id: MODULE:oxidative_phosphorylation title: Oxidative phosphorylation (OXPHOS) module description: >- A taxon-neutral decomposition of oxidative phosphorylation: the coupled process by which a respiratory electron transport chain (ETC) oxidizes reduced cofactors and uses the released free energy to pump protons across a coupling membrane, and an F1Fo-ATP synthase uses the resulting proton-motive force to phosphorylate ADP. The module is deliberately phrased in terms of functional modules, protein complexes, and pathway segments rather than a fixed gene list, so it can represent the mitochondrial inner-membrane chain of eukaryotes and the plasma-membrane respiratory chains of aerobic bacteria. Design intent for complexes (the central modelling question): each respiratory complex is represented as a single PROTEIN_COMPLEX node whose emergent, complex-level catalytic activity is carried by ONE complex-level annoton (the redox half-reaction it performs), with its functionally important subunits exposed as `active_units` on the complex descriptor rather than as separate per-subunit annotons. This mirrors the GO `contributes_to` philosophy: an individual subunit contributes to but does not independently enable the complex activity. Large, internally modular complexes (Complex I; the F1Fo-ATP synthase) are additionally decomposed with `parts` into their functional sub-modules (the N/Q/proton-pumping arms of Complex I; the F1 catalytic head and Fo proton turbine of ATP synthase) — this recursive decomposition is the payoff of the module representation over a flat subunit list. Lineage- and chemistry-specific alternatives that bypass the proton-pumping complexes (type-II NADH dehydrogenase, the alternative oxidase, bacterial bd-type oxidases) are captured as `variant_sets` along explicit axes, so OXPHOS reads as one conserved energy-conservation plan with multiple implementations. Complex assembly/biogenesis is treated as a distinct process from chain operation and kept as an optional sub-module. status: DRAFT evidence: - source_id: GO:0006119 title: oxidative phosphorylation statement: The module is grounded in the GO biological-process term for oxidative phosphorylation. - source_id: GO:0022904 title: respiratory electron transport chain statement: Grounds the electron-transport-chain sub-process that builds the proton-motive force. - source_id: GO:0042776 title: proton motive force-driven mitochondrial ATP synthesis statement: Grounds the chemiosmotic ATP-synthesis sub-process coupled to the ETC. - source_id: PMID:10648801 title: "Progress in understanding structure-function relationships in respiratory chain complex II." statement: >- Review establishing the coordination of the TCA cycle and OXPHOS and the role of Complex II (succinate dehydrogenase) as the shared node feeding electrons from the TCA cycle into the respiratory chain. - source_id: file:projects/OXPHOS.md title: OXPHOS project page statement: >- The sibling gene-by-gene OXPHOS curation project, which this module generalizes from concrete human subunits and assembly factors to a taxon-neutral, recursively decomposable plan. notes: >- Identifiers are grounded only where verified against the local validated OXPHOS gene reviews, the OXPHOS project page, or the sibling photosynthesis module; descriptors without a `term` are deliberate (no confident identifier yet, or no exact GO term exists for the abstraction) rather than oversights. Subunit `active_units` are named by their conserved subunit/homolog families (human gene-symbol families given as orienting names) to keep the module taxon-neutral; a concrete organism module can later specialize these with specific UniProt gene products, stoichiometries, and compartments without the generic module enumerating every protein. Complex II is intentionally modelled here as a respiratory-chain electron-entry complex; its succinate->fumarate half-reaction simultaneously belongs to the TCA cycle and is the canonical dual-pathway node. The plasma membrane substitutes for the mitochondrial inner membrane as the coupling membrane in respiring bacteria. Scope boundaries: the biosynthesis of the quinone pool (e.g. the ubiquinone/CoQ COQ pathway) and of the redox cofactors (heme a/b/c, Fe-S clusters, FAD/FMN, copper centres), as well as the pro-apoptotic role of cytochrome c once released to the cytosol, are upstream or downstream of OXPHOS operation and are intentionally out of scope here; they belong to their own pathways/gene reviews, and this module treats the carriers and cofactors as supplied inputs. Per-complex assembly factors are given by example in the biogenesis sub-module rather than broken out as structured per-complex annotons; a concrete organism-specific specialization can add that detail. module: id: oxidative_phosphorylation label: Oxidative phosphorylation module_type: BIOLOGICAL_PROCESS concepts: - preferred_term: oxidative phosphorylation term: id: GO:0006119 label: oxidative phosphorylation description: >- Synthesis of ATP driven by the transfer of electrons through a membrane-embedded respiratory chain to a terminal acceptor (usually O2), coupled chemiosmotically via a transmembrane proton-motive force. - preferred_term: aerobic respiration term: id: GO:0009060 label: aerobic respiration description: >- The encompassing energy-yielding process when O2 is the terminal electron acceptor; OXPHOS is its membrane-bound, ATP-generating stage. - preferred_term: generation of precursor metabolites and energy term: id: GO:0006091 label: generation of precursor metabolites and energy context: taxa: - preferred_term: aerobic (and facultative) bacteria description: Respiratory chain assembled in the plasma membrane. - preferred_term: mitochondriate eukaryotes description: Respiratory chain assembled in the mitochondrial inner membrane. cellular_components: - preferred_term: mitochondrial inner membrane (eukaryotes) term: id: GO:0005743 label: mitochondrial inner membrane - preferred_term: plasma membrane (respiring bacteria) description: The bacterial coupling membrane, equivalent to the mitochondrial inner membrane. parts: - order: 1 role: respiratory electron transport and proton pumping node: id: respiratory_etc label: Respiratory electron transport chain module_type: BIOLOGICAL_PROCESS description: >- Sequential, exergonic electron transfer from reduced cofactors to a terminal acceptor through membrane redox complexes and two mobile carriers (a quinone pool and a soluble cytochrome/copper carrier), with three of the canonical complexes (I, III, IV) coupling electron flow to vectorial proton translocation that charges the membrane. concepts: - preferred_term: respiratory electron transport chain term: id: GO:0022904 label: respiratory electron transport chain - preferred_term: electron transport chain term: id: GO:0022900 label: electron transport chain parts: - order: 1 role: NADH:quinone oxidoreduction (canonical, proton-pumping) node: id: complex_I label: Complex I (NADH:ubiquinone oxidoreductase) module_type: PROTEIN_COMPLEX description: >- The largest respiratory complex (~1 MDa; ~14 conserved core subunits plus many accessory subunits in eukaryotes). An L-shaped enzyme whose hydrophilic arm oxidizes NADH and relays electrons through a chain of iron-sulfur clusters to reduce ubiquinone at the arm/membrane junction, and whose membrane arm uses the redox free energy to pump four protons per NADH via antiporter-like subunits. Functionally and evolutionarily tripartite: the N (NADH-oxidizing), Q (quinone-reducing) and P (proton-pumping) modules. concepts: - preferred_term: respiratory chain complex I term: id: GO:0045271 label: respiratory chain complex I annotons: - id: complex_I_activity label: NADH:ubiquinone oxidoreductase (proton-pumping) participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: NADH:ubiquinone oxidoreductase complex term: id: GO:0045271 label: respiratory chain complex I active_units: - id: ci_flavoprotein label: FMN/NADH-binding catalytic subunit (NDUFV1/NuoF/Nqo1 family) role: Primary electron acceptor; oxidizes NADH at the FMN, the entry point of the N-module. participant: selector_type: FAMILY family: preferred_term: NDUFV1 / NuoF / Nqo1 flavoprotein family function: preferred_term: NADH dehydrogenase activity (FMN-dependent) term: id: GO:0003954 label: NADH dehydrogenase activity - id: ci_fes_relay label: Iron-sulfur relay subunits (NDUFS1/NDUFV2/NDUFS7/NDUFS8 families) role: Chain of [2Fe-2S]/[4Fe-4S] clusters conducting electrons from FMN to the quinone site. participant: selector_type: FAMILY family: preferred_term: Complex I iron-sulfur subunits (NDUFS1/NuoG, NDUFV2/NuoE, NDUFS7/NuoB, NDUFS8/NuoI) function: preferred_term: electron transfer via iron-sulfur clusters term: id: GO:0009055 label: electron transfer activity - id: ci_quinone_subunit label: Quinone-binding core subunit (NDUFS2/NuoD/Nqo4 family) role: Forms the ubiquinone-reduction site at the junction of the hydrophilic and membrane arms. participant: selector_type: FAMILY family: preferred_term: NDUFS2 / NuoD / Nqo4 family - id: ci_membrane_pumps label: Antiporter-like proton-pumping membrane subunits (ND2/ND4/ND5; NuoL/M/N) role: Mitochondrially (or operon)-encoded membrane subunits that translocate protons driven by quinone-coupled conformational changes. participant: selector_type: FAMILY family: preferred_term: ND2/ND4/ND5 (NuoL/NuoM/NuoN) antiporter-like family function: preferred_term: NADH:ubiquinone oxidoreductase activity term: id: GO:0008137 label: NADH dehydrogenase (ubiquinone) activity substrates: - preferred_term: NADH - preferred_term: ubiquinone - preferred_term: proton (matrix/cytoplasmic side) products: - preferred_term: NAD+ - preferred_term: ubiquinol - preferred_term: proton (intermembrane/periplasmic side) cofactors: - preferred_term: FMN - preferred_term: iron-sulfur clusters processes: - preferred_term: mitochondrial electron transport, NADH to ubiquinone term: id: GO:0006120 label: mitochondrial electron transport, NADH to ubiquinone locations: - preferred_term: mitochondrial inner / bacterial plasma membrane term: id: GO:0005743 label: mitochondrial inner membrane role_description: >- Couples NADH oxidation and ubiquinone reduction to the translocation of ~4 H+ per NADH; the major entry point of electrons into the chain and a principal site of the proton-motive force and of superoxide production. parts: - order: 1 role: NADH oxidation (N-module) node: id: complex_I_N_module label: Complex I N-module (NADH dehydrogenase) module_type: MOLECULAR_FUNCTION description: >- Distal tip of the hydrophilic arm bearing the FMN and the first iron-sulfur clusters; oxidizes NADH and injects electrons into the relay. annotons: - id: ci_n_module_nadh_oxidation label: FMN-dependent NADH oxidation participant: selector_type: FAMILY family: preferred_term: N-module subunits (NDUFV1/NDUFV2/NDUFS1) function: preferred_term: NADH dehydrogenase activity term: id: GO:0003954 label: NADH dehydrogenase activity substrates: - preferred_term: NADH products: - preferred_term: NAD+ cofactors: - preferred_term: FMN - order: 2 role: ubiquinone reduction (Q-module) node: id: complex_I_Q_module label: Complex I Q-module (quinone reduction) module_type: MOLECULAR_FUNCTION description: >- Proximal hydrophilic-arm/membrane junction carrying the terminal iron-sulfur cluster (N2) and the ubiquinone-binding cavity where electrons reduce ubiquinone to ubiquinol. annotons: - id: ci_q_module_quinone_reduction label: Ubiquinone reduction at the Q-site participant: selector_type: FAMILY family: preferred_term: Q-module subunits (NDUFS2/NDUFS3/NDUFS7/NDUFS8) function: preferred_term: ubiquinone reduction description: >- Two-electron reduction of ubiquinone to ubiquinol; modelled as a sub-function of the complex-level NADH:ubiquinone oxidoreductase activity, so no separate exact GO MF id is asserted here. substrates: - preferred_term: ubiquinone products: - preferred_term: ubiquinol - order: 3 role: proton translocation (P-module / membrane arm) node: id: complex_I_P_module label: Complex I P-module (membrane proton-pumping arm) module_type: TRANSPORT_STEP description: >- Membrane arm of antiporter-like subunits that translocate protons; conformational energy from quinone chemistry is transmitted along the arm to drive pumping remote from the redox centres. annotons: - id: ci_p_module_proton_pumping label: Redox-coupled proton translocation participant: selector_type: FAMILY family: preferred_term: Membrane-arm antiporter-like subunits (ND1-ND6, ND4L; NuoH/J/K/L/M/N/A) function: preferred_term: proton transmembrane transporter activity term: id: GO:0015078 label: proton transmembrane transporter activity substrates: - preferred_term: proton (matrix/cytoplasmic side) products: - preferred_term: proton (intermembrane/periplasmic side) processes: - preferred_term: proton transmembrane transport term: id: GO:1902600 label: proton transmembrane transport - order: 2 role: succinate:quinone oxidoreduction (TCA-cycle-linked, non-pumping) node: id: complex_II label: Complex II (succinate dehydrogenase / succinate:quinone oxidoreductase) module_type: PROTEIN_COMPLEX description: >- The only membrane respiratory complex shared with the TCA cycle and the only canonical complex that does not pump protons. Its FAD-bearing flavoprotein oxidizes succinate to fumarate (TCA step 6) and relays electrons through three iron-sulfur clusters and a membrane b-heme to reduce ubiquinone, feeding the quinone pool without contributing to the proton-motive force. concepts: - preferred_term: respiratory chain complex II (succinate dehydrogenase) term: id: GO:0045273 label: respiratory chain complex II (succinate dehydrogenase) annotons: - id: complex_II_activity label: Succinate:ubiquinone oxidoreductase participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: succinate dehydrogenase (ubiquinone) complex term: id: GO:0045273 label: respiratory chain complex II (succinate dehydrogenase) active_units: - id: cii_flavoprotein label: Flavoprotein subunit (SDHA/SdhA family) role: Covalent-FAD subunit; oxidizes succinate to fumarate (the TCA-cycle half-reaction). participant: selector_type: FAMILY family: preferred_term: SDHA / SdhA flavoprotein family function: preferred_term: succinate dehydrogenase activity term: id: GO:0000104 label: succinate dehydrogenase activity - id: cii_fes label: Iron-sulfur subunit (SDHB/SdhB family) role: Three Fe-S clusters relaying electrons from FAD toward the quinone site; tumour-suppressor subunit in humans. participant: selector_type: FAMILY family: preferred_term: SDHB / SdhB iron-sulfur family function: preferred_term: electron transfer activity term: id: GO:0009055 label: electron transfer activity - id: cii_membrane_anchor label: Membrane-anchor / quinone-binding subunits (SDHC+SDHD / SdhC+SdhD) role: Bind heme b and form the ubiquinone-reduction site that delivers electrons to the quinone pool. participant: selector_type: FAMILY family: preferred_term: SDHC/SDHD (SdhC/SdhD) membrane-anchor family function: preferred_term: succinate dehydrogenase (quinone) activity term: id: GO:0008177 label: succinate dehydrogenase (quinone) activity substrates: - preferred_term: succinate - preferred_term: ubiquinone products: - preferred_term: fumarate - preferred_term: ubiquinol cofactors: - preferred_term: FAD - preferred_term: iron-sulfur clusters - preferred_term: heme b processes: - preferred_term: mitochondrial electron transport, succinate to ubiquinone term: id: GO:0006121 label: mitochondrial electron transport, succinate to ubiquinone locations: - preferred_term: mitochondrial inner / bacterial plasma membrane term: id: GO:0005743 label: mitochondrial inner membrane role_description: >- Bridges the TCA cycle and the respiratory chain; does not pump protons, so its electrons enter the quinone pool at no direct energetic gain to the proton-motive force. evidence: - source_id: PMID:10648801 statement: >- Succinate dehydrogenase is the shared node coupling the TCA cycle to the respiratory chain. - order: 3 role: auxiliary quinone-reducing dehydrogenases (additional electron entry) optional: true node: id: auxiliary_quinone_dehydrogenases label: Auxiliary dehydrogenases feeding the quinone pool module_type: BIOLOGICAL_PROCESS description: >- Membrane-associated dehydrogenases that reduce the quinone pool outside of Complexes I/II, coupling other metabolic pathways to respiration. None pump protons. Present to varying degrees across taxa and tissues. annotons: - id: etf_quinone_oxidoreductase label: Electron-transfer-flavoprotein:ubiquinone oxidoreductase (ETF-QO) participant: selector_type: ANY_WITH_FUNCTION required_function: preferred_term: electron-transferring-flavoprotein dehydrogenase activity term: id: GO:0004174 label: electron-transferring-flavoprotein dehydrogenase activity function: preferred_term: electron-transferring-flavoprotein dehydrogenase activity term: id: GO:0004174 label: electron-transferring-flavoprotein dehydrogenase activity substrates: - preferred_term: reduced electron-transfer flavoprotein - preferred_term: ubiquinone products: - preferred_term: oxidized electron-transfer flavoprotein - preferred_term: ubiquinol role_description: Channels electrons from mitochondrial fatty-acid beta-oxidation and amino-acid catabolism into the quinone pool. - id: glycerol_3_phosphate_dehydrogenase label: Mitochondrial glycerol-3-phosphate dehydrogenase (FAD) participant: selector_type: FAMILY family: preferred_term: FAD-dependent glycerol-3-phosphate dehydrogenase (GPD2 family) function: preferred_term: glycerol-3-phosphate:quinone oxidoreductase activity description: >- FAD-linked, outer-face inner-membrane enzyme of the glycerophosphate shuttle that oxidizes glycerol-3-phosphate and reduces ubiquinone; no confident exact GO MF id asserted here. substrates: - preferred_term: sn-glycerol 3-phosphate - preferred_term: ubiquinone products: - preferred_term: dihydroxyacetone phosphate - preferred_term: ubiquinol - id: dihydroorotate_dehydrogenase label: Dihydroorotate dehydrogenase (quinone) participant: selector_type: ANY_WITH_FUNCTION required_function: preferred_term: dihydroorotate dehydrogenase activity term: id: GO:0004152 label: dihydroorotate dehydrogenase activity function: preferred_term: dihydroorotate dehydrogenase (quinone) activity term: id: GO:0004152 label: dihydroorotate dehydrogenase activity substrates: - preferred_term: dihydroorotate - preferred_term: ubiquinone products: - preferred_term: orotate - preferred_term: ubiquinol role_description: Couples de novo pyrimidine biosynthesis to the quinone pool; a major reason respiration is required for nucleotide synthesis. - order: 4 role: mobile electron carrier (quinone pool) node: id: quinone_pool label: Quinone pool (ubiquinone/menaquinone) module_type: MOLECULAR_FUNCTION description: >- Lipid-soluble two-electron/two-proton carrier diffusing within the membrane that collects electrons from all upstream dehydrogenases and delivers them to Complex III (or to a quinol oxidase). The quinone used is lineage-dependent. annotons: - id: quinone_electron_carrier label: Membrane quinone electron/proton carrier participant: selector_type: ANY_PARTICIPANT description: A diffusible membrane quinone (not a protein); represented as a functional carrier node. function: preferred_term: quinone-mediated electron and proton transfer term: id: GO:0009055 label: electron transfer activity cofactors: - preferred_term: ubiquinone (CoQ10) — most eukaryotes and many proteobacteria - preferred_term: menaquinone / demethylmenaquinone — many bacteria locations: - preferred_term: mitochondrial inner / bacterial plasma membrane (lipid bilayer) term: id: GO:0005743 label: mitochondrial inner membrane - order: 5 role: quinol:cytochrome-c oxidoreduction (canonical, proton-pumping) node: id: complex_III label: Complex III (cytochrome bc1 / quinol:cytochrome-c reductase) module_type: PROTEIN_COMPLEX description: >- An obligate homodimer that oxidizes ubiquinol and reduces the soluble carrier (cytochrome c / c2) via the protonmotive Q-cycle, in which bifurcated electron transfer recycles one electron through two b-hemes to a second quinone, doubling the protons translocated per electron reaching cytochrome c. concepts: - preferred_term: respiratory chain complex III term: id: GO:0045275 label: respiratory chain complex III annotons: - id: complex_III_activity label: Quinol:cytochrome-c reductase (Q-cycle) participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: cytochrome bc1 complex (dimeric) term: id: GO:0045275 label: respiratory chain complex III active_units: - id: ciii_cytb label: Cytochrome b (MT-CYB / PetB family) role: Bears the low- and high-potential b-hemes (bL/bH) that carry out Q-cycle electron bifurcation; the only mtDNA-encoded subunit in animals. participant: selector_type: FAMILY family: preferred_term: cytochrome b (MT-CYB / QcrB) family function: preferred_term: electron transfer via b-type hemes term: id: GO:0009055 label: electron transfer activity - id: ciii_cyt_c1 label: Cytochrome c1 (CYC1 family) role: High-potential c1 heme that reduces the soluble cytochrome c carrier. participant: selector_type: FAMILY family: preferred_term: cytochrome c1 (CYC1 / QcrC) family function: preferred_term: electron transfer to cytochrome c term: id: GO:0009055 label: electron transfer activity - id: ciii_rieske label: Rieske iron-sulfur protein (UQCRFS1 / PetA family) role: Mobile [2Fe-2S] head that oxidizes ubiquinol at the Qo site and initiates Q-cycle bifurcation. participant: selector_type: FAMILY family: preferred_term: Rieske Fe-S protein (UQCRFS1 / QcrA / PetA) family function: preferred_term: ubiquinol oxidation via [2Fe-2S] cluster term: id: GO:0009055 label: electron transfer activity function: preferred_term: quinol-cytochrome-c reductase activity term: id: GO:0008121 label: quinol-cytochrome-c reductase activity substrates: - preferred_term: ubiquinol - preferred_term: cytochrome c (oxidized) - preferred_term: proton (matrix/cytoplasmic side) products: - preferred_term: ubiquinone - preferred_term: cytochrome c (reduced) - preferred_term: proton (intermembrane/periplasmic side) processes: - preferred_term: mitochondrial electron transport, ubiquinol to cytochrome c term: id: GO:0006122 label: mitochondrial electron transport, ubiquinol to cytochrome c locations: - preferred_term: mitochondrial inner / bacterial plasma membrane term: id: GO:0005743 label: mitochondrial inner membrane role_description: >- Oxidizes ubiquinol and reduces cytochrome c while translocating protons via the Q-cycle; frequently a rate-controlling step and a site of superoxide generation. - order: 6 role: mobile electron carrier (soluble cytochrome) node: id: cytochrome_c label: Cytochrome c (soluble carrier) module_type: MOLECULAR_FUNCTION description: >- Small soluble c-type cytochrome on the positive (intermembrane space / periplasmic) face that shuttles single electrons from Complex III to Complex IV. In eukaryotes the same protein is a pro-apoptotic signal when released to the cytosol. annotons: - id: cytochrome_c_electron_transfer label: Cytochrome c electron shuttling participant: selector_type: FAMILY family: preferred_term: cytochrome c / cytochrome c2 family function: preferred_term: electron transfer activity term: id: GO:0009055 label: electron transfer activity cofactors: - preferred_term: heme c locations: - preferred_term: intermembrane space / periplasm (positive membrane face) term: id: GO:0005758 label: mitochondrial intermembrane space - order: 7 role: terminal electron transfer to dioxygen (canonical, proton-pumping) node: id: complex_IV label: Complex IV (cytochrome c oxidase) module_type: PROTEIN_COMPLEX description: >- The terminal oxidase of the canonical chain; an aa3-type heme-copper oxidase that accepts electrons from cytochrome c and reduces O2 to water at a binuclear heme a3/CuB centre, both consuming matrix protons for chemistry and pumping additional protons across the membrane. concepts: - preferred_term: respiratory chain complex IV term: id: GO:0045277 label: respiratory chain complex IV annotons: - id: complex_IV_activity label: Cytochrome c oxidase (O2 reduction) participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: cytochrome c oxidase (aa3-type) term: id: GO:0045277 label: respiratory chain complex IV active_units: - id: civ_cox1 label: Catalytic subunit I (MT-CO1 / CoxA family) role: Bears heme a, and the heme a3/CuB binuclear centre where O2 is reduced to water; contains the proton channels. participant: selector_type: FAMILY family: preferred_term: cytochrome c oxidase subunit I (MT-CO1 / CoxA) family function: preferred_term: dioxygen reduction at the heme-copper centre term: id: GO:0004129 label: cytochrome-c oxidase activity - id: civ_cox2 label: Subunit II (MT-CO2 / CoxB family) role: Bears the binuclear CuA centre that receives electrons from cytochrome c. participant: selector_type: FAMILY family: preferred_term: cytochrome c oxidase subunit II (MT-CO2 / CoxB) family function: preferred_term: electron acceptance from cytochrome c (CuA centre) term: id: GO:0009055 label: electron transfer activity - id: civ_cox3 label: Subunit III (MT-CO3 / CoxC family) role: Core membrane subunit important for assembly and proton-pathway integrity; no redox cofactor. participant: selector_type: FAMILY family: preferred_term: cytochrome c oxidase subunit III (MT-CO3 / CoxC) family function: preferred_term: cytochrome-c oxidase activity term: id: GO:0004129 label: cytochrome-c oxidase activity substrates: - preferred_term: cytochrome c (reduced) - preferred_term: dioxygen - preferred_term: proton (matrix/cytoplasmic side) products: - preferred_term: cytochrome c (oxidized) - preferred_term: water - preferred_term: proton (intermembrane/periplasmic side) cofactors: - preferred_term: heme a - preferred_term: heme a3 - preferred_term: CuA - preferred_term: CuB processes: - preferred_term: mitochondrial electron transport, cytochrome c to oxygen term: id: GO:0006123 label: mitochondrial electron transport, cytochrome c to oxygen locations: - preferred_term: mitochondrial inner / bacterial plasma membrane term: id: GO:0005743 label: mitochondrial inner membrane role_description: >- Terminal, essentially irreversible step that reduces O2 to water and pumps protons; sets the directionality of the chain and is a key regulatory and tissue-specific (isoform) node. - order: 8 role: lineage-specific respiratory-chain variants (bypass branches) optional: true node: id: respiratory_chain_variants label: Lineage-specific entry and terminal-oxidase variants module_type: BIOLOGICAL_PROCESS description: >- Alternative implementations of the chain that exist alongside or in place of the canonical proton-pumping complexes. These bypass branches conserve less (or no) free energy as proton-motive force but provide metabolic flexibility, stress tolerance, and redox balancing. variant_sets: - id: nadh_to_quinone_route label: NADH:quinone oxidoreduction route axis: enzyme family / energy conservation selection: ONE_OR_MORE variants: - id: canonical_complex_I_variant label: Proton-pumping Complex I module_type: PROTEIN_COMPLEX description: The canonical, energy-conserving NADH:ubiquinone oxidoreductase (see complex_I node). annotons: - id: canonical_ci_ref label: Complex I (energy-conserving) participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: respiratory chain complex I term: id: GO:0045271 label: respiratory chain complex I role_description: Pumps ~4 H+ per NADH; present in most mitochondria and many bacteria. - id: type_II_ndh_variant label: Type-II NADH dehydrogenase (NDH-2, non-pumping) module_type: MOLECULAR_FUNCTION description: >- Single-subunit, FAD-dependent, rotenone-insensitive alternative NADH:quinone oxidoreductase found in plants, fungi, protists, and many bacteria (and absent in mammals). It reduces the quinone pool without pumping protons, providing a non-energy-conserving NADH bypass. annotons: - id: ndh2_activity label: NDH-2 NADH:quinone oxidoreductase (non-pumping) participant: selector_type: FAMILY family: preferred_term: type-II NADH dehydrogenase (NDH-2 / NDI1 / Ndh) family function: preferred_term: NADH dehydrogenase activity (non-proton-pumping) term: id: GO:0003954 label: NADH dehydrogenase activity substrates: - preferred_term: NADH - preferred_term: quinone products: - preferred_term: NAD+ - preferred_term: quinol role_description: Re-oxidizes NADH and reduces the quinone pool with no charge separation. - id: terminal_oxidase_route label: Route from the quinone pool / cytochrome c to O2 axis: terminal oxidase family / energy conservation selection: ONE_OR_MORE variants: - id: cytochrome_pathway_variant label: Cytochrome pathway (Complex III -> cytochrome c -> Complex IV) module_type: BIOLOGICAL_PROCESS description: The canonical, proton-pumping bc1 -> cytochrome c -> aa3 oxidase route (see complex_III, cytochrome_c, complex_IV nodes). annotons: - id: cytochrome_pathway_ref label: bc1 / cytochrome c / aa3 oxidase route participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: cytochrome pathway terminal segment description: The canonical CIII + cytochrome c + CIV segment of the chain. role_description: Energy-conserving; both CIII and CIV pump protons. - id: alternative_oxidase_variant label: Alternative oxidase (AOX) ubiquinol:O2 bypass module_type: MOLECULAR_FUNCTION description: >- Cyanide-insensitive, non-proton-pumping di-iron ubiquinol oxidase of plants, fungi, and many protists (and some animals) that oxidizes ubiquinol and reduces O2 to water directly, bypassing both Complex III and Complex IV and dissipating the redox energy as heat. annotons: - id: aox_activity label: Alternative oxidase (ubiquinol:O2 oxidoreductase) participant: selector_type: FAMILY family: preferred_term: alternative oxidase (AOX) family function: preferred_term: ubiquinol:oxygen oxidoreductase activity (non-pumping) description: >- Reduces O2 to water using ubiquinol at a non-heme di-iron centre; no proton pumping. No confident exact GO MF id is asserted here for the generic module. substrates: - preferred_term: ubiquinol - preferred_term: dioxygen products: - preferred_term: ubiquinone - preferred_term: water role_description: Provides an overflow/antioxidant electron sink; thermogenic in some plants. - id: bd_oxidase_variant label: Bacterial bd-type quinol oxidase module_type: MOLECULAR_FUNCTION description: >- High-O2-affinity cytochrome bd quinol oxidase used by many bacteria under microaerobic or stress conditions; oxidizes quinol and reduces O2 to water with a lower (or no) proton pumping stoichiometry than heme-copper oxidases. annotons: - id: bd_oxidase_activity label: Cytochrome bd quinol oxidase participant: selector_type: FAMILY family: preferred_term: cytochrome bd ubiquinol oxidase (CydAB) family function: preferred_term: quinol:oxygen oxidoreductase activity description: Reduces O2 to water from quinol; no confident exact GO MF id asserted here for the generic module. substrates: - preferred_term: quinol - preferred_term: dioxygen products: - preferred_term: quinone - preferred_term: water role_description: Confers tolerance to low O2, nitrosative and oxidative stress in bacteria. connections: - source: complex_I target: quinone_pool connection_type: PROVIDES_INPUT_FOR description: Complex I reduces ubiquinone to ubiquinol, charging the quinone pool. - source: complex_II target: quinone_pool connection_type: PROVIDES_INPUT_FOR description: Complex II reduces the quinone pool from succinate (TCA cycle). - source: auxiliary_quinone_dehydrogenases target: quinone_pool connection_type: PROVIDES_INPUT_FOR description: ETF-QO, glycerol-3-phosphate dehydrogenase, and DHODH reduce the quinone pool from other pathways. - source: quinone_pool target: complex_III connection_type: PROVIDES_INPUT_FOR description: Ubiquinol from the pool is the substrate oxidized by Complex III at the Qo site. - source: complex_III target: cytochrome_c connection_type: PROVIDES_INPUT_FOR description: Complex III reduces the soluble cytochrome c carrier. - source: cytochrome_c target: complex_IV connection_type: PROVIDES_INPUT_FOR description: Reduced cytochrome c donates electrons to Complex IV. - source: quinone_pool target: respiratory_chain_variants connection_type: PROVIDES_INPUT_FOR description: The alternative oxidase and bacterial quinol oxidases draw electrons directly from the quinone pool, bypassing CIII/CIV. - order: 2 role: chemiosmotic ATP synthesis from the proton-motive force node: id: atp_synthesis label: ATP synthesis (F1Fo-ATP synthase, Complex V) module_type: PROTEIN_COMPLEX description: >- A rotary molecular motor that couples proton flow down the electrochemical gradient (through the membrane Fo sector) to mechanical rotation that drives ADP phosphorylation at the catalytic F1 head. It is the terminal energy-conserving step of OXPHOS and runs reversibly: under collapse of the proton-motive force it can hydrolyze ATP, a mode restrained by a dedicated inhibitor. concepts: - preferred_term: proton-transporting ATP synthase complex term: id: GO:0045259 label: proton-transporting ATP synthase complex - preferred_term: proton-transporting two-sector ATPase complex term: id: GO:0016469 label: proton-transporting two-sector ATPase complex annotons: - id: complex_V_activity label: Proton-motive-force-driven ATP synthesis (rotational) participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: F1Fo-ATP synthase term: id: GO:0045259 label: proton-transporting ATP synthase complex active_units: - id: cv_f1_catalytic label: F1 catalytic subunits (alpha3/beta3 + central stalk) role: alpha3beta3 hexamer with catalytic sites on the beta subunits; the gamma/delta/epsilon central stalk converts c-ring rotation into catalytic conformational cycling. participant: selector_type: FAMILY family: preferred_term: F1 ATP synthase subunits (ATP5F1A/ATP5F1B/ATP5F1C; AtpA/AtpD/AtpG) function: preferred_term: ATP synthesis at the catalytic beta subunit term: id: GO:0046933 label: "proton-transporting ATP synthase activity, rotational mechanism" - id: cv_fo_rotor label: Fo proton-translocating sector (c-ring + a-subunit) role: The membrane c-ring rotor and stator a-subunit form the two half-channels through which protons cross, driving rotation. participant: selector_type: FAMILY family: preferred_term: Fo c-ring and a-subunit (ATP5MC1-3 / ATP5MK; AtpE/AtpB) function: preferred_term: proton transmembrane transporter activity coupled to rotation term: id: GO:0015078 label: proton transmembrane transporter activity - id: cv_peripheral_stalk label: Peripheral stalk / stator (OSCP, b, d, F6) role: Holds the alpha3beta3 head against the torque of rotation (the stator), coupling proton flow to catalysis. participant: selector_type: FAMILY family: preferred_term: ATP synthase peripheral stalk (ATP5PO/OSCP, ATP5PB, ATP5PD, ATP5PF; AtpF/AtpH) function: preferred_term: "proton-transporting ATP synthase activity, rotational mechanism" term: id: GO:0046933 label: "proton-transporting ATP synthase activity, rotational mechanism" substrates: - preferred_term: ADP - preferred_term: phosphate - preferred_term: proton (intermembrane/periplasmic side) products: - preferred_term: ATP - preferred_term: proton (matrix/cytoplasmic side) processes: - preferred_term: proton motive force-driven mitochondrial ATP synthesis term: id: GO:0042776 label: proton motive force-driven mitochondrial ATP synthesis locations: - preferred_term: mitochondrial inner / bacterial plasma membrane term: id: GO:0005743 label: mitochondrial inner membrane role_description: >- Converts the proton-motive force into the bulk of cellular ATP; also shapes inner-membrane cristae through dimer rows. parts: - order: 1 role: catalytic head (F1) node: id: atp_synthase_F1 label: F1 catalytic head module_type: MOLECULAR_FUNCTION description: >- Soluble alpha3beta3 hexamer with three catalytic sites cycling through open/loose/tight states (binding-change mechanism) as the central stalk rotates; synthesizes ATP from ADP and phosphate. annotons: - id: f1_atp_synthesis label: Rotational ATP synthesis at F1 participant: selector_type: FAMILY family: preferred_term: F1 alpha/beta/gamma subunits function: preferred_term: "proton-transporting ATP synthase activity, rotational mechanism" term: id: GO:0046933 label: "proton-transporting ATP synthase activity, rotational mechanism" substrates: - preferred_term: ADP - preferred_term: phosphate products: - preferred_term: ATP - order: 2 role: proton turbine (Fo) node: id: atp_synthase_Fo label: Fo proton-translocating sector module_type: TRANSPORT_STEP description: >- Membrane sector where protons crossing between the a-subunit half-channels protonate/deprotonate c-ring carboxylates, driving rotation of the c-ring and central stalk. annotons: - id: fo_proton_transport label: Proton-driven c-ring rotation participant: selector_type: FAMILY family: preferred_term: Fo c-ring and a-subunit function: preferred_term: proton transmembrane transporter activity term: id: GO:0015078 label: proton transmembrane transporter activity substrates: - preferred_term: proton (intermembrane/periplasmic side) products: - preferred_term: proton (matrix/cytoplasmic side) processes: - preferred_term: proton transmembrane transport term: id: GO:1902600 label: proton transmembrane transport - order: 3 role: inhibition of reverse (ATP-hydrolysis) mode optional: true node: id: atp_synthase_inhibition label: IF1-mediated inhibition of ATP hydrolysis module_type: REGULATORY_STEP description: >- A pH-sensitive inhibitor (IF1 / ATPIF1 in animals; equivalents elsewhere) binds the F1 catalytic interface when the membrane potential collapses, blocking wasteful ATP hydrolysis without impeding synthesis. annotons: - id: if1_inhibitor label: ATP synthase inhibitory factor participant: selector_type: FAMILY family: preferred_term: ATPase inhibitory factor 1 (ATP5IF1 / IF1) family function: preferred_term: ATPase inhibitor activity description: pH-dependent inhibition of the F1 ATP-hydrolysis (reverse) reaction. No exact GO MF id asserted in the generic module. role_description: Prevents the synthase from running backwards and dissipating ATP under ischemia/uncoupling. connections: - source: if1_inhibitor target: complex_V_activity connection_type: NEGATIVELY_REGULATES description: IF1 inhibits the hydrolytic (reverse) mode of the ATP synthase. - order: 3 role: supercomplex (respirasome) organization optional: true node: id: respirasome_organization label: Respiratory supercomplex (respirasome) organization module_type: CELLULAR_COMPONENT description: >- In many eukaryotes (and some bacteria) Complexes I, III2, and IV associate into supercomplexes/respirasomes, and the ATP synthase forms cristae-shaping dimer rows. Supercomplex assembly is promoted by dedicated factors and is thought to aid stability, assembly, and possibly substrate channeling; it is a distinct higher-order organization layered on top of the individual complexes. annotons: - id: respirasome_assembly label: Respirasome (I+III2+IV) and ATP synthase dimer organization participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: respiratory chain supercomplex / respirasome description: >- Higher-order assembly of Complex I, the Complex III dimer, and Complex IV (with assembly factors such as COX7A2L/SCAF1); no single generic GO complex id is asserted here. role_description: >- Organizes the individual respiratory complexes into supercomplexes and the ATP synthase into cristae-shaping rows; an organizational, not catalytic, module. - order: 4 role: biogenesis of the respiratory complexes (supporting context) optional: true node: id: oxphos_biogenesis label: OXPHOS complex biogenesis (assembly factors and cofactor delivery) module_type: BIOLOGICAL_PROCESS description: >- Each respiratory complex is built by dedicated assembly factors and cofactor-maturation enzymes that are NOT stable subunits and do NOT themselves carry out electron transport — they should be annotated to assembly/cofactor-insertion processes, not to the chain's catalytic activities. This sub-module captures that distinction generically rather than enumerating the (dozens of) factors per complex. annotons: - id: complex_assembly_factors label: Respiratory-complex assembly factors participant: selector_type: ANY_PARTICIPANT description: >- Examples by complex (human): Complex I — NDUFAF1-8, ACAD9, TMEM126B, NUBPL (Fe-S); Complex II — SDHAF1-4 (Fe-S/FAD); Complex III — BCS1L, LYRM7, TTC19; Complex IV — SURF1, SCO1/2, COX10/COX15 (heme A), COA factors; Complex V — TMEM70, ATPAF1/2. function: preferred_term: respiratory-complex assembly and cofactor maturation description: >- Chaperone-, scaffold-, and cofactor-insertion activities that build and mature the complexes (Fe-S cluster transfer, heme A/heme O biosynthesis, copper delivery, FAD insertion). Modelled as a process distinct from chain operation. role_description: >- Distinguishes complex biogenesis from complex function; loss of an assembly factor causes a complex deficiency without the factor being part of the mature electron-transport machinery. connections: - source: respiratory_etc target: atp_synthesis connection_type: PRECEDES description: >- The electron transport chain pumps protons to build the proton-motive force that the ATP synthase consumes. This is energetic (chemiosmotic) coupling across the membrane, not a direct metabolite hand-off; the two are obligately coupled but can be uncoupled (e.g. by uncoupling proteins or protonophores).