{"doi":"10.3390/biophysica5030041","title":"Resistance of Nitric Oxide Dioxygenase and Cytochrome c Oxidase to Inhibition by Nitric Oxide and Other Indications of the Spintronic Control of Electron Transfer","abstract":"Heme enzymes that bind and reduce O2 are susceptible to poisoning by NO. The high reactivity and affinity of NO for ferrous heme produces stable ferrous-NO complexes, which in theory should preclude O2 binding and turnover. However, NO inhibition is often competitive with respect to O2 and rapidly reversible, thus providing cellular and organismal survival advantages. This kinetic paradox has prompted a search for mechanisms for reversal and hence resistance. Here, I critically review proposed resistance mechanisms for NO dioxygenase (NOD) and cytochrome c oxidase (CcO), which substantiate reduction or oxidation of the tightly bound NO but nevertheless fail to provide kinetically viable solutions. A ferrous heme intermediate is clearly not available during rapid steady-state turnover. Reversible inhibition can be attributed to NO competing with O2 in transient low-affinity interactions with either the ferric heme in NOD or the ferric heme-cupric center in CcO. Toward resolution, I review the underlying principles and evidence for kinetic control of ferric heme reduction via an O2-triggered ferric heme spin crossover and an electronically-forced motion of the heme and structurally-linked protein side chains that elicit electron transfer and activate O2 in the flavohemoglobin-type NOD. For CcO, kinetics, structures, and density functional theory point to the existence of an analogous O2 and reduced oxygen intermediate-controlled electron-transfer gate with a linked proton pump function. A catalytic cycle and mechanism for CcO is finally at hand that links each of the four O2-reducing electrons to each of the four pumped protons in time and space. A novel proton-conducting tunnel and channel, electron path, and pump mechanism, most notably first hypothesized by Mårten Wikström in 1977 and pursued since, are laid out for further scrutiny. In both models, low-energy spin-orbit couplings or ‘spintronic’ interactions with O2 and NO or copper trigger the electronic motions within heme that activate electron transfer to O2, and the exergonic reactions of transient reactive oxygen intermediates ultimately drive all enzyme, electron, and proton motions.","journal":"Biophysica","year":2025,"id":528839,"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":0.9438,"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":515001,"name":"Paul R. Gardner","orcid":"0000-0001-8189-0903","position":0,"is_corresponding":true}],"reference_count":262,"raw_metadata":null,"created_at":"2026-07-19T02:50:52.565868Z","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":[]}