Dual oxidase 1

DUOX1
Identifiers
Aliases	DUOX1, LNOX1, NOXEF1, THOX1, dual oxidase 1
External IDs	OMIM: 606758; MGI: 2139422; HomoloGene: 68136; GeneCards: DUOX1; OMA:DUOX1 - orthologs
Gene location (Human) Chr. Chromosome 15 (human) Band 15q21.1 Start 45,129,933 bp End 45,165,576 bp
Gene location (Mouse) Chr. Chromosome 2 (mouse) Band 2|2 E5 Start 122,146,153 bp End 122,178,453 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right lobe of thyroid gland left lobe of thyroid gland right lung bronchial epithelial cell gums gingival epithelium right uterine tube skin of abdomen skin of leg lower lobe of lung Top expressed in esophagus lip conjunctival fornix transitional epithelium of urinary bladder skin of external ear knee joint lumbar subsegment of spinal cord cornea embryo nucleus of stria terminalis More reference expression data BioGPS More reference expression data
Gene ontology Molecular function calcium ion binding peroxidase activity metal ion binding heme binding NADP binding oxidoreductase activity NAD(P)H oxidase H2O2-forming activity protein binding superoxide-generating NAD(P)H oxidase activity Cellular component integral component of membrane membrane plasma membrane apical plasma membrane endoplasmic reticulum cell surface cell leading edge NADPH oxidase complex Biological process cuticle development cytokine-mediated signaling pathway cellular oxidant detoxification response to oxidative stress reactive oxygen species metabolic process superoxide anion generation thyroid hormone generation hydrogen peroxide catabolic process hydrogen peroxide biosynthetic process response to cAMP hormone biosynthetic process positive regulation of wound healing positive regulation of cell motility defense response Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 53905 99439 Ensembl ENSG00000137857 ENSMUSG00000033268 UniProt Q9NRD9 A2AQ92 RefSeq (mRNA) NM_017434 NM_175940 NM_001099297 RefSeq (protein) NP_059130 NP_787954 NP_001092767 Location (UCSC) Chr 15: 45.13 – 45.17 Mb Chr 2: 122.15 – 122.18 Mb PubMed search
Wikidata
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Dual oxidase 1, also known as DUOX1 or ThOX1 (for thyroid oxidase), is an enzyme which in humans is encoded by the DUOX1 gene. DUOX1 was first identified in the mammalian thyroid gland. In humans, two isoforms are found; hDUOX1 and hDUOX2. Human DUOX protein localization is not exclusive to thyroid tissue; hDUOX1 is prominent in airway epithelial cells and hDUOX2 in the salivary glands and gastrointestinal tract.

Function

Investigations into reactive oxygen species (ROS) in biological systems have, until recently, focused on characterization of phagocytic cell processes. It is now well accepted that production of such species is not restricted to phagocytic cells and can occur in eukaryotic, non-phagocytic cell types via NADPH oxidase (NOX) or dual oxidase (DUOX). This new family of proteins, termed the NOX/DUOX family or NOX family of NADPH oxidases, consists of homologs to the catalytic moiety of phagocytic NADPH-oxidase, gp91^phox. Members of the NOX/DUOX family have been found throughout eukaryotic species, including invertebrates, insects, nematodes, fungi, amoeba, alga, and plants (not found in prokaryotes). These enzymes clearly demonstrate regulated production of ROS as their sole function. Genetic analyses have implicated NOX/DUOX derived ROS in biological roles and pathological conditions including hypertension (NOX1), innate immunity (NOX2/DUOX), otoconia formation in the inner ear (NOX3), and thyroid hormone biosynthesis (DUOX1/2). The family currently has seven members including NOX1, NOX2 (formerly known as gp91^phox), NOX3, NOX4, NOX5, DUOX1 (this enzyme) and DUOX2.

The current model for ROS generation by C. elegans DUOX1 (CeDUOX1) proposes that superoxide is generated through reduction of oxygen by two electrons extracted from oxidation of NADPH at the C-terminal NADPH oxidase domain. This unstable superoxide, generated at the extracellular surface, may rapidly convert to hydrogen peroxide and be utilized by the N-terminal peroxidase domain to facilitate tyrosine cross-linking. This model for CeDUOX1 activity was recently supported by a study of two point mutations localized within the peroxidase domain of CeDUOX1; G246D and D392N. Both mutations result in a blistering cuticle phenotype, resulting from the loss of tyrosine cross-linking activity. Neither mutant demonstrates a significant decrease in ROS production. These results suggest this peroxidase-like region is directly involved in enzymatic tyrosine cross-linking, but not responsible for ROS production.

Structure

Dual oxidases are characterized by a defining N-terminal, extracellular domain exhibiting considerable sequence identity with the mammalian peroxidases, a transmembrane (TM) segment appended to an EF-hand calcium-binding cytosolic region and a NOX2 homologous structure (six TMs tethered to NADPH oxidase). Topological studies place this peroxidase domain on the opposite side of the membrane from the NADPH oxidase domain.

hDUOX1 and hDUOX2 are 83% homologous, ~190 kDa in size (after extensive glycosylation contributing ~30 kDa in mass), and require maturation factors (DUOXA1 and DUOXA2) to achieve heterologous expression in full-length, active form. Mature DUOX enzymes produce H₂O₂; this activity is regulated by Ca²⁺ concentration through triggered dissociation of NOXA1 and possibly other as yet unidentified interacting proteins. When sequence alignments were performed against other mammalian peroxidases, the histidine residues responsible for heme coordination were not conserved. Due to this critical disparity, much speculation has surrounded the function of the DUOX peroxidase domain(s). Proposals for functionality include: superoxide dismutase activity, instead of peroxidase activity; a novel peroxidase mechanism; a protein-protein or Ca²⁺ induced conformational change which subsequently allows heme binding for peroxidase activity; or simply inactivity, as a vestigial domain.

Recent in vitro investigations into the ability of the DUOX1 domain to act as a peroxidase demonstrated that cell lysate from peroxidase expression in C. elegans and E. coli had tyrosine cross-linking activity. Further in vitro studies of human DUOX1 (hDUOX1_1-593) and C. elegans DUOX1 (CeDUOX1_1-589) were made possible by expression and purification via a baculovirus system. Evaluation of these proteins demonstrated that the isolated hDUOX1_1-593 does not bind heme and has no intrinsic peroxidase activity. In contrast, CeDUOX1_1-589 binds heme covalently and exhibits a modest peroxidase activity, but does not oxidize bromide ion. Surprisingly, the heme appears to have two covalent links to the C. elegans protein despite the absence of a second conserved carboxyl group in the active site.

Two alternatively spliced transcript variants encoding the same protein have been described for this gene.

Further reading

• Lambeth JD (2002). "Nox/Duox family of nicotinamide adenine dinucleotide (phosphate) oxidases". Curr. Opin. Hematol. 9 (1): 11–7. doi:10.1097/00062752-200201000-00003. PMID 11753072. S2CID 29968089.
• Dupuy C, Ohayon R, Valent A, Noël-Hudson MS, Dème D, Virion A (2000). "Purification of a novel flavoprotein involved in the thyroid NADPH oxidase. Cloning of the porcine and human cdnas". J. Biol. Chem. 274 (52): 37265–9. doi:10.1074/jbc.274.52.37265. PMID 10601291.
• De Deken X, Wang D, Many MC, Costagliola S, Libert F, Vassart G, Dumont JE, Miot F (2000). of Two Human Thyroid cDNAs Encoding New Members of the NADPH Oxidase Family.pdf "Cloning of two human thyroid cDNAs encoding new members of the NADPH oxidase family" (PDF). J. Biol. Chem. 275 (30): 23227–33. doi:10.1074/jbc.M000916200. PMID 10806195. S2CID 19424568. {{cite journal}}: Check |url= value (help)
• Caillou B, Dupuy C, Lacroix L, Nocera M, Talbot M, Ohayon R, Dème D, Bidart JM, Schlumberger M, Virion A (2001). "Expression of reduced nicotinamide adenine dinucleotide phosphate oxidase (ThoX, LNOX, Duox) genes and proteins in human thyroid tissues". J. Clin. Endocrinol. Metab. 86 (7): 3351–8. doi:10.1210/jcem.86.7.7646. PMID 11443211.
• De Deken X, Wang D, Dumont JE, Miot F (2002). of ThOX Proteins as Components of the Thyroid H2O2-Generating System.pdf "Characterization of ThOX proteins as components of the thyroid H(2)O(2)-generating system" (PDF). Exp. Cell Res. 273 (2): 187–96. doi:10.1006/excr.2001.5444. PMID 11822874. {{cite journal}}: Check |url= value (help)
• Kalinina N, Agrotis A, Tararak E, Antropova Y, Kanellakis P, Ilyinskaya O, Quinn MT, Smirnov V, Bobik A (2002). "Cytochrome b558-dependent NAD(P)H oxidase-phox units in smooth muscle and macrophages of atherosclerotic lesions". Arterioscler. Thromb. Vasc. Biol. 22 (12): 2037–43. doi:10.1161/01.ATV.0000040222.02255.0F. PMID 12482831.
• Geiszt M, Witta J, Baffi J, Lekstrom K, Leto TL (2003). "Dual oxidases represent novel hydrogen peroxide sources supporting mucosal surface host defense". FASEB J. 17 (11): 1502–4. doi:10.1096/fj.02-1104fje. PMID 12824283. S2CID 2187431.
• Pachucki J, Wang D, Christophe D, Miot F (2004). "Structural and functional characterization of the two human ThOX/Duox genes and their 5'-flanking regions". Mol. Cell. Endocrinol. 214 (1–2): 53–62. doi:10.1016/j.mce.2003.11.026. PMID 15062544. S2CID 13241525.
• Schwarzer C, Machen TE, Illek B, Fischer H (2004). "NADPH oxidase-dependent acid production in airway epithelial cells". J. Biol. Chem. 279 (35): 36454–61. doi:10.1074/jbc.M404983200. PMID 15210697.
• Wang D, De Deken X, Milenkovic M, Song Y, Pirson I, Dumont JE, Miot F (2005). "Identification of a novel partner of duox: EFP1, a thioredoxin-related protein". J. Biol. Chem. 280 (4): 3096–103. doi:10.1074/jbc.M407709200. PMID 15561711.
• Shao MX, Nadel JA (2005). "Dual oxidase 1-dependent MUC5AC mucin expression in cultured human airway epithelial cells". Proc. Natl. Acad. Sci. U.S.A. 102 (3): 767–72. Bibcode:2005PNAS..102..767S. doi:10.1073/pnas.0408932102. PMC 545521. PMID 15640347.
• Forteza R, Salathe M, Miot F, Forteza R, Conner GE (2005). "Regulated hydrogen peroxide production by Duox in human airway epithelial cells". Am. J. Respir. Cell Mol. Biol. 32 (5): 462–9. doi:10.1165/rcmb.2004-0302OC. PMID 15677770.
• Ameziane-El-Hassani R, Morand S, Boucher JL, Frapart YM, Apostolou D, Agnandji D, Gnidehou S, Ohayon R, Noël-Hudson MS, Francon J, Lalaoui K, Virion A, Dupuy C (2005). "Dual oxidase-2 has an intrinsic Ca2+-dependent H2O2-generating activity". J. Biol. Chem. 280 (34): 30046–54. doi:10.1074/jbc.M500516200. PMID 15972824.
• Harper RW, Xu C, Eiserich JP, Chen Y, Kao CY, Thai P, Setiadi H, Wu R (2005). "Differential regulation of dual NADPH oxidases/peroxidases, Duox1 and Duox2, by Th1 and Th2 cytokines in respiratory tract epithelium". FEBS Lett. 579 (21): 4911–7. doi:10.1016/j.febslet.2005.08.002. PMID 16111680. S2CID 34266530.