title: The four aldehyde oxidases of Drosophila melanogaster have different gene expression patterns and enzyme substrate specificities.
abstract: In the genome of Drosophila melanogaster, four genes coding for aldehyde oxidases (AOX1-4) were identified on chromosome 3. Phylogenetic analysis showed that the AOX gene cluster evolved via independent duplication events in the vertebrate and invertebrate lineages. The functional role and the substrate specificity of the distinct Drosophila AOX enzymes is unknown. Two loss-of-function mutant alleles in this gene region, low pyridoxal oxidase (Po(lpo)) and aldehyde oxidase-1 (Aldox-1(n1)) are associated with a phenotype characterized by undetectable AOX enzymatic activity. However, the genes involved and the corresponding mutations have not yet been identified. In this study we characterized the activities, substrate specificities and expression profiles of the four AOX enzymes in D. melanogaster. We show that the Po(lpo)-associated phenotype is the consequence of a structural alteration of the AOX1 gene. We identified an 11-bp deletion in the Po(lpo) allele, resulting in a frame-shift event, which removes the molybdenum cofactor domain of the encoded enzyme. Furthermore, we show that AOX2 activity is detectable only during metamorphosis and characterize a Minos-AOX2 insertion in this developmental gene that disrupts its activity. We demonstrate that the Aldox-1(n1) phenotype maps to the AOX3 gene and AOX4 activity is not detectable in our assays.
authors.affiliation: Institute of Biochemistry and Biology, Department of Molecular Enzymology, University of Potsdam, 14476 Potsdam, Germany.
authors.forename: Zvonimir
authors.initials: Z
authors.lastname: Marelja
authors.affiliation: Institute of Biochemistry and Biology, Department of Molecular Enzymology, University of Potsdam, 14476 Potsdam, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Dambowsky
authors.affiliation: Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri IRCCS, via La Masa 19, 20157 Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Bolis
authors.affiliation: Institute of Biochemistry and Biology, Department of Molecular Enzymology, University of Potsdam, 14476 Potsdam, Germany.
authors.forename: Marina L
authors.initials: ML
authors.lastname: Georgiou
authors.affiliation: Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri IRCCS, via La Masa 19, 20157 Milan, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Garattini
authors.affiliation: Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados, Av. IPN 2508, CP 07360 Mexico City, Mexico fanis@fisio.cinvestav.mx sleim@uni-potsdam.de.
authors.forename: Fanis
authors.initials: F
authors.lastname: Missirlis
authors.affiliation: Institute of Biochemistry and Biology, Department of Molecular Enzymology, University of Potsdam, 14476 Potsdam, Germany fanis@fisio.cinvestav.mx sleim@uni-potsdam.de.
authors.forename: Silke
authors.initials: S
authors.lastname: Leimkühler
mesh_terms: D042931:Aldehyde Oxidase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000483:Alleles; D000818:Animals; D004331:Drosophila melanogaster / Q000737:chemistry / Q000201:enzymology* / Q000235:genetics*; D019143:Evolution, Molecular; D015971:Gene Expression Regulation, Enzymologic; D019476:Insect Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D010802:Phylogeny; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D013379:Substrate Specificity
chemical_list: D019476:Insect Proteins; D042931:Aldehyde Oxidase
keywords: Aldehyde oxidase; Drosophila melanogaster; Gene duplication; Molybdoenzymes; Substrate specificities
references.citation: Drug Metab Dispos. 2011 Oct;39(10):1939-45
references.pmid: 21705476
references.citation: Genetics. 1970 Nov;66(3):487-96
references.pmid: 4997169
references.citation: Genetics. 2005 Oct;171(2):571-81
references.pmid: 15972463
references.citation: Mol Biol Evol. 1997 Jul;14(7):685-95
references.pmid: 9254330
references.citation: Nature. 2009 Jun 18;459(7249):927-30
references.pmid: 19536255
references.citation: Arch Biochem Biophys. 1971 Jul;145(1):27-34
references.pmid: 4256441
references.citation: Expert Opin Drug Metab Toxicol. 2012 Apr;8(4):487-503
references.pmid: 22335465
references.citation: Genetics. 1961 Nov;46:1455-63
references.pmid: 13894114
references.citation: J Neurosci. 1989 Apr;9(4):1341-53
references.pmid: 2703880
references.citation: Genetics. 1959 Mar;44(2):153-62
references.pmid: 17247815
references.citation: Q Rev Biophys. 1988 Aug;21(3):299-329
references.pmid: 3065813
references.citation: Prog Clin Biol Res. 1990;344:1-18
references.pmid: 2118264
references.citation: Biochem Genet. 1982 Apr;20(3-4):315-32
references.pmid: 6808989
references.citation: Trends Immunol. 2003 Sep;24(9):512-7
references.pmid: 12967676
references.citation: Science. 1958 Nov 7;128(3332):1135
references.pmid: 13592296
references.citation: J Biol Chem. 2009 Mar 27;284(13):8760-7
references.pmid: 19109252
references.citation: Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):10723-8
references.pmid: 11005854
references.citation: Nature. 2007 Jul 12;448(7150):151-6
references.pmid: 17625558
references.citation: Arch Biochem Biophys. 2000 Nov 15;383(2):281-7
references.pmid: 11185564
references.citation: J Med Chem. 2010 Dec 23;53(24):8441-60
references.pmid: 20853847
references.citation: FEBS Lett. 2008 Aug 20;582(19):2916-22
references.pmid: 18657538
references.citation: Drug Metab Rev. 2011 Aug;43(3):374-86
references.pmid: 21428696
references.citation: Mol Gen Genet. 1981;184(1):92-6
references.pmid: 6950197
references.citation: J Biol Chem. 1982 Feb 10;257(3):1354-9
references.pmid: 6276383
references.citation: Proc Natl Acad Sci U S A. 1992 May 15;89(10):4343-7
references.pmid: 1316606
references.citation: Hum Genomics. 2009 Dec;4(2):119-30
references.pmid: 20038499
references.citation: Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13413-7
references.pmid: 14576276
references.citation: Cell Mol Life Sci. 2013 May;70(10):1807-30
references.pmid: 23263164
references.citation: Genetics. 1969 Apr;61(4):833-9
references.pmid: 5364965
references.citation: Science. 1956 Oct 19;124(3225):725-6
references.pmid: 13371315
references.citation: Adv Comp Physiol Biochem. 1982;8:2-51
references.pmid: 6814204
references.citation: J Biol Chem. 2012 Nov 23;287(48):40690-702
references.pmid: 23019336
references.citation: Chem Rev. 1996 Nov 7;96(7):2757-2816
references.pmid: 11848841
references.citation: Gene. 2007 Dec 1;404(1-2):31-40
references.pmid: 17904312
references.citation: Biochem J. 2003 May 15;372(Pt 1):15-32
references.pmid: 12578558
references.citation: FEBS J. 2009 Nov;276(22):6798-809
references.pmid: 19843177
references.citation: PLoS One. 2009;4(4):e5348
references.pmid: 19401776
references.citation: Somat Cell Mol Genet. 1995 Mar;21(2):121-31
references.pmid: 7570184
references.citation: Genetics. 1987 May;116(1):67-73
references.pmid: 3036646
references.citation: Mol Gen Genet. 1992 Oct;235(1):11-21
references.pmid: 1331746
references.citation: Dev Biol. 1976 Oct 15;53(2):241-9
references.pmid: 825401
references.citation: Cell Mol Life Sci. 2008 Apr;65(7-8):1019-48
references.pmid: 18066686
references.citation: Biometals. 2011 Aug;24(4):679-86
references.pmid: 21293906
references.citation: Science. 2000 Mar 24;287(5461):2185-95
references.pmid: 10731132
references.citation: Biochem Biophys Res Commun. 2005 Jun 24;332(1):4-10
references.pmid: 15896291
references.citation: J Biol Chem. 1990 Nov 15;265(32):19712-5
references.pmid: 2246254
references.citation: Nucleic Acids Res. 2013 Jan;41(Database issue):D744-50
references.pmid: 23203866
references.citation: Biochem Genet. 1981 Jun;19(5-6):567-83
references.pmid: 6794563
references.citation: Curr Pharm Des. 2005;11(32):4145-51
references.pmid: 16375736
references.citation: Genetics. 1976 Oct;84(2):233-55
references.pmid: 826445
references.citation: J Biol Chem. 2006 Jul 14;281(28):19748-61
references.pmid: 16672219
references.citation: Metallomics. 2013 Aug;5(8):997-1005
references.pmid: 23771129
references.citation: J Biol Chem. 2004 Nov 26;279(48):50482-98
references.pmid: 15383531
references.citation: Arch Biochem Biophys. 2005 Jan 1;433(1):279-87
references.pmid: 15581583
references.citation: Biol Chem. 2003 Mar;384(3):463-72
references.pmid: 12715897