Dual oxidase 1
DUOX1 | |||
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Gene ontology | |||
Molecular function | |||
Cellular component | |||
Biological process |
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Sources:Amigo / QuickGO |
Ensembl | |||||||||
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UniProt | |||||||||
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RefSeq (protein) | |||||||||
Location (UCSC) | Chr 15: 45.13 – 45.17 Mb | Chr 2: 122.15 – 122.18 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
Dual oxidase 1, also known as DUOX1 or ThOX1 (for thyroid oxidase), is an enzyme which in humans is encoded by the DUOX1 gene.[5] DUOX1 was first identified in the mammalian thyroid gland.[6] 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.[7][8]
Function
Investigations into reactive oxygen species (
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.[15][16] 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.[17] When sequence alignments were performed against other mammalian peroxidases, the histidine residues responsible for heme coordination were not conserved.[18] 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 (hDUOX11-593) and C. elegans DUOX1 (CeDUOX11-589) were made possible by expression and purification via a baculovirus system. Evaluation of these proteins demonstrated that the isolated hDUOX11-593 does not bind heme and has no intrinsic peroxidase activity. In contrast, CeDUOX11-589 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.[19]
Two alternatively spliced transcript variants encoding the same protein have been described for this gene.[20]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000137857 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000033268 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- )
- S2CID 34266530.
- S2CID 2187431.
- PMID 15591162.
- PMID 1851438.
- PMID 16321800.
- PMID 16246966.
- S2CID 12476863.
- PMID 16431374.
- PMID 12110737.
- PMID 19687201.
- ^ Meitzler JL, Brandman, R, Ortiz de Montellano, Perturbed heme binding is responsible for the blistering phenotype associated with mutations in the Caenorhabditis elegans dual oxidase 1 (DUOX1) peroxidase domain J. Biol. Chem. 2010, 285, 40991-41000.
- PMID 18606821.
- PMID 11514595.
- PMID 19460756.
- ^ "Entrez Gene: DUOX1 dual oxidase 1".
Further reading
- Lambeth JD (2002). "Nox/Duox family of nicotinamide adenine dinucleotide (phosphate) oxidases". Curr. Opin. Hematol. 9 (1): 11–7. 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. 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. )
- 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. 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. )
- 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. 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. 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. 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. 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. 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. 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. 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. 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. S2CID 34266530.