AOXA_CAVPO
ID AOXA_CAVPO Reviewed; 1332 AA.
AC H9TB17; H0WDM9;
DT 19-FEB-2014, integrated into UniProtKB/Swiss-Prot.
DT 19-FEB-2014, sequence version 2.
DT 03-AUG-2022, entry version 50.
DE RecName: Full=Aldehyde oxidase 1 {ECO:0000250|UniProtKB:Q06278};
DE EC=1.2.3.1 {ECO:0000250|UniProtKB:O54754};
DE AltName: Full=Azaheterocycle hydroxylase 1;
DE EC=1.17.3.- {ECO:0000269|PubMed:7786031, ECO:0000269|PubMed:9224775};
GN Name=AOX1 {ECO:0000250|UniProtKB:Q06278}; Synonyms=AO;
OS Cavia porcellus (Guinea pig).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Hystricomorpha; Caviidae;
OC Cavia.
OX NCBI_TaxID=10141;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND IDENTIFICATION OF PARALOGS.
RX PubMed=23263164; DOI=10.1007/s00018-012-1229-5;
RA Kurosaki M., Bolis M., Fratelli M., Barzago M.M., Pattini L., Perretta G.,
RA Terao M., Garattini E.;
RT "Structure and evolution of vertebrate aldehyde oxidases: from gene
RT duplication to gene suppression.";
RL Cell. Mol. Life Sci. 70:1807-1830(2013).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=2N;
RX PubMed=21993624; DOI=10.1038/nature10530;
RA Lindblad-Toh K., Garber M., Zuk O., Lin M.F., Parker B.J., Washietl S.,
RA Kheradpour P., Ernst J., Jordan G., Mauceli E., Ward L.D., Lowe C.B.,
RA Holloway A.K., Clamp M., Gnerre S., Alfoldi J., Beal K., Chang J.,
RA Clawson H., Cuff J., Di Palma F., Fitzgerald S., Flicek P., Guttman M.,
RA Hubisz M.J., Jaffe D.B., Jungreis I., Kent W.J., Kostka D., Lara M.,
RA Martins A.L., Massingham T., Moltke I., Raney B.J., Rasmussen M.D.,
RA Robinson J., Stark A., Vilella A.J., Wen J., Xie X., Zody M.C., Baldwin J.,
RA Bloom T., Chin C.W., Heiman D., Nicol R., Nusbaum C., Young S.,
RA Wilkinson J., Worley K.C., Kovar C.L., Muzny D.M., Gibbs R.A., Cree A.,
RA Dihn H.H., Fowler G., Jhangiani S., Joshi V., Lee S., Lewis L.R.,
RA Nazareth L.V., Okwuonu G., Santibanez J., Warren W.C., Mardis E.R.,
RA Weinstock G.M., Wilson R.K., Delehaunty K., Dooling D., Fronik C.,
RA Fulton L., Fulton B., Graves T., Minx P., Sodergren E., Birney E.,
RA Margulies E.H., Herrero J., Green E.D., Haussler D., Siepel A., Goldman N.,
RA Pollard K.S., Pedersen J.S., Lander E.S., Kellis M.;
RT "A high-resolution map of human evolutionary constraint using 29 mammals.";
RL Nature 478:476-482(2011).
RN [3]
RP FUNCTION AS AZAHETEROCYCLE OXIDASE, AND SUBSTRATE SPECIFICITY.
RX PubMed=7786031; DOI=10.1006/abbi.1995.1320;
RA Beedham C., Critchley D.J., Rance D.J.;
RT "Substrate specificity of human liver aldehyde oxidase toward substituted
RT quinazolines and phthalazines: a comparison with hepatic enzyme from guinea
RT pig, rabbit, and baboon.";
RL Arch. Biochem. Biophys. 319:481-490(1995).
RN [4]
RP FUNCTION AS AZAHETEROCYCLE OXIDASE, CATALYTIC ACTIVITY, ACTIVITY
RP REGULATION, BIOPHYSICOCHEMICAL PROPERTIES, SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RX PubMed=9224775;
RA Rashidi M.R., Smith J.A., Clarke S.E., Beedham C.;
RT "In vitro oxidation of famciclovir and 6-deoxypenciclovir by aldehyde
RT oxidase from human, guinea pig, rabbit, and rat liver.";
RL Drug Metab. Dispos. 25:805-813(1997).
CC -!- FUNCTION: Oxidase with broad substrate specificity, oxidizing aromatic
CC azaheterocycles, such as N1-methylnicotinamide, N-methylphthalazinium
CC and phthalazine, as well as aldehydes, such as benzaldehyde, retinal,
CC pyridoxal, and vanillin. Plays a key role in the metabolism of
CC xenobiotics and drugs containing aromatic azaheterocyclic substituents.
CC Participates in the bioactivation of prodrugs such as famciclovir,
CC catalyzing the oxidation step from 6-deoxypenciclovir to penciclovir,
CC which is a potent antiviral agent. Is probably involved in the
CC regulation of reactive oxygen species homeostasis. May be a prominent
CC source of superoxide generation via the one-electron reduction of
CC molecular oxygen. May also catalyze nitric oxide (NO) production via
CC the reduction of nitrite to NO with NADH or aldehyde as electron donor.
CC May play a role in adipogenesis. {ECO:0000269|PubMed:7786031,
CC ECO:0000269|PubMed:9224775}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an aldehyde + H2O + O2 = a carboxylate + H(+) + H2O2;
CC Xref=Rhea:RHEA:16829, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:16240, ChEBI:CHEBI:17478,
CC ChEBI:CHEBI:29067; EC=1.2.3.1;
CC Evidence={ECO:0000250|UniProtKB:O54754};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + O2 + retinal = H(+) + H2O2 + retinoate;
CC Xref=Rhea:RHEA:56736, ChEBI:CHEBI:15035, ChEBI:CHEBI:15036,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:16240; Evidence={ECO:0000250|UniProtKB:O54754};
CC -!- COFACTOR:
CC Name=[2Fe-2S] cluster; Xref=ChEBI:CHEBI:190135;
CC Evidence={ECO:0000250|UniProtKB:O54754};
CC Note=Binds 2 [2Fe-2S] clusters per subunit.
CC {ECO:0000250|UniProtKB:O54754};
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000250|UniProtKB:O54754};
CC Note=Binds 1 FAD per subunit. {ECO:0000250|UniProtKB:O54754};
CC -!- COFACTOR:
CC Name=Mo-molybdopterin; Xref=ChEBI:CHEBI:71302;
CC Evidence={ECO:0000250|UniProtKB:O54754};
CC Note=Binds 1 Mo-molybdopterin (Mo-MPT) cofactor per subunit.
CC {ECO:0000250|UniProtKB:O54754};
CC -!- ACTIVITY REGULATION: Inhibited by menadione and isovanillin. Not
CC inhibited by allopurinol, a xanthine dehydrogenase potent inhibitor.
CC {ECO:0000269|PubMed:9224775}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.41 mM for 6-deoxypenciclovir (at 37 degrees Celsius and pH 7)
CC {ECO:0000269|PubMed:9224775};
CC KM=0.17 mM for famciclovir (at 37 degrees Celsius and pH 7)
CC {ECO:0000269|PubMed:9224775};
CC Vmax=209 nmol/min/mg enzyme with 6-deoxypenciclovir as substrate
CC {ECO:0000269|PubMed:9224775};
CC Vmax=439 nmol/min/mg enzyme with famciclovir as substrate
CC {ECO:0000269|PubMed:9224775};
CC -!- SUBUNIT: Homodimer. {ECO:0000250|UniProtKB:Q06278}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:9224775}.
CC -!- TISSUE SPECIFICITY: Expressed in liver. {ECO:0000269|PubMed:9224775}.
CC -!- MISCELLANEOUS: AOX genes evolved from a xanthine oxidoreductase
CC ancestral precursor via a series of gene duplication and
CC suppression/deletion events. Different animal species contain a
CC different complement of AOX genes encoding an equivalent number of AOX
CC isoenzymes. In mammals, the two extremes are represented by certain
CC rodents such as mice and rats, which are endowed with 4 AOX genes, and
CC by humans, whose genome is characterized by a single active gene
CC (PubMed:23263164). {ECO:0000305|PubMed:23263164}.
CC -!- SIMILARITY: Belongs to the xanthine dehydrogenase family.
CC {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; JQ280309; AFG18181.1; -; mRNA.
DR EMBL; AAKN02051283; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR RefSeq; NP_001295371.1; NM_001308442.1.
DR AlphaFoldDB; H9TB17; -.
DR SMR; H9TB17; -.
DR STRING; 10141.ENSCPOP00000021102; -.
DR BindingDB; H9TB17; -.
DR ChEMBL; CHEMBL4523115; -.
DR PRIDE; H9TB17; -.
DR GeneID; 100720210; -.
DR KEGG; cpoc:100720210; -.
DR CTD; 316; -.
DR eggNOG; KOG0430; Eukaryota.
DR OrthoDB; 48717at2759; -.
DR TreeFam; TF353036; -.
DR SABIO-RK; H9TB17; -.
DR Proteomes; UP000005447; Unassembled WGS sequence.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0051537; F:2 iron, 2 sulfur cluster binding; ISS:UniProtKB.
DR GO; GO:0004031; F:aldehyde oxidase activity; ISS:UniProtKB.
DR GO; GO:0071949; F:FAD binding; IEA:InterPro.
DR GO; GO:0050660; F:flavin adenine dinucleotide binding; ISS:UniProtKB.
DR GO; GO:0005506; F:iron ion binding; ISS:UniProtKB.
DR GO; GO:0043546; F:molybdopterin cofactor binding; ISS:UniProtKB.
DR GO; GO:0051287; F:NAD binding; IEA:InterPro.
DR GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB.
DR GO; GO:0006629; P:lipid metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0006805; P:xenobiotic metabolic process; ISS:UniProtKB.
DR Gene3D; 3.10.20.30; -; 1.
DR Gene3D; 3.30.43.10; -; 1.
DR Gene3D; 3.30.465.10; -; 1.
DR InterPro; IPR002888; 2Fe-2S-bd.
DR InterPro; IPR036884; 2Fe-2S-bd_dom_sf.
DR InterPro; IPR036010; 2Fe-2S_ferredoxin-like_sf.
DR InterPro; IPR001041; 2Fe-2S_ferredoxin-type.
DR InterPro; IPR006058; 2Fe2S_fd_BS.
DR InterPro; IPR000674; Ald_Oxase/Xan_DH_a/b.
DR InterPro; IPR036856; Ald_Oxase/Xan_DH_a/b_sf.
DR InterPro; IPR016208; Ald_Oxase/xanthine_DH.
DR InterPro; IPR014313; Aldehyde_oxidase.
DR InterPro; IPR008274; AldOxase/xan_DH_Mopterin-bd.
DR InterPro; IPR037165; AldOxase/xan_DH_Mopterin-bd_sf.
DR InterPro; IPR012675; Beta-grasp_dom_sf.
DR InterPro; IPR005107; CO_DH_flav_C.
DR InterPro; IPR036683; CO_DH_flav_C_dom_sf.
DR InterPro; IPR016166; FAD-bd_PCMH.
DR InterPro; IPR036318; FAD-bd_PCMH-like_sf.
DR InterPro; IPR016167; FAD-bd_PCMH_sub1.
DR InterPro; IPR016169; FAD-bd_PCMH_sub2.
DR InterPro; IPR002346; Mopterin_DH_FAD-bd.
DR InterPro; IPR022407; OxRdtase_Mopterin_BS.
DR PANTHER; PTHR11908; PTHR11908; 1.
DR Pfam; PF01315; Ald_Xan_dh_C; 1.
DR Pfam; PF02738; Ald_Xan_dh_C2; 1.
DR Pfam; PF03450; CO_deh_flav_C; 1.
DR Pfam; PF00941; FAD_binding_5; 1.
DR Pfam; PF00111; Fer2; 1.
DR Pfam; PF01799; Fer2_2; 1.
DR PIRSF; PIRSF000127; Xanthine_DH; 1.
DR SMART; SM01008; Ald_Xan_dh_C; 1.
DR SMART; SM01092; CO_deh_flav_C; 1.
DR SUPFAM; SSF47741; SSF47741; 1.
DR SUPFAM; SSF54292; SSF54292; 1.
DR SUPFAM; SSF54665; SSF54665; 1.
DR SUPFAM; SSF55447; SSF55447; 1.
DR SUPFAM; SSF56003; SSF56003; 1.
DR SUPFAM; SSF56176; SSF56176; 1.
DR TIGRFAMs; TIGR02969; mam_aldehyde_ox; 1.
DR PROSITE; PS00197; 2FE2S_FER_1; 1.
DR PROSITE; PS51085; 2FE2S_FER_2; 1.
DR PROSITE; PS51387; FAD_PCMH; 1.
DR PROSITE; PS00559; MOLYBDOPTERIN_EUK; 1.
PE 1: Evidence at protein level;
KW 2Fe-2S; Cytoplasm; FAD; Flavoprotein; Iron; Iron-sulfur; Lipid metabolism;
KW Metal-binding; Molybdenum; Oxidoreductase; Reference proteome.
FT CHAIN 1..1332
FT /note="Aldehyde oxidase 1"
FT /id="PRO_0000425242"
FT DOMAIN 4..91
FT /note="2Fe-2S ferredoxin-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00465"
FT DOMAIN 234..419
FT /note="FAD-binding PCMH-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00718"
FT ACT_SITE 1264
FT /note="Proton acceptor; for azaheterocycle hydroxylase
FT activity"
FT /evidence="ECO:0000250|UniProtKB:O54754"
FT BINDING 43
FT /ligand="[2Fe-2S] cluster"
FT /ligand_id="ChEBI:CHEBI:190135"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q06278"
FT BINDING 48
FT /ligand="[2Fe-2S] cluster"
FT /ligand_id="ChEBI:CHEBI:190135"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q06278"
FT BINDING 51
FT /ligand="[2Fe-2S] cluster"
FT /ligand_id="ChEBI:CHEBI:190135"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q06278"
FT BINDING 73
FT /ligand="[2Fe-2S] cluster"
FT /ligand_id="ChEBI:CHEBI:190135"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q06278"
FT BINDING 112
FT /ligand="Mo-molybdopterin"
FT /ligand_id="ChEBI:CHEBI:71302"
FT /evidence="ECO:0000250|UniProtKB:Q06278"
FT BINDING 113
FT /ligand="[2Fe-2S] cluster"
FT /ligand_id="ChEBI:CHEBI:190135"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q06278"
FT BINDING 116
FT /ligand="[2Fe-2S] cluster"
FT /ligand_id="ChEBI:CHEBI:190135"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q06278"
FT BINDING 148
FT /ligand="[2Fe-2S] cluster"
FT /ligand_id="ChEBI:CHEBI:190135"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q06278"
FT BINDING 150
FT /ligand="[2Fe-2S] cluster"
FT /ligand_id="ChEBI:CHEBI:190135"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q06278"
FT BINDING 150
FT /ligand="Mo-molybdopterin"
FT /ligand_id="ChEBI:CHEBI:71302"
FT /evidence="ECO:0000250|UniProtKB:Q06278"
FT BINDING 262..269
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q06278"
FT BINDING 343
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q06278"
FT BINDING 352
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q06278"
FT BINDING 356
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q06278"
FT BINDING 365
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q06278"
FT BINDING 409
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q06278"
FT BINDING 800..801
FT /ligand="Mo-molybdopterin"
FT /ligand_id="ChEBI:CHEBI:71302"
FT /evidence="ECO:0000250|UniProtKB:Q06278"
FT BINDING 1041
FT /ligand="Mo-molybdopterin"
FT /ligand_id="ChEBI:CHEBI:71302"
FT /evidence="ECO:0000250|UniProtKB:Q06278"
FT BINDING 1082..1085
FT /ligand="Mo-molybdopterin"
FT /ligand_id="ChEBI:CHEBI:71302"
FT /evidence="ECO:0000250|UniProtKB:Q06278"
FT BINDING 1197
FT /ligand="Mo-molybdopterin"
FT /ligand_id="ChEBI:CHEBI:71302"
FT /evidence="ECO:0000250|UniProtKB:Q06278"
FT BINDING 1262
FT /ligand="Mo-molybdopterin"
FT /ligand_id="ChEBI:CHEBI:71302"
FT /evidence="ECO:0000250|UniProtKB:Q06278"
FT CONFLICT 519
FT /note="S -> N (in Ref. 1; AFG18181)"
FT /evidence="ECO:0000305"
FT CONFLICT 677
FT /note="E -> G (in Ref. 1; AFG18181)"
FT /evidence="ECO:0000305"
FT CONFLICT 695
FT /note="E -> G (in Ref. 1; AFG18181)"
FT /evidence="ECO:0000305"
FT CONFLICT 1137
FT /note="R -> T (in Ref. 1; AFG18181)"
FT /evidence="ECO:0000305"
FT CONFLICT 1201
FT /note="A -> P (in Ref. 1; AFG18181)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1332 AA; 145275 MW; 348556EBE581FE04 CRC64;
MEPSTLYFYV NGRRVTEKNV DPETMLLPYL GRNLRLTGTK YGCGGGGCGA CTVMVSRYDR
GTGQIRHYPA CACLTPLCSL HGAAVTTVEG VGSTRTRLHP VQERIAKSHG TQCGFCTPGM
VMSLYALLRS HPQPSEEQLL EALAGNLCRC TGYRPILDAG KTFCKTSGCC QSKENGVCCL
DQGVNGVQEA EGEQTSQELC SEEEFVPLDP TQELIFPPEL MILAQKQPQK SRVFTGDRVT
WISPVTLKDL LEAKAKNPRA PVVMGNTSVG PEMKFKGVFH PVIISPDGIE ELSVIKQGNE
GLTLGAGLSL AQVQDVLADV VQQLPEEKTQ TLCALLKQLR TLAGSQIRNM ASLGGHIMSR
HLDSDLNPVL AAASCTLHVP SQEGDRQIPL DEHFLSRSPS ADLRPQEVLL SVTIPYSRKW
EFVSAFRQAQ RKRSARAIVN VGMRVFFGAG DGVISELCIL YGGVGPAIVC ATDACRKLVG
RHWTEEMLDE ACRLVLGEVA IPGAAPGGRV EFRRTLLVSF LFRFYLQVSQ SLSRMDPGRY
PSLVGKYESA LEDLCLGHHQ RTFELQSADA KQLPQDPIGR PIMHLSGIKH TTGEAIYCDD
MPLVDRELSL AFVTSSRAHA AILSMDLSEA LSLPGVVDIV TAEHLGDANS FAKETLLATD
KVLCVGHLVC AVIADSEVQA KRAAEKVKIV YQDLEPLILT IEEAIQHDSF FETERKLESG
DVAEAFRTAE QVLEGSIHMG GQEHFYMETQ SMLAVPKGED QEIDLYVSTQ FPTYIQEIVA
STLKLPVNKV MCHVRRVGGA FGGKVGKTAI LAAITAFAAL KHCRAVRCIL ERGEDMLITG
GRHPYLGKYK VGFRNNGQVV ALDMEHYSNA GSTLDESLMV VEMGLLKMEN AYKFPNLRCR
GHACKTNLPS NTALRGFGFP QSGLITEACI VEVAARCGLS PEEVREVNMY RGTEQTHYGQ
EIHTQRLAQC WSECKAKATF SLRRAAVDRF NAGSPWKKRG LAMVPLKFPV GLGSVAMGQA
AALVHVYLDG SVLLTHGGIE MGQGVHTKMI QVVSRELKMP MANVHLRGTS TETVPNANVS
GGSVVADLNG LAVKDACQTL LKRLEPIISK NPKGTWKEWA QAAFDQSISL SAIGYFRGYD
ADMDWEKGKG HPFEYFVYGA ACSEVEIDCL TGNHKNIRTD IVMDVGRSIN PALDLGQVEG
AFIQGMGLYT SEELKYGPQG ALYTRGPDQY KIPAVCDVPA ELHVFFLPPS KNSNTLYSSK
GLGESGVFLG CSVLFAIWDA VSAARRERGL PGTLALSCPL TPEKIRMACE DRFTKMIPRD
TPGSYVPWDV VV
