KMO_RAT
ID KMO_RAT Reviewed; 478 AA.
AC O88867;
DT 04-APR-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1998, sequence version 1.
DT 03-AUG-2022, entry version 142.
DE RecName: Full=Kynurenine 3-monooxygenase {ECO:0000255|HAMAP-Rule:MF_03018};
DE EC=1.14.13.9 {ECO:0000255|HAMAP-Rule:MF_03018};
DE AltName: Full=Kynurenine 3-hydroxylase {ECO:0000255|HAMAP-Rule:MF_03018};
GN Name=Kmo {ECO:0000312|RGD:620610};
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1] {ECO:0000305, ECO:0000312|EMBL:AAC62614.1}
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Magagnin S., Covini N., Cini M., Bormetti R., Molinari A., Speciale C.,
RA Post C., Benatti L.;
RL Submitted (MAR-1998) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3] {ECO:0000305}
RP CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, SUBCELLULAR LOCATION,
RP AND TISSUE SPECIFICITY.
RX PubMed=1332540; DOI=10.1016/0003-2697(92)90432-7;
RA Erickson J.B., Flanagan E.M., Russo S., Reinhard J.F. Jr.;
RT "A radiometric assay for kynurenine 3-hydroxylase based on the release of
RT 3H2O during hydroxylation of L-[3,5-3H]kynurenine.";
RL Anal. Biochem. 205:257-262(1992).
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 development.";
RL Nat. Rev. Drug Discov. 1:609-620(2002).
RN [5]
RP FUNCTION, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=26752518; DOI=10.1038/nm.4020;
RA Mole D.J., Webster S.P., Uings I., Zheng X., Binnie M., Wilson K.,
RA Hutchinson J.P., Mirguet O., Walker A., Beaufils B., Ancellin N.,
RA Trottet L., Beneton V., Mowat C.G., Wilkinson M., Rowland P., Haslam C.,
RA McBride A., Homer N.Z., Baily J.E., Sharp M.G., Garden O.J., Hughes J.,
RA Howie S.E., Holmes D.S., Liddle J., Iredale J.P.;
RT "Kynurenine-3-monooxygenase inhibition prevents multiple organ failure in
RT rodent models of acute pancreatitis.";
RL Nat. Med. 22:202-209(2016).
RN [6]
RP FUNCTION.
RX PubMed=28398044; DOI=10.1021/acs.jmedchem.7b00055;
RA Walker A.L., Ancellin N., Beaufils B., Bergeal M., Binnie M., Bouillot A.,
RA Clapham D., Denis A., Haslam C.P., Holmes D.S., Hutchinson J.P., Liddle J.,
RA McBride A., Mirguet O., Mowat C.G., Rowland P., Tiberghien N., Trottet L.,
RA Uings I., Webster S.P., Zheng X., Mole D.J.;
RT "Development of a Series of Kynurenine 3-Monooxygenase Inhibitors Leading
RT to a Clinical Candidate for the Treatment of Acute Pancreatitis.";
RL J. Med. Chem. 60:3383-3404(2017).
CC -!- FUNCTION: Catalyzes the hydroxylation of L-kynurenine (L-Kyn) to form
CC 3-hydroxy-L-kynurenine (L-3OHKyn). Required for synthesis of quinolinic
CC acid, a neurotoxic NMDA receptor antagonist and potential endogenous
CC inhibitor of NMDA receptor signaling in axonal targeting,
CC synaptogenesis and apoptosis during brain development. Quinolinic acid
CC may also affect NMDA receptor signaling in pancreatic beta cells,
CC osteoblasts, myocardial cells, and the gastrointestinal tract.
CC {ECO:0000255|HAMAP-Rule:MF_03018, ECO:0000269|PubMed:26752518,
CC ECO:0000269|PubMed:28398044}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+) + L-kynurenine + NADPH + O2 = 3-hydroxy-L-kynurenine +
CC H2O + NADP(+); Xref=Rhea:RHEA:20545, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:57959, ChEBI:CHEBI:58125, ChEBI:CHEBI:58349;
CC EC=1.14.13.9; Evidence={ECO:0000255|HAMAP-Rule:MF_03018,
CC ECO:0000269|PubMed:1332540};
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000250|UniProtKB:O15229,
CC ECO:0000255|HAMAP-Rule:MF_03018};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=258 uM for L-kynurenine {ECO:0000269|PubMed:26752518};
CC KM=11.3 uM for NADPH {ECO:0000269|PubMed:1332540};
CC KM=316 uM for NADH {ECO:0000269|PubMed:1332540};
CC -!- PATHWAY: Cofactor biosynthesis; NAD(+) biosynthesis; quinolinate from
CC L-kynurenine: step 1/3. {ECO:0000255|HAMAP-Rule:MF_03018}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion outer membrane {ECO:0000255|HAMAP-
CC Rule:MF_03018, ECO:0000269|PubMed:1332540}; Multi-pass membrane protein
CC {ECO:0000255|HAMAP-Rule:MF_03018, ECO:0000269|PubMed:1332540}.
CC -!- TISSUE SPECIFICITY: Highest activity in liver and kidney. Low activity
CC in spleen, stomach, intestinal tract, esophagus, heart and lung.
CC {ECO:0000269|PubMed:1332540}.
CC -!- DOMAIN: Transmembrane domains are required for enzymatic activity.
CC {ECO:0000250|UniProtKB:O15229}.
CC -!- MISCELLANEOUS: Increased in neuroinflammatory conditions. Inhibitors
CC are investigated as potential neuroprotective drugs since they lead to
CC an increased level of kynurenic acid, a neuroprotective NMDA receptor
CC agonist.
CC -!- SIMILARITY: Belongs to the aromatic-ring hydroxylase family. KMO
CC subfamily. {ECO:0000255|HAMAP-Rule:MF_03018}.
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DR EMBL; AF056031; AAC62614.1; -; mRNA.
DR EMBL; BC088142; AAH88142.1; -; mRNA.
DR RefSeq; NP_067604.1; NM_021593.1.
DR PDB; 6LKD; X-ray; 3.00 A; A/B=1-478.
DR PDB; 6LKE; X-ray; 3.00 A; A/B=1-478.
DR PDBsum; 6LKD; -.
DR PDBsum; 6LKE; -.
DR AlphaFoldDB; O88867; -.
DR SMR; O88867; -.
DR STRING; 10116.ENSRNOP00000005005; -.
DR BindingDB; O88867; -.
DR ChEMBL; CHEMBL3457; -.
DR iPTMnet; O88867; -.
DR PhosphoSitePlus; O88867; -.
DR PaxDb; O88867; -.
DR PRIDE; O88867; -.
DR Ensembl; ENSRNOT00000005005; ENSRNOP00000005005; ENSRNOG00000003709.
DR GeneID; 59113; -.
DR KEGG; rno:59113; -.
DR UCSC; RGD:620610; rat.
DR CTD; 8564; -.
DR RGD; 620610; Kmo.
DR eggNOG; KOG2614; Eukaryota.
DR GeneTree; ENSGT00390000000747; -.
DR HOGENOM; CLU_023210_0_1_1; -.
DR InParanoid; O88867; -.
DR OMA; REFMFIA; -.
DR OrthoDB; 462247at2759; -.
DR PhylomeDB; O88867; -.
DR TreeFam; TF312990; -.
DR BRENDA; 1.14.13.9; 5301.
DR Reactome; R-RNO-71240; Tryptophan catabolism.
DR SABIO-RK; O88867; -.
DR UniPathway; UPA00253; UER00328.
DR PRO; PR:O88867; -.
DR Proteomes; UP000002494; Chromosome 13.
DR Bgee; ENSRNOG00000003709; Expressed in adult mammalian kidney and 12 other tissues.
DR Genevisible; O88867; RN.
DR GO; GO:0005615; C:extracellular space; IDA:RGD.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005741; C:mitochondrial outer membrane; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IDA:RGD.
DR GO; GO:0071949; F:FAD binding; ISS:UniProtKB.
DR GO; GO:0050660; F:flavin adenine dinucleotide binding; ISO:RGD.
DR GO; GO:0004502; F:kynurenine 3-monooxygenase activity; IDA:UniProtKB.
DR GO; GO:0016174; F:NAD(P)H oxidase H2O2-forming activity; ISS:UniProtKB.
DR GO; GO:0034354; P:'de novo' NAD biosynthetic process from tryptophan; IEA:UniProtKB-UniRule.
DR GO; GO:0007568; P:aging; IEP:RGD.
DR GO; GO:0043420; P:anthranilate metabolic process; IEA:UniProtKB-UniRule.
DR GO; GO:0071347; P:cellular response to interleukin-1; IEP:RGD.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IEP:RGD.
DR GO; GO:0034276; P:kynurenic acid biosynthetic process; IMP:RGD.
DR GO; GO:0070189; P:kynurenine metabolic process; IDA:UniProtKB.
DR GO; GO:0097052; P:L-kynurenine metabolic process; IDA:RGD.
DR GO; GO:0019674; P:NAD metabolic process; IDA:UniProtKB.
DR GO; GO:0014049; P:positive regulation of glutamate secretion; IMP:RGD.
DR GO; GO:1903296; P:positive regulation of glutamate secretion, neurotransmission; IMP:RGD.
DR GO; GO:1901216; P:positive regulation of neuron death; IMP:RGD.
DR GO; GO:0019805; P:quinolinate biosynthetic process; IEA:UniProtKB-UniRule.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEP:RGD.
DR GO; GO:0009651; P:response to salt stress; ISO:RGD.
DR GO; GO:0006569; P:tryptophan catabolic process; IEA:UniProtKB-UniRule.
DR Gene3D; 3.50.50.60; -; 1.
DR HAMAP; MF_01971; Kynurenine_monooxygenase; 1.
DR InterPro; IPR002938; FAD-bd.
DR InterPro; IPR036188; FAD/NAD-bd_sf.
DR InterPro; IPR027545; Kynurenine_monooxygenase.
DR Pfam; PF01494; FAD_binding_3; 1.
DR SUPFAM; SSF51905; SSF51905; 1.
PE 1: Evidence at protein level;
KW 3D-structure; FAD; Flavoprotein; Membrane; Mitochondrion;
KW Mitochondrion outer membrane; Monooxygenase; NADP; Oxidoreductase;
KW Pyridine nucleotide biosynthesis; Reference proteome; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..478
FT /note="Kynurenine 3-monooxygenase"
FT /evidence="ECO:0000305"
FT /id="PRO_0000229745"
FT TRANSMEM 385..404
FT /note="Helical"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03018"
FT TRANSMEM 425..445
FT /note="Helical"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03018"
FT BINDING 19
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:O15229"
FT BINDING 37..40
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:O15229"
FT BINDING 57
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:O15229"
FT BINDING 85
FT /ligand="L-kynurenine"
FT /ligand_id="ChEBI:CHEBI:57959"
FT /evidence="ECO:0000250|UniProtKB:Q84HF5"
FT BINDING 99
FT /ligand="L-kynurenine"
FT /ligand_id="ChEBI:CHEBI:57959"
FT /evidence="ECO:0000250|UniProtKB:Q84HF5"
FT BINDING 111
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:O15229"
FT BINDING 136
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:O15229"
FT BINDING 172
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:O15229"
FT BINDING 304
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:O15229"
FT BINDING 317..318
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:O15229"
FT BINDING 363
FT /ligand="L-kynurenine"
FT /ligand_id="ChEBI:CHEBI:57959"
FT /evidence="ECO:0000250|UniProtKB:Q84HF5"
FT BINDING 398
FT /ligand="L-kynurenine"
FT /ligand_id="ChEBI:CHEBI:57959"
FT /evidence="ECO:0000250|UniProtKB:Q84HF5"
FT STRAND 10..14
FT /evidence="ECO:0007829|PDB:6LKD"
FT HELIX 18..28
FT /evidence="ECO:0007829|PDB:6LKD"
FT TURN 29..31
FT /evidence="ECO:0007829|PDB:6LKD"
FT STRAND 33..40
FT /evidence="ECO:0007829|PDB:6LKD"
FT TURN 43..45
FT /evidence="ECO:0007829|PDB:6LKD"
FT STRAND 54..58
FT /evidence="ECO:0007829|PDB:6LKD"
FT HELIX 60..67
FT /evidence="ECO:0007829|PDB:6LKD"
FT TURN 68..70
FT /evidence="ECO:0007829|PDB:6LKD"
FT HELIX 72..77
FT /evidence="ECO:0007829|PDB:6LKD"
FT STRAND 79..82
FT /evidence="ECO:0007829|PDB:6LKD"
FT STRAND 84..88
FT /evidence="ECO:0007829|PDB:6LKD"
FT STRAND 94..98
FT /evidence="ECO:0007829|PDB:6LKD"
FT STRAND 106..110
FT /evidence="ECO:0007829|PDB:6LKD"
FT HELIX 111..124
FT /evidence="ECO:0007829|PDB:6LKD"
FT STRAND 128..132
FT /evidence="ECO:0007829|PDB:6LKD"
FT STRAND 150..153
FT /evidence="ECO:0007829|PDB:6LKE"
FT STRAND 161..165
FT /evidence="ECO:0007829|PDB:6LKD"
FT HELIX 172..177
FT /evidence="ECO:0007829|PDB:6LKD"
FT STRAND 184..199
FT /evidence="ECO:0007829|PDB:6LKD"
FT STRAND 205..208
FT /evidence="ECO:0007829|PDB:6LKD"
FT STRAND 210..217
FT /evidence="ECO:0007829|PDB:6LKD"
FT STRAND 219..227
FT /evidence="ECO:0007829|PDB:6LKD"
FT STRAND 229..231
FT /evidence="ECO:0007829|PDB:6LKD"
FT STRAND 233..240
FT /evidence="ECO:0007829|PDB:6LKD"
FT HELIX 241..246
FT /evidence="ECO:0007829|PDB:6LKD"
FT HELIX 250..260
FT /evidence="ECO:0007829|PDB:6LKD"
FT HELIX 264..267
FT /evidence="ECO:0007829|PDB:6LKD"
FT HELIX 272..277
FT /evidence="ECO:0007829|PDB:6LKD"
FT STRAND 283..291
FT /evidence="ECO:0007829|PDB:6LKD"
FT TURN 296..298
FT /evidence="ECO:0007829|PDB:6LKD"
FT STRAND 299..301
FT /evidence="ECO:0007829|PDB:6LKD"
FT HELIX 303..305
FT /evidence="ECO:0007829|PDB:6LKD"
FT STRAND 311..314
FT /evidence="ECO:0007829|PDB:6LKD"
FT HELIX 316..333
FT /evidence="ECO:0007829|PDB:6LKD"
FT TURN 334..336
FT /evidence="ECO:0007829|PDB:6LKD"
FT HELIX 338..369
FT /evidence="ECO:0007829|PDB:6LKD"
FT HELIX 373..389
FT /evidence="ECO:0007829|PDB:6LKD"
FT TURN 391..393
FT /evidence="ECO:0007829|PDB:6LKD"
FT HELIX 397..402
FT /evidence="ECO:0007829|PDB:6LKD"
FT HELIX 408..442
FT /evidence="ECO:0007829|PDB:6LKD"
SQ SEQUENCE 478 AA; 54353 MW; 72E775D1C05CFFAB CRC64;
MASSDTEGKR VVVIGGGLVG ALNACFLAKR NFQVDVYEAR EDIRVANFMR GRSINLALSY
RGRQALKAVG LEDQIVSKGV PMKARMIHSL SGKKSAIPYG NKSQYILSIS REKLNKDLLT
AVESYPNAKV HFGHKLSKCC PEEGILTMLG PNKVPRDITC DLIVGCDGAY STVRAHLMKK
PRFDYSQQYI PHGYMELTIP PKNGEYAMEP NCLHIWPRNA FMMIALPNMD KSFTCTLFMS
FEEFEKLPTH SDVLDFFQKN FPDAIPLMGE QALMRDFFLL PAQPMISVKC SPFHLKSRCV
LMGDAAHAIV PFFGQGMNAG FEDCLVFDEL MDKFNNDLSV CLPEFSRFRI PDDHAISDLS
MYNYIEMRAH VNSRWFLFQR LLDKFLHALM PSTFIPLYTM VAFTRIRYHE AVLRWHWQKK
VINRGLFVLG SLVAIGSAYI LVHHLSPRPL ELLRSAWTGT SGHWNRSADI SPRVPWSH
