NQO2 (NRH:quinone oxidoreductase 2 / quinone reductase 2, QR2; UniProt recommended name ribosyldihydronicotinamide dehydrogenase [quinone], EC 1.10.5.1) is a cytosolic FAD-dependent flavoprotein of the NAD(P)H:quinone oxidoreductase family and a paralog of NQO1. It functions as a homodimer, with each subunit binding one FAD and one structural zinc ion. NQO2 catalyzes the two-electron reduction of quinones to hydroquinones (quinols), a reaction linked to quinone detoxification and to the metabolism/bioactivation of quinone-derived and nitroaromatic compounds (e.g. the prodrug CB1954). Its defining biochemical feature, distinguishing it from NQO1, is that it does not use NAD(P)H efficiently; its efficient reactions instead use dihydronicotinamide riboside (NRH) or other reduced N-ribosyl/N-alkyl dihydronicotinamides as electron donors. Weak NADH-dependent quinone reduction is measurable in vitro, whereas its physiological contribution remains uncertain. NQO2 is also the cytosolic "MT3" melatonin binding site: melatonin and the polyphenol resveratrol are high-affinity active-site inhibitors, making QR2 a notable pharmacological target.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003955 NAD(P)H dehydrogenase (quinone) activity | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: NQO2 strongly favors NRH but retains weak measurable NADH-dependent quinone reduction. The NAD(P)H reaction is a secondary catalytic capability, not its efficient core reaction. Reason: PTHR10204 places the ancestral NAD(P)H-quinone activity at PTN000024521. NQO2 has diverged in cofactor efficiency, but the reaction term specifies chemistry without an efficiency threshold. PMID:35517822 explicitly describes extremely inefficient NADH/NADPH usage and summarizes measured human NQO2 NADH turnover; this does not establish efficient physiological NAD(P)H utilization. The existing OpenScientist report correctly identifies NRH preference but its removal recommendation treats inefficient usage as absence. Retain this inherited activity as non-core and keep GO:0001512 as the defining efficient activity. Supporting Evidence: PMID:35517822 it uses conventional dihydronicotinamide cosubstrates, NADH and NADPH, extremely inefficiently file:human/NQO2/NQO2-hypotheses/function-hypothesis-go-0003955/openscientist.md recommend REMOVAL of the IBA GO:0003955 |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation of cytosolic localization, consistent with UniProt (SUBCELLULAR LOCATION: Cytoplasm) and with direct experimental evidence for QR2 as a soluble cytosolic enzyme. Reason: Core localization. NQO2/QR2 is a well-established cytosolic enzyme; the IBA agrees with the IDA and TAS cytosol annotations. |
| GO:0001512 dihydronicotinamide riboside quinone reductase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (IEA) annotation of the NRH:quinone reductase activity. This is the correct, cofactor-specific molecular function for NQO2 (EC 1.10.5.1; RHEA:12364), corroborated by IDA. Reason: Core catalytic function. Matches UniProt EC 1.10.5.1 and the demonstrated NRH-dependent quinone reduction; agrees with the IDA annotation of the same term. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Automated (IEA) cytoplasm annotation from UniProt subcellular-location mapping. Correct but a general parent of the more precise cytosol annotations. Reason: Consistent general localization; cytosol (GO:0005829) is the more informative core term. |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | REMOVE | Summary: Generic protein binding from a large-scale (Y2H) human interactome mapping effort. Records a physical interaction but conveys no specific functional information. Reason: The interaction evidence can be retained in the reference record, but generic protein binding does not describe the quinone-reductase function. Remove the uninformative GO term without disputing the reported interaction or inferring an unsupported replacement. |
| GO:0005515 protein binding | IPI PMID:24606901 Cochaperone binding to LYR motifs confers specificity of iro... | UNDECIDED | Summary: The HSC20 study does not resolve the specific NQO2 interaction in the available relevant text. Reason: The accessible source establishes HSC20 recognition of LYR motifs but does not identify the NQO2-specific assay or a functional interaction class. Do not dismiss the curated IPI observation from incomplete coverage or invent a replacement; the specific binding annotation remains unresolved. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Generic protein binding from a proteome-scale human interactome network map (systematic Y2H). Reason: The interaction evidence can be retained in the reference record, but generic protein binding does not describe the quinone-reductase function. Remove the uninformative GO term without disputing the reported interaction or inferring an unsupported replacement. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | REMOVE | Summary: Generic protein binding from an interactome-perturbation study of genetic variants. Reason: The interaction evidence can be retained in the reference record, but generic protein binding does not describe the quinone-reductase function. Remove the uninformative GO term without disputing the reported interaction or inferring an unsupported replacement. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from the HuRI reference map of the human binary protein interactome. Reason: The interaction evidence can be retained in the reference record, but generic protein binding does not describe the quinone-reductase function. Remove the uninformative GO term without disputing the reported interaction or inferring an unsupported replacement. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Direct (immunofluorescence-based) evidence for cytosolic localization of NQO2. Reason: Core localization, directly supported and consistent with all other cytosol annotations. |
| GO:1901662 quinone catabolic process | IDA PMID:18254726 Kinetic, thermodynamic and X-ray structural insights into th... | ACCEPT | Summary: NQO2 converts quinones to reduced products; whether that conversion detoxifies or bioactivates them depends on the substrate. Reason: The primary structural and enzymatic study supports quinone conversion by NQO2. A detoxification-only interpretation is too narrow because some reduced quinones or drug products are more reactive. Retain quinone catabolism while separating catalytic conversion from its toxicological outcome. Supporting Evidence: PMID:18254726 it was believed that QR2 might also serve as a detoxification enzyme that can produce hydroquinones which are less toxic to cells compared with the parent quinones |
| GO:0016661 oxidoreductase activity, acting on other nitrogenous compounds as donors | IDA PMID:10945627 Bioactivation of 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB ... | MODIFY | Summary: General oxidoreductase term used for the NRH-dependent reductase activity. This term maps to EC 1.7.-.- (nitrogenous compounds as donors), a different EC branch than NQO2's EC 1.10.5.1; it mis-classifies the activity relative to the specific NRH:quinone reductase term. Reason: Replace with the specific, correctly-branched GO:0001512 (EC 1.10.5.1), which describes the demonstrated NRH:quinone reductase reaction and is already annotated here by IDA. Proposed replacements: dihydronicotinamide riboside quinone reductase activity |
| GO:0005829 cytosol | IDA PMID:10945627 Bioactivation of 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB ... | ACCEPT | Summary: Direct experimental evidence for cytosolic localization from the CB1954 bioactivation study. Reason: Core localization, directly supported. |
| GO:0009055 electron transfer activity | IDA PMID:10945627 Bioactivation of 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB ... | ACCEPT | Summary: NQO2 transfers electrons from reduced nicotinamide donors to quinone acceptors through FAD. Reason: The current GO:0009055 definition includes enzymatic redox transformations; it is not restricted to respiratory-chain carriers. Direct quinone reductase assays demonstrate the relevant electron transfer, so the former over-annotation judgment imposed an unsupported restriction on the term. |
| GO:0009055 electron transfer activity | IDA PMID:18254726 Kinetic, thermodynamic and X-ray structural insights into th... | ACCEPT | Summary: NQO2 transfers electrons from reduced nicotinamide donors to quinone acceptors through FAD. Reason: The current GO:0009055 definition includes enzymatic redox transformations; it is not restricted to respiratory-chain carriers. Direct quinone reductase assays demonstrate the relevant electron transfer, so the former over-annotation judgment imposed an unsupported restriction on the term. |
| GO:0016491 oxidoreductase activity | IDA PMID:10945627 Bioactivation of 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB ... | ACCEPT | Summary: Oxidoreductase activity is an accurate broad molecular function for NQO2. Reason: The two-electron reduction of quinones is the defining catalytic reaction. Breadth and coexistence with a more specific NRH-dependent term do not make this core redox function non-core. |
| GO:0001512 dihydronicotinamide riboside quinone reductase activity | IDA PMID:18254726 Kinetic, thermodynamic and X-ray structural insights into th... | ACCEPT | Summary: Direct experimental annotation of the NRH:quinone reductase activity, the core catalytic function of NQO2 (EC 1.10.5.1; RHEA:12364). Structural/kinetic work characterized the QR2 active site and its dihydronicotinamide donor. Reason: Core molecular function, directly supported and matching UniProt EC and the Rhea reaction. Supporting Evidence: PMID:10945627 its activity is normally latent, and a nonbiogenic co-substrate such as NRH [nicotinamide riboside (reduced)] is required for enzymatic activity |
| GO:0008270 zinc ion binding | IDA PMID:18254726 Kinetic, thermodynamic and X-ray structural insights into th... | ACCEPT | Summary: Direct evidence for zinc binding. QR2 binds one structural Zn2+ per subunit (UniProt COFACTOR), resolved in the crystal structures. Reason: Bona fide structural cofactor of NQO2 (1 Zn2+/subunit), integral to the folded enzyme. |
| GO:0031404 chloride ion binding | IDA PMID:18254726 Kinetic, thermodynamic and X-ray structural insights into th... | KEEP AS NON CORE | Summary: Chloride ion binding observed in a QR2 crystal structure. Chloride is not listed among NQO2's functional cofactors (UniProt COFACTOR gives only FAD and Zn2+) and most likely reflects a crystallographic/buffer ion rather than a functional interaction. Reason: Real crystallographic observation but not a recognized functional cofactor; not part of the core function. |
| GO:0042803 protein homodimerization activity | IPI PMID:18254726 Kinetic, thermodynamic and X-ray structural insights into th... | ACCEPT | Summary: NQO2 is an obligate homodimer, with the active sites formed at the dimer interface; this is a specific, structurally-supported interaction (unlike generic protein binding). Reason: Genuine, informative homodimerization supported by crystal structures and confirmed as the biological unit (UniProt SUBUNIT: Homodimer). Non-core relative to catalysis but valid. |
| GO:0071949 FAD binding | IDA PMID:18254726 Kinetic, thermodynamic and X-ray structural insights into th... | ACCEPT | Summary: Direct evidence for FAD binding. NQO2 is a flavoprotein; each subunit binds FAD, the redox cofactor essential for the two-electron quinone reduction. Reason: Core cofactor binding; FAD is obligatory for catalysis and resolved in the QR2 structures. |
| GO:1904408 melatonin binding | IDA PMID:18254726 Kinetic, thermodynamic and X-ray structural insights into th... | KEEP AS NON CORE | Summary: Direct evidence that NQO2/QR2 binds melatonin - QR2 is the cytosolic "MT3" melatonin binding site. Melatonin is a competitive active-site inhibitor (vs the dihydronicotinamide donor), seen crystallographically in multiple active-site orientations. Reason: Well-evidenced and biologically notable (defining pharmacology of QR2/MT3), but it is inhibitor/ligand binding at the active site rather than the core catalytic function. Supporting Evidence: PMID:18254726 MT3 was purified to homogeneity and identified as QR2 (quinone reductase 2) PMID:18254726 melatonin binds in multiple orientations within the active sites of the QR2 dimer as opposed to an allosteric site |
| GO:1905594 resveratrol binding | IDA PMID:18254726 Kinetic, thermodynamic and X-ray structural insights into th... | KEEP AS NON CORE | Summary: Direct evidence for resveratrol binding. In the annotated paper the evidence is a biophysical binding assay - isothermal titration calorimetry (ITC) gave a Kd of ~39 nM - together with IC50 inhibition assays; resveratrol was used there as a positive-control active-site ligand. The QR2:resveratrol crystal structure itself is from an earlier study (Buryanovskyy et al. 2004, PDB 1SG0), which this paper reuses for molecular replacement and docking. Note the contrast with cao-1, where resveratrol is a substrate rather than an inhibitor. GO is obsoleting GO:1905594 resveratrol binding (go-ontology issues #32321/#32333, Jul 2026); NQO2 (P16083) is one of the two EXP-annotated proteins that triggered the obsoletion, the other being cao-1. Reason: Robustly evidenced inhibitor/ligand binding (ITC Kd ~39 nM), pharmacologically important, but not the core physiological catalytic function. The IDA to PMID:18254726 is supported by that paper's own ITC measurement; the primary structural evidence (PDB 1SG0) resides in Buryanovskyy et al. 2004 (Biochemistry; PMID:15350128), added to the references here. IMPORTANT distinction for the pending obsoletion: the obsoletion issue recommends reannotating both proteins "to enzyme activity with chebi id", but that fits only cao-1, where resveratrol is the catalytic SUBSTRATE (-> the new GO:7770086 resveratrol dioxygenase activity, go-ontology PR #32332 merged 2026-07-17). For NQO2 resveratrol is a competitive ACTIVE-SITE INHIBITOR, not a substrate or product, so there is no molecular-function replacement; on obsoletion this annotation should simply be dropped, not reannotated to a catalytic term. This is exactly the substrate-versus-inhibitor ambiguity that made GO:1905594 ill-defined. Supporting Evidence: PMID:18254726 Resveratrol was found to interact strongly with QR2 with a Kd of 39 nM |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8936519 | ACCEPT | Summary: Traceable-author-statement cytosol annotation from Reactome (NQO2:FAD dimer reduces quinones to hydroquinones). Reason: Consistent core localization; corroborates the IDA/IBA cytosol annotations. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: High-throughput proteomic detection of NQO2 in exosomes (prostatic-secretion/urine exosome proteomics). Common for abundant cytosolic proteins; not evidence of a functional extracellular localization. Reason: Mass-spectrometry detection in an exosome preparation; NQO2 is fundamentally a cytosolic enzyme, so this is not a functionally informative localization. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: High-throughput proteomic detection of NQO2 in urinary exosomes. Reason: Proteomics detection in exosomes; not a functional localization for this cytosolic enzyme. |
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Experiment: Structure-guided separation-of-function mutants (active-site vs Zn/FAD sites) assayed for NRH: quinone reductase activity and for melatonin/resveratrol inhibition, to dissect the catalytic versus ligand-binding (MT3) roles of the active site.
Experiment: Metabolomic comparison of NQO2-proficient vs NQO2-null human cells challenged with model quinones, to determine which quinones are detoxified versus bioactivated and to test the NRH dependence in a cellular context.
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