Dual oxidase 1

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Dual oxidase 1
Identifiers
Symbols DUOX1 ; LNOX1; NOXEF1; THOX1
External IDs OMIM606758 MGI2139422 HomoloGene68136 GeneCards: DUOX1 Gene
EC number 1.6.3.1
RNA expression pattern
PBB GE DUOX1 219597 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 53905 99439
Ensembl ENSG00000137857 ENSMUSG00000033268
UniProt Q9NRD9 A2AQ92
RefSeq (mRNA) NM_017434 NM_001099297
RefSeq (protein) NP_059130 NP_001092767
Location (UCSC) Chr 15:
45.42 – 45.46 Mb
Chr 2:
122.32 – 122.35 Mb
PubMed search [1] [2]

Dual oxidase 1, also known as DUOX1 or ThOX1 (for thyroid oxidase), is an enzyme which in humans is encoded by the DUOX1 gene.[1] DUOX1 was first identified in the mammalian thyroid gland.[2] 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.[3][4]

Function[edit]

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).[5][6] 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),[7] innate immunity (NOX2/DUOX),[8] otoconia formation in the inner ear (NOX3),[9] and thyroid hormone biosynthesis (DUOX1/2).[10] 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.[11] [12] 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[edit]

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.[13] Interestingly, when sequence alignments were performed against other mammalian peroxidases, the histidine residues responsible for heme coordination were not conserved.[14] 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.[15]

Two alternatively spliced transcript variants encoding the same protein have been described for this gene.[16]

References[edit]

  1. ^ 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. 
  2. ^ 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. 
  3. ^ 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. 
  4. ^ 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. 
  5. ^ 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. 
  6. ^ 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. 
  7. ^ 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. 
  8. ^ 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. 
  9. ^ 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. 
  10. ^ 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. 
  11. ^ 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. 
  12. ^ 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.
  13. ^ 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. 
  14. ^ 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. 
  15. ^ 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. 
  16. ^ "Entrez Gene: DUOX1 dual oxidase 1". 

Further reading[edit]