DUOX1 encodes dual oxidase 1, a large multi-pass plasma-membrane NADPH oxidase of the NOX/DUOX family that makes hydrogen peroxide outside the cell. Its cytosolic dehydrogenase domain binds NADPH and FAD and passes electrons through two hemes in the transmembrane ferric-reductase domain to oxygen at the outer face of the membrane, releasing H2O2 rather than superoxide. Calcium binding to EF-hand modules in the long intracellular loop switches the enzyme on. DUOX1 works as a complex with the maturation factor DUOXA1, which takes it from the endoplasmic reticulum to the apical plasma membrane of polarized epithelia. A large extracellular N-terminal domain resembles animal heme peroxidases but in mammals lacks the heme-ligating residues and has no peroxidase activity. In mammals the H2O2 is a co-substrate for lactoperoxidase in airway host defense and for thyroid peroxidase in thyroid hormone synthesis, and acts as a local signal in epithelial wound responses. Nothing has been measured on the horse protein: these functions are inferred from human DUOX1, which is in the same PANTHER subfamily (PTHR11972:SF75). The UniProt entry F6YEX2 (1516 aa) is the Ensembl canonical product of horse DUOX1 and carries all calcium, heme and FAD binding residues of human DUOX1, but its gene model stops 35 residues short of the human C-terminus, which other horse DUOX1 transcripts do encode.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004601 peroxidase activity | IEA GO_REF:0000002 | REMOVE | Summary: Peroxidase activity assigned by the InterPro haem-peroxidase superfamily signature (IPR010255), which matches the extracellular N-terminal peroxidase-homology domain of DUOX1. Reason: The peroxidase-homology domain of mammalian DUOX1 is not a functional peroxidase. The purified human DUOX1 domain binds no heme and has no peroxidase activity, and the cryo-EM structure shows that the heme-ligating histidine is absent; human DUOX1 carries a curated NOT peroxidase activity annotation from that work. The horse record carries the PROSITE PRU00298 caution that conserved residues needed to propagate the peroxidase features are missing, and the horse domain is present in full and of the same SF75 subfamily as human, so there is no basis for expecting it to differ. Only the nematode orthologue's domain binds heme and is weakly active. An earlier report of peroxidase activity in lysates (PMID:11514595) is contradicted for the human domain by the purified-protein study. No PAINT node in PTHR11972 asserts peroxidase activity, which agrees with this. The InterPro mapping is a fold-level transfer to a pseudo-peroxidase domain. Supporting Evidence: PMID:19460756 the isolated hDUOX1(1-593) does not bind heme and has no intrinsic peroxidase activity PMID:33420071 key residues for heme binding, such as the heme ligand histidine, are missing in the PHD of hDUOX1 file:HORSE/DUOX1__F6YEX2/DUOX1__F6YEX2-uniprot.txt Lacks conserved residue(s) required for the propagation of feature annotation. |
| GO:0005509 calcium ion binding | IEA GO_REF:0000120 | ACCEPT | Summary: Calcium ion binding through the EF-hand modules in the long intracellular loop between TM1 and TM2, plus the structural Ca2+ site in the peroxidase-homology domain. Reason: DUOX1 activity is switched on by Ca2+ binding to its EF-hands, and mutation of those Ca2+ sites abolishes activation in human DUOX1. F6YEX2 retains all 15 Ca2+-ligand residues mapped in human DUOX1 and both EF-hand PROSITE motifs, unlike the alternative horse product A0A9L0SQG9 that lacks EF-hand 1. The binding is regulatory rather than catalytic, but it is how the enzyme is controlled. No experiment has been done on horse DUOX1; this is an inference from human DUOX1 within PANTHER subfamily PTHR11972:SF75. Supporting Evidence: PMID:33420071 the functional DUOX protein has an additional large N-terminal extracellular peroxidase homology domain (PHD) and a long intracellular loop 0 containing two EF-hand domains, and it requires an auxiliary DUOXA protein for proper function PMID:33420071 It is reported that mutations of any of these calcium-binding sites abolished calcium activation file:HORSE/DUOX1/DUOX1-bioinformatics/RESULTS-rereview.md | F6YEX2 | 1516 | PTHR11972:SF75;PTHR11972 | ENSECAT00000026134 | True | 91.4% | 1-1516 | none | Ca(2+) 15/15; heme 13/13; FAD 8/8; NADPH 6/11 | file:HORSE/DUOX1__F6YEX2/DUOX1__F6YEX2-uniprot.txt PROSITE; PS00018; EF_HAND_1; 2. |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Endoplasmic reticulum, transferred by Ensembl Compara from human DUOX1. Reason: DUOX enzymes fold, pair with DUOXA and are N-glycosylated in the ER before moving to the cell surface; the ER pool is a maturation compartment, not where the enzyme acts. The direct ER evidence is mostly from DUOX2 and from the human DUOX1 co-expression work. Kept as true but peripheral, as in the human review. Supporting Evidence: PMID:25761904 The oxidative folding of DUOX2 that takes place in the endoplasmic reticulum (ER) appears to be a key event in the trafficking of the DUOX2/DUOXA2 complex PMID:22814254 DUOX activator (DUOXA) proteins act as organizing elements for surface expression and activity of the DUOX enzymes. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Plasma membrane, from PAINT node PTN001735877 (NOX/DUOX/RBOH clade), whose seeds include human DUOX1. Reason: DUOX1 is a multi-pass plasma-membrane enzyme that moves electrons from cytosolic NADPH to extracellular O2. F6YEX2 sits inside the clade that inherited the PAINT assertion (PTHR11972:SF75), has a predicted signal peptide and all seven human TM helices, and there is no evidence of loss. The term is correct; apical plasma membrane, also carried, is the more specific polarized-epithelium location. Supporting Evidence: PMID:33420071 Dual oxidases (DUOXs) produce hydrogen peroxide by transferring electrons from intracellular NADPH to extracellular oxygen. file:HORSE/DUOX1/DUOX1-bioinformatics/RESULTS-rereview.md | TM helix 1 (592-616) | 1.00 | 1.00 | 0.40 | 1.00 | file:HORSE/DUOX1__F6YEX2/DUOX1__F6YEX2-uniprot.txt PANTHER; PTHR11972:SF75; DUAL OXIDASE 1; 1. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Plasma membrane, from the UniProt combined automated pipeline (human and mouse DUOX1 orthologs). Reason: Same claim as the IBA row and accepted for the same reasons: DUOX1 acts at the cell surface, and F6YEX2 keeps all transmembrane segments of the human protein. Supporting Evidence: PMID:33420071 Dual oxidases (DUOXs) produce hydrogen peroxide by transferring electrons from intracellular NADPH to extracellular oxygen. PMID:39126279 DUOX1 and DUOX2 are correctly sorted to the apical membrane via the membrane-spanning DUOX maturation proteins DUOXA1 and DUOXA2, respectively, when co-expressed in MDCK epithelial cells |
| GO:0006590 thyroid hormone generation | IEA GO_REF:0000041 | KEEP AS NON CORE | Summary: Thyroid hormone generation, from the UniPathway thyroid hormone biosynthesis mapping. Reason: DUOX enzymes supply the H2O2 that thyroid peroxidase uses to iodinate thyroglobulin, and DUOX1 catalyses that H2O2-forming step itself, so this is participation rather than mere necessity. It is non-core for DUOX1: DUOX2 is the dominant thyroid paralog, and DUOX1 is mainly an airway enzyme. There is no horse thyroid data. Kept as non-core, matching the human review. Supporting Evidence: PMID:10806195 Two cDNAs encoding NADPH oxidases and constituting the thyroid H(2)O(2) generating system have been cloned. PMID:15062544 The limiting factor of this reaction is the supply of hydrogen peroxide. |
| GO:0006952 defense response | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Defense response, from the deep NOX/DUOX ancestral node PTN000239643. Reason: The PAINT placement at the family root is reasonable: NOX and DUOX oxidants serve host defense across eukaryotes, and human DUOX1 supplies H2O2 for lactoperoxidase-dependent airway defense. For DUOX1 this is a consequence of its oxidase activity in mucosal epithelium rather than its core molecular role, so it is kept as non-core. The term is broad but is as specific as the phylogenetic inference supports. Supporting Evidence: PMID:19386603 Activation of the NADPH oxidase homolog dual oxidase 1 (DUOX1) within the airway epithelium represents a key mechanism of innate airway host defense, through enhanced production of H2O2 PMID:34168077 In primary human tracheobronchial epithelial cells, OSCN- is generated by LPO using DUOX1-derived H2O2 and inactivates several influenza strains in vitro. |
| GO:0006979 response to oxidative stress | IEA GO_REF:0000002 | REMOVE | Summary: Response to oxidative stress, assigned by the haem-peroxidase superfamily signature (IPR010255). Reason: This InterPro2GO mapping is made on the assumption that the domain is a peroxide-consuming peroxidase. The DUOX1 peroxidase-homology domain binds no heme and has no peroxidase activity, and DUOX1 generates oxidant rather than responding to it. The annotation rests only on the domain signature and has no independent support. Removed, as in the human DUOX1 review; no PAINT node in the family carries this term. Supporting Evidence: PMID:19460756 the isolated hDUOX1(1-593) does not bind heme and has no intrinsic peroxidase activity PMID:33420071 Dual oxidases (DUOXs) produce hydrogen peroxide by transferring electrons from intracellular NADPH to extracellular oxygen. |
| GO:0009986 cell surface | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Cell surface, transferred by Ensembl Compara from human DUOX1 (IGI). Reason: DUOXA maturation factors bring DUOX enzymes to the cell surface, consistent with plasma-membrane residence. The term is broader and less informative than plasma membrane and apical plasma membrane, but it is not wrong; kept as non-core as in the human review. Supporting Evidence: PMID:22814254 DUOX activator (DUOXA) proteins act as organizing elements for surface expression and activity of the DUOX enzymes. |
| GO:0016174 NAD(P)H oxidase H2O2-forming activity | IBA GO_REF:0000033 | ACCEPT | Summary: NAD(P)H oxidase H2O2-forming activity, from the DUOX-specific PAINT node PTN000944147 (seeds include human DUOX1, DUOX2, pig and rat DUOX, Drosophila and C. elegans Duox). Reason: This is the core activity. The PAINT curators placed the H2O2-forming activity at the DUOX node and kept superoxide generation at the deeper NOX node, which matches the experimental record for DUOX enzymes. F6YEX2 is in PTHR11972:SF75, the DUOX1 subfamily that contains human DUOX1, and conserves all 13 heme and 8 FAD contact residues. It lacks the last 35 residues of the human protein, including 5 of 11 NADPH contacts, but the other horse DUOX1 transcripts of the same gene (for example A0A9L0SA70) cover the full human C-terminus with all 11 NADPH contacts, so the truncation is a property of this gene model, not of the horse gene. The activity is inferred, not measured in horse. Supporting Evidence: PMID:33420071 we found the co-expression of DUOX1 and DUOXA1 resulted in cell membranes that showed robust calcium-activated, NADPH-dependent hydrogen peroxide production detected by the Amplex Red assay file:HORSE/DUOX1/DUOX1-bioinformatics/RESULTS-rereview.md | F6YEX2 | 1516 | PTHR11972:SF75;PTHR11972 | ENSECAT00000026134 | True | 91.4% | 1-1516 | none | Ca(2+) 15/15; heme 13/13; FAD 8/8; NADPH 6/11 | file:HORSE/DUOX1/DUOX1-bioinformatics/RESULTS-rereview.md | A0A9L0SA70 | 1508 | PTHR11972:SF75;PTHR11972 | ENSECAT00000094364 | False | 92.0% | 1-1551 | 940-940; 963-1004 | Ca(2+) 15/15; heme 13/13; FAD 8/8; NADPH 11/11 | |
| GO:0016174 NAD(P)H oxidase H2O2-forming activity | IEA GO_REF:0000003 | ACCEPT | Summary: NAD(P)H oxidase H2O2-forming activity, from the EC 1.6.3.1 mapping. Reason: Same claim as the IBA row. EC 1.6.3.1 (NAD(P)H oxidase, H2O2-forming) is the right EC class for DUOX enzymes, which reduce O2 to H2O2 using NADPH. The EC number on the horse record is ARBA-assigned, so the support here is the human experimental data and the subfamily placement rather than the record itself. Supporting Evidence: PMID:33420071 we found the co-expression of DUOX1 and DUOXA1 resulted in cell membranes that showed robust calcium-activated, NADPH-dependent hydrogen peroxide production detected by the Amplex Red assay PMID:15972824 The particulate fractions of these cells stably or transiently transfected with human or porcine DUOX cDNA demonstrate a functional NADPH/Ca2+-dependent H2O2-generating activity. file:HORSE/DUOX1/DUOX1-bioinformatics/RESULTS-rereview.md | F6YEX2 | 1516 | PTHR11972:SF75;PTHR11972 | ENSECAT00000026134 | True | 91.4% | 1-1516 | none | Ca(2+) 15/15; heme 13/13; FAD 8/8; NADPH 6/11 | |
| GO:0016175 superoxide-generating NAD(P)H oxidase activity | IBA GO_REF:0000033 | MODIFY | Summary: Superoxide-generating NAD(P)H oxidase activity, from the deep NOX/DUOX ancestral node PTN000239643 (seeded by NOX1, NOX2, NOX4, NOX5 and relatives). Reason: A lateral correction argued from the phylogeny. PAINT placed superoxide generation at the deep NOX ancestor and placed the H2O2-forming activity separately at the DUOX node PTN000944147, whose seeds include human DUOX1. The DUOX experimental record matches that split: the mature enzyme releases H2O2, not superoxide, and the DUOXA1 C-terminus directs DUOX1 to H2O2 output. The superoxide claim is true of the family root but not of this subfamily, so the replacement is the sibling activity the DUOX node carries. Same action as in the human DUOX1 review. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000239643 · deep NOX/DUOX ancestral node carrying the IBD SUPPORTS SOURCE BUT NOT TARGET Node seeded by NOX-branch members (NOX1, CYBB/NOX2, NOX4, NOX5 and rodent and amoebal homologues); superoxide output is a property of that branch, not of the DUOX clade below it, which includes horse DUOX1 (PTHR11972:SF75). PANTHER:PTN000944147 · DUOX-specific node carrying the H2O2-forming IBD SUPPORTS TRANSFER Seeds include human DUOX1 (Q9NRD9), DUOX2 and the fly and nematode Duox proteins; PAINT placed NAD(P)H oxidase H2O2-forming activity here, which is the activity this row should carry. UniProtKB:P04839 · CYBB/NOX2 (human) SUPPORTS SOURCE BUT NOT TARGET Experimentally a superoxide generator; the seed is sound for the node and wrong for DUOX1. Proposed replacements: NAD(P)H oxidase H2O2-forming activity Supporting Evidence: PMID:15972824 it was shown that mature thyroid NADPH oxidase does not release O2*- but H2O2 PMID:22814254 We have shown that the COOH-terminal end of DUOXA1 is responsible for DUOX1-dependent H(2)O(2) generation. |
| GO:0016324 apical plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Apical plasma membrane, from the UniProt SubCell mapping (SL-0015) transferred from human DUOX1. Reason: Human DUOX1 is sorted to the apical membrane of polarized epithelial cells by DUOXA1, and apical staining is seen in airway epithelium. This is the most specific supported location and the one where the enzyme releases H2O2 into the lumen or airway surface liquid. No experiment has been done on horse DUOX1; this is an inference from human DUOX1 within PANTHER subfamily PTHR11972:SF75. Supporting Evidence: PMID:39126279 DUOX1 and DUOX2 are correctly sorted to the apical membrane via the membrane-spanning DUOX maturation proteins DUOXA1 and DUOXA2, respectively, when co-expressed in MDCK epithelial cells PMID:15210697 Anti-Duox antibody staining resulted in prominent apical staining in hTE but no significant staining in Calu-3. |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000002 | MODIFY | Summary: Oxidoreductase activity, from the FAD-binding and NAD-binding ferric-reductase-family InterPro signatures. Reason: Correct but too general. The specific activity, NAD(P)H oxidase H2O2-forming activity, is supported by the DUOX PAINT node and human biochemistry and is already carried by this gene (IBA and EC rows). Replaced with that descendant. Proposed replacements: NAD(P)H oxidase H2O2-forming activity Supporting Evidence: PMID:33420071 we found the co-expression of DUOX1 and DUOXA1 resulted in cell membranes that showed robust calcium-activated, NADPH-dependent hydrogen peroxide production detected by the Amplex Red assay file:HORSE/DUOX1/DUOX1-bioinformatics/RESULTS-rereview.md | FAD-binding FR-type (1270-1376) | 1.00 | 1.00 | 1.00 | 1.00 | |
| GO:0019221 cytokine-mediated signaling pathway | IEA GO_REF:0000107 | MODIFY | Summary: Cytokine-mediated signaling pathway, transferred by Ensembl Compara from a human DUOX1 IDA. Reason: The human evidence is that DUOX1 expression rises after IL-4 and IL-13 treatment of airway epithelium. A gene induced by a cytokine responds to it; it does not carry out a step of the receptor-proximal signal transduction pathway. The defensible term is the parent-level cellular response to cytokine stimulus, as chosen in the human review. Non-core. Proposed replacements: cellular response to cytokine stimulus Supporting Evidence: PMID:16111680 we determined that Duox1 expression was increased several-fold by treatment with the Th2 cytokines IL-4 and IL-13 |
| GO:0020037 heme binding | IEA GO_REF:0000120 | ACCEPT | Summary: Heme binding, from the UniProt combined pipeline (human and mouse DUOX1, and the haem-peroxidase signature). Reason: DUOX1 binds two b-type hemes in its transmembrane ferric-reductase domain, which carry electrons across the membrane. The haem-peroxidase signature contributing to this IEA points at the wrong domain (the peroxidase-homology domain binds no heme in mammals), but the claim is right for the protein because of the transmembrane hemes. F6YEX2 conserves all 13 heme-contact residues of human DUOX1. No experiment has been done on horse DUOX1; this is an inference from human DUOX1 within PANTHER subfamily PTHR11972:SF75. Supporting Evidence: PMID:33420071 The transmembrane layer is formed by 24 transmembrane helices and harbors the heme-binding sites that provide the electron transfer pathway across the membrane file:HORSE/DUOX1/DUOX1-bioinformatics/RESULTS-rereview.md | F6YEX2 | 1516 | PTHR11972:SF75;PTHR11972 | ENSECAT00000026134 | True | 91.4% | 1-1516 | none | Ca(2+) 15/15; heme 13/13; FAD 8/8; NADPH 6/11 | |
| GO:0031252 cell leading edge | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Cell leading edge, transferred by Ensembl Compara from human DUOX1. Reason: Functional DUOX1 concentrates at the leading edge of migrating airway cells. This is a context-dependent location secondary to the plasma membrane; kept as non-core, as in the human review. Supporting Evidence: PMID:19339556 Functional Duox1 and Duox2 localize to the leading edge of migrating cells, augmenting motility and wound healing. |
| GO:0032757 positive regulation of interleukin-8 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of interleukin-8 production, transferred by Ensembl Compara from a human DUOX1 IMP. Reason: In human airway epithelium, bacterial stimuli trigger ATP release and DUOX1 activation, and DUOX1-derived H2O2 drives EGFR/ERK signalling that raises IL-8 production. DUOX1 acts upstream through its oxidant product, so this is a downstream signalling consequence of its activity rather than its core role. Kept as non-core, as in the human review; there is no horse data. Supporting Evidence: PMID:19386603 this study demonstrates that airway epithelial IL-8 production in response to several bacterial stimuli involves ATP release and DUOX1 activation |
| GO:0042335 cuticle development | IEA GO_REF:0000107 | REMOVE | Summary: Cuticle development, transferred by Ensembl Compara from human DUOX1, whose annotation came from work on C. elegans Duox. Reason: Mammals have no cuticle. The source annotation on human DUOX1 rests on a study of the nematode orthologue, which cross-links cuticle tyrosines in hypodermal cells, and the human review removes it. Its Compara transfer to horse is equally unsupported. The nematode Duox peroxidase domain binds heme and is active, unlike the mammalian domain, so even the mechanism does not carry over. Supporting Evidence: PMID:11514595 Ce-Duox1 is expressed in hypodermal cells underlying the cuticle of larval animals. PMID:19460756 the isolated hDUOX1(1-593) does not bind heme and has no intrinsic peroxidase activity |
| GO:0042554 superoxide anion generation | IBA GO_REF:0000033 | MODIFY | Summary: Superoxide anion generation, from the deep NOX/DUOX ancestral node PTN000239643. Reason: The process counterpart of the superoxide activity row and corrected the same way. Note that human DUOX1 is not among the seeds of this IBD (its seeds are NOX enzymes, DUOX2 and amoebal relatives), and the mature DUOX enzyme releases H2O2, not superoxide. The process DUOX1 performs is hydrogen peroxide biosynthesis, which the gene also carries. Same action as in the human DUOX1 review. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000239643 · deep NOX/DUOX ancestral node carrying the IBD SUPPORTS SOURCE BUT NOT TARGET Node seeded by NOX-branch members (NOX1, CYBB/NOX2, NOX4, NOX5 and rodent and amoebal homologues); superoxide output is a property of that branch, not of the DUOX clade below it, which includes horse DUOX1 (PTHR11972:SF75). PANTHER:PTN000944147 · DUOX-specific node carrying the H2O2-forming IBD SUPPORTS TRANSFER Seeds include human DUOX1 (Q9NRD9) and DUOX2; PAINT placed the H2O2-forming activity here, whose process counterpart (hydrogen peroxide biosynthetic process) is the replacement for this row. UniProtKB:P04839 · CYBB/NOX2 (human) SUPPORTS SOURCE BUT NOT TARGET Experimentally a superoxide generator; the seed is sound for the node and wrong for DUOX1. Proposed replacements: hydrogen peroxide biosynthetic process Supporting Evidence: PMID:15972824 it was shown that mature thyroid NADPH oxidase does not release O2*- but H2O2 PMID:22814254 We have shown that the COOH-terminal end of DUOXA1 is responsible for DUOX1-dependent H(2)O(2) generation. |
| GO:0043020 NADPH oxidase complex | IBA GO_REF:0000033 | ACCEPT | Summary: NADPH oxidase complex, from PAINT node PTN000239643, whose seeds include human DUOX1. Reason: DUOX1 functions only as a complex with its maturation factor DUOXA1, and the cryo-EM structure of human DUOX1 is of that complex. The NOX catalytic subunits all work as membrane complexes with a partner subunit, so the root placement is sound and F6YEX2 is inside the clade. No experiment has been done on horse DUOX1; this is an inference from human DUOX1 within PANTHER subfamily PTHR11972:SF75. Supporting Evidence: PMID:33420071 the functional DUOX protein has an additional large N-terminal extracellular peroxidase homology domain (PHD) and a long intracellular loop 0 containing two EF-hand domains, and it requires an auxiliary DUOXA protein for proper function PMID:19339556 Characterization of novel DuoxA1 isoforms and mispaired Duox-DuoxA complexes revealed that heterodimerization is a prerequisite for reactive oxygen species production. |
| GO:0043020 NADPH oxidase complex | IEA GO_REF:0000120 | ACCEPT | Summary: NADPH oxidase complex, from the UniProt combined pipeline (human and mouse DUOX1). Reason: Same claim as the IBA row, accepted for the same reasons. Supporting Evidence: PMID:19339556 Duox proteins form functional heterodimers with their respective DuoxA subunits, in close analogy to the phagocyte NADPH oxidase. PMID:33420071 the functional DUOX protein has an additional large N-terminal extracellular peroxidase homology domain (PHD) and a long intracellular loop 0 containing two EF-hand domains, and it requires an auxiliary DUOXA protein for proper function |
| GO:0046982 protein heterodimerization activity | IEA GO_REF:0000107 | ACCEPT | Summary: Protein heterodimerization activity, transferred by Ensembl Compara from mouse Duox1. Reason: DUOX enzymes form functional heterodimers with their DUOXA subunits, and heterodimerization is needed for ROS production. This describes the DUOX1-DUOXA1 pairing better than generic protein binding. The DUOXA-interacting transmembrane region is intact in F6YEX2. No experiment has been done on horse DUOX1; this is an inference from human DUOX1 within PANTHER subfamily PTHR11972:SF75. Supporting Evidence: PMID:19339556 Duox proteins form functional heterodimers with their respective DuoxA subunits, in close analogy to the phagocyte NADPH oxidase. PMID:19339556 Characterization of novel DuoxA1 isoforms and mispaired Duox-DuoxA complexes revealed that heterodimerization is a prerequisite for reactive oxygen species production. |
| GO:0050665 hydrogen peroxide biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Hydrogen peroxide biosynthetic process, from the UniProt combined pipeline (human and mouse DUOX1). Reason: DUOX1 catalyses the H2O2-forming reaction itself, so it performs this process rather than being required for it. This is the process counterpart of the accepted H2O2-forming activity. The horse product keeps every heme and FAD contact residue of human DUOX1; its gene model is C-terminally short, but the same horse gene's other transcripts encode the full NADPH-binding C-terminus. No experiment has been done on horse DUOX1; this is an inference from human DUOX1 within PANTHER subfamily PTHR11972:SF75. Supporting Evidence: PMID:33420071 we found the co-expression of DUOX1 and DUOXA1 resulted in cell membranes that showed robust calcium-activated, NADPH-dependent hydrogen peroxide production detected by the Amplex Red assay file:HORSE/DUOX1/DUOX1-bioinformatics/RESULTS-rereview.md | F6YEX2 | 1516 | PTHR11972:SF75;PTHR11972 | ENSECAT00000026134 | True | 91.4% | 1-1516 | none | Ca(2+) 15/15; heme 13/13; FAD 8/8; NADPH 6/11 | file:HORSE/DUOX1/DUOX1-bioinformatics/RESULTS-rereview.md | A0A9L0SA70 | 1508 | PTHR11972:SF75;PTHR11972 | ENSECAT00000094364 | False | 92.0% | 1-1551 | 940-940; 963-1004 | Ca(2+) 15/15; heme 13/13; FAD 8/8; NADPH 11/11 | |
| GO:0051591 response to cAMP | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Response to cAMP, transferred by Ensembl Compara from human DUOX1. Reason: Human DUOX1 is induced by forskolin at the protein level and by thyrotropin, which act through cAMP in thyrocytes. The IDA on the human gene is from a promoter study that found the promoters are not positively controlled by cAMP, so the support is weak, and the claim concerns regulation of DUOX1 expression rather than its function. Kept as non-core with that caveat, matching the human review. Supporting Evidence: file:human/DUOX1/DUOX1-uniprot.txt INDUCTION: By forskolin (at protein level). |
| GO:0070402 NADPH binding | IEA GO_REF:0000120 | ACCEPT | Summary: NADPH binding, from the UniProt combined pipeline (human and mouse DUOX1). Reason: The cytosolic dehydrogenase domain binds NADPH, the electron donor. F6YEX2 is a C-terminally short gene model: it keeps 6 of the 11 NADPH-contact residues mapped in human DUOX1 and lacks the final 35 residues that carry the other 5. Other transcripts of the same horse gene encode the full C-terminus with all 11 contacts (for example A0A9L0SA70), so NADPH binding is a property of the horse gene product even if this particular model may not represent it completely. No experiment has been done on horse DUOX1; this is an inference from human DUOX1 within PANTHER subfamily PTHR11972:SF75. Supporting Evidence: PMID:33420071 The DH domain binds intracellular substrate NADPH and cofactor FAD file:HORSE/DUOX1/DUOX1-bioinformatics/RESULTS-rereview.md | F6YEX2 | 1516 | PTHR11972:SF75;PTHR11972 | ENSECAT00000026134 | True | 91.4% | 1-1516 | none | Ca(2+) 15/15; heme 13/13; FAD 8/8; NADPH 6/11 | file:HORSE/DUOX1/DUOX1-bioinformatics/RESULTS-rereview.md | A0A9L0SA70 | 1508 | PTHR11972:SF75;PTHR11972 | ENSECAT00000094364 | False | 92.0% | 1-1551 | 940-940; 963-1004 | Ca(2+) 15/15; heme 13/13; FAD 8/8; NADPH 11/11 | |
| GO:0071949 FAD binding | IEA GO_REF:0000120 | ACCEPT | Summary: FAD binding, from the UniProt combined pipeline (human and mouse DUOX1). Reason: FAD is the flavin cofactor of the dehydrogenase domain and accepts electrons from NADPH. F6YEX2 conserves the whole FAD-binding FR-type domain and all 8 FAD-contact residues mapped in human DUOX1. No experiment has been done on horse DUOX1; this is an inference from human DUOX1 within PANTHER subfamily PTHR11972:SF75. Supporting Evidence: PMID:33420071 The DH domain binds intracellular substrate NADPH and cofactor FAD file:HORSE/DUOX1/DUOX1-bioinformatics/RESULTS-rereview.md | FAD-binding FR-type (1270-1376) | 1.00 | 1.00 | 1.00 | 1.00 | file:HORSE/DUOX1/DUOX1-bioinformatics/RESULTS-rereview.md | F6YEX2 | 1516 | PTHR11972:SF75;PTHR11972 | ENSECAT00000026134 | True | 91.4% | 1-1516 | none | Ca(2+) 15/15; heme 13/13; FAD 8/8; NADPH 6/11 | |
| GO:0090303 positive regulation of wound healing | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of wound healing, transferred by Ensembl Compara from human DUOX1 (IGI). Reason: Functional DUOX1 at the leading edge of migrating airway cells augments motility and wound healing. This is a downstream cellular effect of local H2O2 production, not a core function; kept as non-core, as in the human review. Supporting Evidence: PMID:19339556 Functional Duox1 and Duox2 localize to the leading edge of migrating cells, augmenting motility and wound healing. |
| GO:0098869 cellular oxidant detoxification | IEA GO_REF:0000108 | REMOVE | Summary: Cellular oxidant detoxification, inferred from the peroxidase activity annotation by inter-ontology links. Reason: This is derived entirely from GO:0004601 peroxidase activity, which is removed here because the mammalian DUOX1 peroxidase-homology domain binds no heme and is inactive. DUOX1 produces oxidant; it does not detoxify it. No PAINT node in the family carries this term. Supporting Evidence: PMID:19460756 the isolated hDUOX1(1-593) does not bind heme and has no intrinsic peroxidase activity PMID:33420071 Dual oxidases (DUOXs) produce hydrogen peroxide by transferring electrons from intracellular NADPH to extracellular oxygen. |
| GO:0140374 antiviral innate immune response | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Antiviral innate immune response, from the UniProt combined pipeline (human and mouse DUOX1). Reason: Duox1-deficient mice handle influenza worse, and in human airway cells lactoperoxidase uses DUOX1-derived H2O2 to make hypothiocyanite, which inactivates influenza virus. DUOX1 contributes the oxidant co-substrate, which is real participation, but the role is tissue-specific and secondary to its enzymatic function. Kept as non-core, as in the human review. Supporting Evidence: PMID:34168077 Here, we show that Duox1 promotes antiviral innate immunity in vivo. PMID:34168077 In primary human tracheobronchial epithelial cells, OSCN- is generated by LPO using DUOX1-derived H2O2 and inactivates several influenza strains in vitro. |
| GO:1900426 positive regulation of defense response to bacterium | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of defense response to bacterium, transferred by Ensembl Compara from human DUOX1 (IDA). Reason: DUOX1 activation in airway epithelium increases H2O2 production as part of innate host defense against bacterial stimuli. A downstream, tissue-specific role of the oxidase; kept as non-core, as in the human review. Supporting Evidence: PMID:19386603 Activation of the NADPH oxidase homolog dual oxidase 1 (DUOX1) within the airway epithelium represents a key mechanism of innate airway host defense, through enhanced production of H2O2 |
| GO:2000147 positive regulation of cell motility | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of cell motility, transferred by Ensembl Compara from human DUOX1 (IGI). Reason: DUOX1 at the leading edge of migrating airway epithelial cells augments motility. A downstream cellular effect of its H2O2 production; kept as non-core, as in the human review. Supporting Evidence: PMID:19339556 Functional Duox1 and Duox2 localize to the leading edge of migrating cells, augmenting motility and wound healing. |
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Download this section (compressed HTML)Q: Is the 18-nt final coding exon of the canonical horse DUOX1 transcript ENSECAT00000026134 (giving the 1516-residue F6YEX2) a gene-model or assembly artefact, given that the other three horse DUOX1 transcripts encode a full C-terminus matching human residues 1517-1551?
Q: Which horse DUOX1 transcripts are actually translated in airway epithelium and thyroid, and does the EF-hand-deleted product A0A9L0SQG9 exist as protein?
Experiment: Express horse DUOX1 (full-length coding sequence, including the C-terminus present in the non-canonical transcripts) with horse DUOXA1 in HEK293 cells and measure calcium-stimulated, NADPH-dependent H2O2 release with Amplex Red, to confirm the orthology-based activity assignment.
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