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Dual oxidase 1

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DUOX1
Identifiers
AliasesDUOX1, LNOX1, NOXEF1, THOX1, dual oxidase 1
External IDsOMIM: 606758; MGI: 2139422; HomoloGene: 68136; GeneCards: DUOX1; OMA:DUOX1 - orthologs
Orthologs
SpeciesHumanMouse
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 MbChr 2: 122.15 – 122.18 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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 (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).[9][10] 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, gp91phox. 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),[11] innate immunity (NOX2/DUOX),[12] otoconia formation in the inner ear (NOX3),[13] and thyroid hormone biosynthesis (DUOX1/2).[14] The family currently has seven members including NOX1, NOX2 (formerly known as gp91phox), 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.[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] Interestingly, 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

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000137857 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000033268 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ De Deken X, Wang D, Many MC, Costagliola S, Libert F, Vassart G, Dumont JE, Miot F (July 2000). "Cloning of two human thyroid cDNAs encoding new members of the NADPH oxidase family". J. Biol. Chem. 275 (30): 23227–33. doi:10.1074/jbc.M000916200. PMID 10806195.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  6. ^ Harper RW, Xu C, Eiserich JP, Chen Y, Kao CY, Thai P, Setiadi H, Wu R (August 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.
  7. ^ Geiszt M, Witta J, Baffi J, Lekstrom K, Leto TL (August 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  8. ^ El Hassani RA, Benfares N, Caillou B, Talbot M, Sabourin JC, Belotte V, Morand S, Gnidehou S, Agnandji D, Ohayon R, Kaniewski J, Noël-Hudson MS, Bidart JM, Schlumberger M, Virion A, Dupuy C (May 2005). "Dual oxidase2 is expressed all along the digestive tract". Am. J. Physiol. Gastrointest. Liver Physiol. 288 (5): G933–42. doi:10.1152/ajpgi.00198.2004. PMID 15591162.
  9. ^ Cross AR, Jones OT (May 1991). "Enzymic mechanisms of superoxide production". Biochim. Biophys. Acta. 1057 (3): 281–98. doi:10.1016/S0005-2728(05)80140-9. PMID 1851438.
  10. ^ Donkó A, Péterfi Z, Sum A, Leto T, Geiszt M (December 2005). "Dual oxidases". Philos. Trans. R. Soc. Lond., B, Biol. Sci. 360 (1464): 2301–8. doi:10.1098/rstb.2005.1767. PMC 1569583. PMID 16321800.
  11. ^ Matsuno K, Yamada H, Iwata K, Jin D, Katsuyama M, Matsuki M, Takai S, Yamanishi K, Miyazaki M, Matsubara H, Yabe-Nishimura C (October 2005). "Nox1 is involved in angiotensin II-mediated hypertension: a study in Nox1-deficient mice". Circulation. 112 (17): 2677–85. doi:10.1161/CIRCULATIONAHA.105.573709. PMID 16246966.
  12. ^ Ha EM, Oh CT, Bae YS, Lee WJ (November 2005). "A direct role for dual oxidase in Drosophila gut immunity". Science. 310 (5749): 847–50. doi:10.1126/science.1117311. PMID 16272120.
  13. ^ Kiss PJ, Knisz J, Zhang Y, Baltrusaitis J, Sigmund CD, Thalmann R, Smith RJ, Verpy E, Bánfi B (January 2006). "Inactivation of NADPH oxidase organizer 1 results in severe imbalance". Curr. Biol. 16 (2): 208–13. doi:10.1016/j.cub.2005.12.025. PMID 16431374.
  14. ^ Moreno JC, Bikker H, Kempers MJ, van Trotsenburg AS, Baas F, de Vijlder JJ, Vulsma T, Ris-Stalpers C (July 2002). "Inactivating mutations in the gene for thyroid oxidase 2 (THOX2) and congenital hypothyroidism". N. Engl. J. Med. 347 (2): 95–102. doi:10.1056/NEJMoa012752. PMID 12110737.
  15. ^ Chávez V, Mohri-Shiomi A, Garsin DA (November 2009). "Ce-Duox1/BLI-3 generates reactive oxygen species as a protective innate immune mechanism in Caenorhabditis elegans". Infect. Immun. 77 (11): 4983–9. doi:10.1128/IAI.00627-09. PMC 2772517. PMID 19687201.
  16. ^ 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.
  17. ^ Pacquelet S, Lehmann M, Luxen S, Regazzoni K, Frausto M, Noack D, Knaus UG (September 2008). "Inhibitory action of NoxA1 on dual oxidase activity in airway cells". J. Biol. Chem. 283 (36): 24649–58. doi:10.1074/jbc.M709108200. PMC 2529001. PMID 18606821.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  18. ^ Edens WA, Sharling L, Cheng G, Shapira R, Kinkade JM, Lee T, Edens HA, Tang X, Sullards C, Flaherty DB, Benian GM, Lambeth JD (August 2001). "Tyrosine cross-linking of extracellular matrix is catalyzed by Duox, a multidomain oxidase/peroxidase with homology to the phagocyte oxidase subunit gp91phox". J. Cell Biol. 154 (4): 879–91. doi:10.1083/jcb.200103132. PMC 2196470. PMID 11514595.
  19. ^ Meitzler JL, Ortiz de Montellano PR (July 2009). "Caenorhabditis elegans and human dual oxidase 1 (DUOX1) "peroxidase" domains: insights into heme binding and catalytic activity". J. Biol. Chem. 284 (28): 18634–43. doi:10.1074/jbc.M109.013581. PMC 2707201. PMID 19460756.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  20. ^ "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. doi:10.1097/00062752-200201000-00003. PMID 11753072.
  • 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • De Deken X, Wang D, Many MC, Costagliola S, Libert F, Vassart G, Dumont JE, Miot F (2000). "Cloning of two human thyroid cDNAs encoding new members of the NADPH oxidase family". J. Biol. Chem. 275 (30): 23227–33. doi:10.1074/jbc.M000916200. PMID 10806195.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • 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/jc.86.7.3351. PMID 11443211.
  • De Deken X, Wang D, Dumont JE, Miot F (2002). "Characterization of ThOX proteins as components of the thyroid H(2)O(2)-generating system". Exp. Cell Res. 273 (2): 187–96. doi:10.1006/excr.2001.5444. PMID 11822874.
  • 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • 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.
  • 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • 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. 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • 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.
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