeler","orcid":null,"position":4,"is_corresponding":false},{"id":600020,"name":"Tatiana N. Laremore","orcid":"0000-0002-1036-8963","position":5,"is_corresponding":false},{"id":238647,"name":"Steve Silletti","orcid":null,"position":6,"is_corresponding":false},{"id":318431,"name":"Elizabeth A. Komives","orcid":"0000-0001-5264-3866","position":7,"is_corresponding":false},{"id":1218085,"name":"Benjamin D. Allen","orcid":"0000-0001-6914-5572","position":8,"is_corresponding":false},{"id":827640,"name":"Alexey Silakov","orcid":"0000-0002-9285-1253","position":9,"is_corresponding":false},{"id":304952,"name":"Carsten Krebs","orcid":"0000-0002-3302-7053","position":10,"is_corresponding":false},{"id":304951,"name":"J. Martin Bollinger","orcid":"0000-0003-0751-8585","position":11,"is_corresponding":false},{"id":272543,"name":"Chi‐Yun Lin","orcid":"0000-0001-6555-8767","position":12,"is_corresponding":false},{"id":642752,"name":"Amie K. Boal","orcid":"0000-0002-1234-8472","position":13,"is_corresponding":false},{"id":1229582,"name":"Olivia M. Peduzzi","orcid":"0000-0002-6867-4955","position":0,"is_corresponding":true}],"reference_count":145,"raw_metadata":null,"created_at":"2026-07-19T02:53:32.285899Z","pmid":"40877217","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":[]}