FMO2_RABIT
ID FMO2_RABIT Reviewed; 535 AA.
AC P17635;
DT 01-AUG-1990, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 3.
DT 03-AUG-2022, entry version 139.
DE RecName: Full=Dimethylaniline monooxygenase [N-oxide-forming] 2 {ECO:0000250|UniProtKB:Q99518};
DE EC=1.14.13.- {ECO:0000269|PubMed:10950853, ECO:0000269|PubMed:15144220, ECO:0000269|PubMed:15294458, ECO:0000269|PubMed:16620765};
DE EC=1.14.13.8 {ECO:0000269|PubMed:11302936, ECO:0000269|PubMed:3785145};
DE AltName: Full=Dimethylaniline oxidase 2;
DE AltName: Full=FMO 1B1;
DE AltName: Full=Pulmonary flavin-containing monooxygenase 2;
DE Short=FMO 2;
GN Name=FMO2 {ECO:0000250|UniProtKB:Q99518};
OS Oryctolagus cuniculus (Rabbit).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Lagomorpha; Leporidae; Oryctolagus.
OX NCBI_TaxID=9986;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE.
RC STRAIN=New Zealand white;
RX PubMed=2318837; DOI=10.1016/s0021-9258(19)39441-4;
RA Lawton M.P., Gasser R., Tynes R.E., Hodgson E., Philpot R.M.;
RT "The flavin-containing monooxygenase enzymes expressed in rabbit liver and
RT lung are products of related but distinctly different genes.";
RL J. Biol. Chem. 265:5855-5861(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=New Zealand white; TISSUE=Lung;
RX PubMed=1306120; DOI=10.1097/00008571-199210000-00003;
RA Nikbakht K.N., Lawton M.P., Philpot R.M.;
RT "Guinea pig or rabbit lung flavin-containing monooxygenases with distinct
RT mobilities in SDS-PAGE are allelic variants that differ at only two
RT positions.";
RL Pharmacogenetics 2:207-216(1992).
RN [3]
RP PARTIAL PROTEIN SEQUENCE, AND ACETYLATION AT ALA-2.
RC TISSUE=Lung;
RX PubMed=1911780; DOI=10.1021/bi00105a012;
RA Guan S., Falick A.M., Williams D.E., Cashman J.R.;
RT "Evidence for complex formation between rabbit lung flavin-containing
RT monooxygenase and calreticulin.";
RL Biochemistry 30:9892-9900(1991).
RN [4]
RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=3785145;
RA Poulsen L.L., Taylor K., Williams D.E., Masters B.S., Ziegler D.M.;
RT "Substrate specificity of the rabbit lung flavin-containing monooxygenase
RT for amines: oxidation products of primary alkylamines.";
RL Mol. Pharmacol. 30:680-685(1986).
RN [5]
RP FUNCTION, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=10950853;
RA Rodriguez R.J., Miranda C.L.;
RT "Isoform specificity of N-deacetyl ketoconazole by human and rabbit flavin-
RT containing monooxygenases.";
RL Drug Metab. Dispos. 28:1083-1086(2000).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=11302936;
RA Krueger S.K., Yueh M.F., Martin S.R., Pereira C.B., Williams D.E.;
RT "Characterization of expressed full-length and truncated FMO2 from rhesus
RT monkey.";
RL Drug Metab. Dispos. 29:693-700(2001).
RN [7]
RP FUNCTION, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=15294458; DOI=10.1016/j.bcp.2004.05.051;
RA Henderson M.C., Krueger S.K., Siddens L.K., Stevens J.F., Williams D.E.;
RT "S-oxygenation of the thioether organophosphate insecticides phorate and
RT disulfoton by human lung flavin-containing monooxygenase 2.";
RL Biochem. Pharmacol. 68:959-967(2004).
RN [8]
RP FUNCTION, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=15144220; DOI=10.1021/tx034253s;
RA Henderson M.C., Krueger S.K., Stevens J.F., Williams D.E.;
RT "Human flavin-containing monooxygenase form 2 S-oxygenation: sulfenic acid
RT formation from thioureas and oxidation of glutathione.";
RL Chem. Res. Toxicol. 17:633-640(2004).
RN [9]
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF 510-PHE--PHE-535.
RX PubMed=16620765; DOI=10.1016/j.abb.2006.03.012;
RA Krueger S.K., Siddens L.K., Henderson M.C., VanDyke J.E., Karplus P.A.,
RA Pereira C.B., Williams D.E.;
RT "C-Terminal truncation of rabbit flavin-containing monooxygenase isoform 2
RT enhances solubility.";
RL Arch. Biochem. Biophys. 450:149-156(2006).
CC -!- FUNCTION: Catalyzes the oxidative metabolism of numerous xenobiotics,
CC including mainly therapeutic drugs and insecticides that contain a soft
CC nucleophile, most commonly nitrogen and sulfur and participates to
CC their bioactivation (PubMed:3785145, PubMed:10950853, PubMed:16620765,
CC PubMed:11302936, PubMed:15144220, PubMed:15294458). Most drug
CC substrates are tertiary amines such as prochlorperazine and
CC trifluoperazine which are N-oxygenated to form the N-oxide, or sulfides
CC such as thiourea and ethionamide, which are S-oxygenated to the
CC sulfoxide (PubMed:3785145, PubMed:15144220, PubMed:16620765). Others
CC include primary alkylamines such as N-dodecylamine and octan-1-amine
CC that are sequentially monooxygenated to oximes through intermediate
CC hydroxylamines and both steps are NADPH- and oxygen-dependent
CC (PubMed:3785145). Also metabolized N-Deacetyl ketoconazole (DAK) to N-
CC hydroxy-DAK and appears to further metabolizes N-hydroxy-DAK to two
CC others metabolites (PubMed:10950853). Also catalyzes S-oxygenation of
CC the thioether-containing organophosphate insecticides, phorate and
CC disulfoton (PubMed:15294458). {ECO:0000269|PubMed:10950853,
CC ECO:0000269|PubMed:11302936, ECO:0000269|PubMed:15144220,
CC ECO:0000269|PubMed:15294458, ECO:0000269|PubMed:16620765,
CC ECO:0000269|PubMed:3785145}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+) + N,N-dimethylaniline + NADPH + O2 = H2O + N,N-
CC dimethylaniline N-oxide + NADP(+); Xref=Rhea:RHEA:24468,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:16269, ChEBI:CHEBI:17735, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349; EC=1.14.13.8;
CC Evidence={ECO:0000269|PubMed:11302936, ECO:0000269|PubMed:3785145};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:24469;
CC Evidence={ECO:0000305|PubMed:11302936};
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692; Evidence={ECO:0000250};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000250};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=36 uM for thiourea {ECO:0000269|PubMed:15144220};
CC KM=21 uM for ethylenethiourea {ECO:0000269|PubMed:15144220};
CC KM=82 uM for N-phenylthiourea {ECO:0000269|PubMed:15144220};
CC KM=25 uM for ANTU {ECO:0000269|PubMed:15144220};
CC KM=310 uM for N,N-dimethylaniline {ECO:0000269|PubMed:11302936};
CC KM=500 uM for (S)-nicotine {ECO:0000269|PubMed:11302936};
CC KM=330 uM for N,N-dimethylaniline {ECO:0000269|PubMed:3785145};
CC KM=46 uM for N,N-dimethyloctylamine {ECO:0000269|PubMed:3785145};
CC KM=31 uM for trifluoperazine {ECO:0000269|PubMed:3785145};
CC KM=1000 uM for desmethylperazine {ECO:0000269|PubMed:3785145};
CC KM=120 uM for N-methyloctylamine {ECO:0000269|PubMed:3785145};
CC KM=17 uM for N-methyloctylhydroxylamine {ECO:0000269|PubMed:3785145};
CC KM=12000 uM for octan-1-amine {ECO:0000269|PubMed:3785145};
CC KM=290 uM for N-dodecylamine {ECO:0000269|PubMed:3785145};
CC KM=70 uM for N-methyloctylhydroxylamine {ECO:0000269|PubMed:3785145};
CC KM=3 uM for N-dodecylhydroxylamine {ECO:0000269|PubMed:3785145};
CC KM=57 uM for phorate {ECO:0000269|PubMed:15294458};
CC KM=32 uM for disulfoton {ECO:0000269|PubMed:15294458};
CC Vmax=450 nmol/min/mg enzyme toward N,N-dimethylaniline
CC {ECO:0000269|PubMed:3785145};
CC Vmax=450 nmol/min/mg enzyme toward N,N-dimethyloctylamine
CC {ECO:0000269|PubMed:3785145};
CC Vmax=450 nmol/min/mg enzyme toward trifluoperazine
CC {ECO:0000269|PubMed:3785145};
CC Vmax=900 nmol/min/mg enzyme toward desmethylperazine 1
CC {ECO:0000269|PubMed:3785145};
CC Vmax=550 nmol/min/mg enzyme toward N-methyloctylamine
CC {ECO:0000269|PubMed:3785145};
CC Vmax=500 nmol/min/mg enzyme toward N-methyloctylhydroxylamine
CC {ECO:0000269|PubMed:3785145};
CC Vmax=1600 nmol/min/mg enzyme toward octan-1-amine
CC {ECO:0000269|PubMed:3785145};
CC Vmax=1600 nmol/min/mg enzyme toward N-dodecylamine
CC {ECO:0000269|PubMed:3785145};
CC Vmax=600 nmol/min/mg enzyme toward N-methyloctylhydroxylamine
CC {ECO:0000269|PubMed:3785145};
CC Vmax=600 nmol/min/mg enzyme toward N-dodecylhydroxylamine
CC {ECO:0000269|PubMed:3785145};
CC -!- SUBCELLULAR LOCATION: Microsome membrane {ECO:0000269|PubMed:16620765};
CC Single-pass membrane protein {ECO:0000269|PubMed:16620765}. Endoplasmic
CC reticulum membrane {ECO:0000305|PubMed:16620765}; Single-pass membrane
CC protein {ECO:0000269|PubMed:16620765}.
CC -!- TISSUE SPECIFICITY: Lung.
CC -!- POLYMORPHISM: There are two allelic forms.
CC -!- SIMILARITY: Belongs to the FMO family. {ECO:0000305}.
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DR EMBL; M32029; AAA31442.1; -; mRNA.
DR PIR; B35182; B35182.
DR RefSeq; NP_001075753.1; NM_001082284.1.
DR AlphaFoldDB; P17635; -.
DR SMR; P17635; -.
DR STRING; 9986.ENSOCUP00000004486; -.
DR iPTMnet; P17635; -.
DR PRIDE; P17635; -.
DR GeneID; 100009119; -.
DR KEGG; ocu:100009119; -.
DR CTD; 2327; -.
DR eggNOG; KOG1399; Eukaryota.
DR InParanoid; P17635; -.
DR OrthoDB; 405736at2759; -.
DR BRENDA; 1.14.13.8; 1749.
DR Proteomes; UP000001811; Unplaced.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0016020; C:membrane; ISS:UniProtKB.
DR GO; GO:0050660; F:flavin adenine dinucleotide binding; IEA:InterPro.
DR GO; GO:0004499; F:N,N-dimethylaniline monooxygenase activity; IEA:UniProtKB-EC.
DR GO; GO:0050661; F:NADP binding; IEA:InterPro.
DR GO; GO:0070995; P:NADPH oxidation; ISS:UniProtKB.
DR Gene3D; 3.50.50.60; -; 4.
DR InterPro; IPR036188; FAD/NAD-bd_sf.
DR InterPro; IPR000960; Flavin_mOase.
DR InterPro; IPR020946; Flavin_mOase-like.
DR InterPro; IPR002254; Flavin_mOase_2.
DR Pfam; PF00743; FMO-like; 1.
DR PIRSF; PIRSF000332; FMO; 1.
DR PRINTS; PR00370; FMOXYGENASE.
DR PRINTS; PR01122; FMOXYGENASE2.
DR SUPFAM; SSF51905; SSF51905; 2.
PE 1: Evidence at protein level;
KW Acetylation; Direct protein sequencing; Endoplasmic reticulum; FAD;
KW Flavoprotein; Isopeptide bond; Magnesium; Membrane; Microsome;
KW Monooxygenase; NADP; Oxidoreductase; Reference proteome; Transmembrane;
KW Transmembrane helix; Ubl conjugation.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000269|PubMed:1911780"
FT CHAIN 2..535
FT /note="Dimethylaniline monooxygenase [N-oxide-forming] 2"
FT /id="PRO_0000147650"
FT TRANSMEM 510..530
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 9..13
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q9HFE4"
FT BINDING 32
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q9HFE4"
FT BINDING 40..41
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q9HFE4"
FT BINDING 60..61
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q9HFE4"
FT BINDING 61..62
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q9HFE4"
FT BINDING 195..198
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q9HFE4"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0000269|PubMed:1911780"
FT CROSSLNK 492
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT /evidence="ECO:0000250|UniProtKB:Q99518"
FT VARIANT 120
FT /note="A -> S (in PFMO-2 and PFMO-4)"
FT VARIANT 136
FT /note="Q -> E (in PFMO-2 and PFMO-4)"
FT MUTAGEN 510..535
FT /note="Missing: Increases protein solubility in the absence
FT of detergent."
FT /evidence="ECO:0000269|PubMed:16620765"
SQ SEQUENCE 535 AA; 61144 MW; D51910BDA41C55C2 CRC64;
MAKKVAVIGA GVSGLISLKC CVDEGLEPTC FERTEDIGGL WRFKENVEDG RASIYQSVIT
NTSKEMSCFS DFPMPEDFPN FLHNSKLLEY FRIFAKKFDL LKYIQFQTTV ISVKKRPDFA
SSGQWEVVTQ SNSKQQSAVF DAVMVCSGHH ILPNIPLKSF PGIEKFKGQY FHSRQYKHPA
GLEGKRILVI GIGNSASDIA VELSKKAAQV YISTRKGSWV MSRISEDGYP WDMVFHTRFS
SMLRNVLPRM IVKWMMEQQM NRWFNHENYG LAPENKYLMK EPVLNDDLPS RILYGTIKVK
RRVKELTESA AIFEDGTVEE DIDVIVFATG YTFAFPFLEE SLVKIEDNMV SLYKYMFPPQ
LEKSTFACLG LIQPLGSIFP TVELQARWAT RVFKGLCSLP SKETMMADII KRNENRIALF
GESLSQKLQT NYIDYLDELA LEIGAKPDLV SFLFKDPKLA VKLYFGPCNS YQYRLVGPGQ
WEGARNAIFT QKQRILKPLK TRTLKASSNF PVSFLLKFLG LFALVLAFLF QLQWF
