ID   KMO_HUMAN               Reviewed;         486 AA.
AC   O15229; A2A2U8; A2A2U9; A2A2V0; Q5SY07; Q5SY08; Q5SY09;
DT   04-APR-2006, integrated into UniProtKB/Swiss-Prot.
DT   20-FEB-2007, sequence version 2.
DT   07-JUL-2009, entry version 64.
DE   RecName: Full=Kynurenine 3-monooxygenase;
DE            EC=1.14.13.9;
DE   AltName: Full=Kynurenine 3-hydroxylase;
GN   Name=KMO;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC   Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC   Catarrhini; Hominidae; Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), CATALYTIC ACTIVITY,
RP   BIOPHYSICOCHEMICAL PROPERTIES, SUBCELLULAR LOCATION, TISSUE
RP   SPECIFICITY, AND VARIANT CYS-452.
RC   TISSUE=Liver;
RX   PubMed=9237672; DOI=10.1016/S0014-5793(97)00627-3;
RA   Alberati-Giani D., Cesura A.M., Broger C., Warren W.D., Rover S.,
RA   Malherbe P.;
RT   "Cloning and functional expression of human kynurenine 3-
RT   monooxygenase.";
RL   FEBS Lett. 410:407-412(1997).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), CATALYTIC ACTIVITY, COFACTOR,
RP   BIOPHYSICOCHEMICAL PROPERTIES, AND VARIANT CYS-452.
RC   TISSUE=Liver;
RX   PubMed=10672018; DOI=10.1046/j.1432-1327.2000.01104.x;
RA   Breton J., Avanzi N., Magagnin S., Covini N., Magistrelli G.,
RA   Cozzi L., Isacchi A.;
RT   "Functional characterization and mechanism of action of recombinant
RT   human kynurenine 3-hydroxylase.";
RL   Eur. J. Biochem. 267:1092-1099(2000).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16710414; DOI=10.1038/nature04727;
RA   Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA   Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA   Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA   McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA   Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA   Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA   Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA   Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA   Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA   Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA   Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA   Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA   Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA   Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA   Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA   Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA   Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA   Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA   Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA   Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA   Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA   Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA   Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA   Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA   Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA   Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA   Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA   Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA   Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA   Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA   Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA   Beck S., Rogers J., Bentley D.R.;
RT   "The DNA sequence and biological annotation of human chromosome 1.";
RL   Nature 441:315-321(2006).
RN   [4]
RP   REVIEW.
RX   PubMed=12402501; DOI=10.1038/nrd870;
RA   Stone T.W., Darlington L.G.;
RT   "Endogenous kynurenines as targets for drug discovery and
RT   development.";
RL   Nat. Rev. Drug Discov. 1:609-620(2002).
CC   -!- FUNCTION: Catalyzes the hydroxylation of L-kynurenine (L-Kyn) to
CC       form 3-hydroxy-L-kynurenine (L-3OHKyn). Required for synthesis of
CC       quinolinic acid, a neurotoxic NMDA receptor antagonist and
CC       potential endogenous inhibitor of NMDA receptor signaling in
CC       axonal targeting, synaptogenesis and apoptosis during brain
CC       development. Quinolinic acid may also affect NMDA receptor
CC       signaling in pancreatic beta cells, osteoblasts, myocardial cells,
CC       and the gastrointestinal tract.
CC   -!- CATALYTIC ACTIVITY: L-kynurenine + NADPH + O(2) = 3-hydroxy-L-
CC       kynurenine + NADP(+) + H(2)O.
CC   -!- COFACTOR: FAD.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=24.1 uM for L-kynurenine;
CC         Vmax=8.5 umol/min/mg enzyme;
CC       pH dependence:
CC         Optimum pH is 7.5;
CC   -!- PATHWAY: Cofactor biosynthesis; NAD(+) biosynthesis; pyridine-2,3-
CC       dicarboxylate from L-kynurenine: step 1/3.
CC   -!- SUBCELLULAR LOCATION: Mitochondrion outer membrane; Multi-pass
CC       membrane protein.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=3;
CC       Name=1;
CC         IsoId=O15229-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=O15229-2; Sequence=VSP_051973;
CC         Note=Gene model based on cDNA data. No experimental confirmation
CC         available;
CC       Name=3;
CC         IsoId=O15229-3; Sequence=VSP_051972;
CC         Note=Gene model based on mouse cDNA data. No experimental
CC         confirmation available;
CC   -!- TISSUE SPECIFICITY: Highest levels in placenta and liver.
CC       Detectable in kidney.
CC   -!- MISCELLANEOUS: Increased in neuroinflammatory conditions.
CC       Inhibitors are investigated as potential neuroprotective drugs
CC       since they lead to an increased level of kynurenic acid, a
CC       neuroprotective NMDA receptor agonist.
CC   -!- SIMILARITY: Belongs to the aromatic-ring hydroxylase family. KMO
CC       subfamily.
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DR   EMBL; Y13153; CAA73613.1; -; mRNA.
DR   EMBL; AF056032; AAC62615.1; -; mRNA.
DR   EMBL; AL133390; CAM28226.1; -; Genomic_DNA.
DR   EMBL; AL591898; CAM28226.1; JOINED; Genomic_DNA.
DR   EMBL; AL133390; CAM28227.1; -; Genomic_DNA.
DR   EMBL; AL591898; CAM28227.1; JOINED; Genomic_DNA.
DR   EMBL; AL133390; CAM28228.1; -; Genomic_DNA.
DR   EMBL; AL591898; CAM28228.1; JOINED; Genomic_DNA.
DR   EMBL; AL591898; CAI13905.1; -; Genomic_DNA.
DR   EMBL; AL133390; CAI13905.1; JOINED; Genomic_DNA.
DR   EMBL; AL591898; CAI13906.1; -; Genomic_DNA.
DR   EMBL; AL133390; CAI13906.1; JOINED; Genomic_DNA.
DR   EMBL; AL591898; CAI13907.1; -; Genomic_DNA.
DR   EMBL; AL133390; CAI13907.1; JOINED; Genomic_DNA.
DR   IPI; IPI00515018; -.
DR   IPI; IPI00642771; -.
DR   IPI; IPI00645486; -.
DR   RefSeq; NP_003670.2; -.
DR   UniGene; Hs.714771; -.
DR   PhosphoSite; O15229; -.
DR   PRIDE; O15229; -.
DR   Ensembl; ENSG00000117009; Homo sapiens.
DR   GeneID; 8564; -.
DR   KEGG; hsa:8564; -.
DR   NMPDR; fig|9606.3.peg.3320; -.
DR   UCSC; uc009xgo.1; human.
DR   GeneCards; GC01P239781; -.
DR   H-InvDB; HIX0001738; -.
DR   HGNC; HGNC:6381; KMO.
DR   MIM; 603538; gene.
DR   PharmGKB; PA30172; -.
DR   HOGENOM; O15229; -.
DR   HOVERGEN; O15229; -.
DR   OMA; O15229; LHAIMPS.
DR   BRENDA; 1.14.13.9; 247.
DR   Reactome; REACT_11193; Metabolism of vitamins and cofactors.
DR   Reactome; REACT_13; Metabolism of amino acids.
DR   NextBio; 32109; -.
DR   ArrayExpress; O15229; -.
DR   Bgee; O15229; -.
DR   CleanEx; HS_KMO; -.
DR   GermOnline; ENSG00000117009; Homo sapiens.
DR   GO; GO:0005829; C:cytosol; EXP:Reactome.
DR   GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR   GO; GO:0005741; C:mitochondrial outer membrane; ISS:UniProtKB.
DR   GO; GO:0009055; F:electron carrier activity; IDA:UniProtKB.
DR   GO; GO:0050660; F:FAD binding; IDA:UniProtKB.
DR   GO; GO:0004502; F:kynurenine 3-monooxygenase activity; IDA:UniProtKB.
DR   GO; GO:0016174; F:NAD(P)H oxidase activity; IDA:UniProtKB.
DR   GO; GO:0070189; P:kynurenine metabolic process; IDA:UniProtKB.
DR   GO; GO:0019674; P:NAD metabolic process; EXP:Reactome.
DR   GO; GO:0055114; P:oxidation reduction; IEA:UniProtKB-KW.
DR   GO; GO:0019363; P:pyridine nucleotide biosynthetic process; IEA:UniProtKB-KW.
DR   GO; GO:0009651; P:response to salt stress; IDA:UniProtKB.
DR   InterPro; IPR002938; mOase_FAD_bd.
DR   InterPro; IPR003042; Rng_hydrolase-like.
DR   Pfam; PF01494; FAD_binding_3; 1.
DR   PRINTS; PR00420; RNGMNOXGNASE.
PE   1: Evidence at protein level;
KW   Alternative splicing; Complete proteome; FAD; Flavoprotein; Membrane;
KW   Mitochondrion; Mitochondrion outer membrane; Monooxygenase; NADP;
KW   Oxidoreductase; Phosphoprotein; Polymorphism;
KW   Pyridine nucleotide biosynthesis; Transmembrane.
FT   CHAIN         1    486       Kynurenine 3-monooxygenase.
FT                                /FTId=PRO_0000229742.
FT   TRANSMEM    385    404       Potential.
FT   TRANSMEM    425    445       Potential.
FT   MOD_RES     399    399       Phosphothreonine (By similarity).
FT   VAR_SEQ     367    400       Missing (in isoform 3).
FT                                /FTId=VSP_051972.
FT   VAR_SEQ     367    379       Missing (in isoform 2).
FT                                /FTId=VSP_051973.
FT   VARIANT     452    452       R -> C (in dbSNP:rs1053230).
FT                                /FTId=VAR_030845.
SQ   SEQUENCE   486 AA;  55810 MW;  164870D52E62A08A CRC64;
     MDSSVIQRKK VAVIGGGLVG SLQACFLAKR NFQIDVYEAR EDTRVATFTR GRSINLALSH
     RGRQALKAVG LEDQIVSQGI PMRARMIHSL SGKKSAIPYG TKSQYILSVS RENLNKDLLT
     AAEKYPNVKM HFNHRLLKCN PEEGMITVLG SDKVPKDVTC DLIVGCDGAY STVRSHLMKK
     PRFDYSQQYI PHGYMELTIP PKNGDYAMEP NYLHIWPRNT FMMIALPNMN KSFTCTLFMP
     FEEFEKLLTS NDVVDFFQKY FPDAIPLIGE KLLVQDFFLL PAQPMISVKC SSFHFKSHCV
     LLGDAAHAIV PFFGQGMNAG FEDCLVFDEL MDKFSNDLSL CLPVFSRLRI PDDHAISDLS
     MYNYIEMRAH VNSSWFIFQK NMERFLHAIM PSTFIPLYTM VTFSRIRYHE AVQRWHWQKK
     VINKGLFFLG SLIAISSTYL LIHYMSPRSF LRLRRPWNWI AHFRNTTCFP AKAVDSLEQI
     SNLISR
//