FSQB_ASPFU
ID FSQB_ASPFU Reviewed; 497 AA.
AC Q4WD43;
DT 15-FEB-2017, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2005, sequence version 1.
DT 03-AUG-2022, entry version 70.
DE RecName: Full=Amino acid oxidase fsqB {ECO:0000303|PubMed:27065235};
DE EC=1.5.3.- {ECO:0000269|PubMed:27065235, ECO:0000269|PubMed:30194285};
DE AltName: Full=Fumipyrrole biosynthesis protein A {ECO:0000303|PubMed:25582336};
DE AltName: Full=Fumisoquins biosynthesis protein B {ECO:0000303|PubMed:27065235};
GN Name=fsqB {ECO:0000303|PubMed:27065235};
GN Synonyms=fmpA {ECO:0000303|PubMed:25582336}; ORFNames=AFUA_6G03440;
OS Neosartorya fumigata (strain ATCC MYA-4609 / Af293 / CBS 101355 / FGSC
OS A1100) (Aspergillus fumigatus).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC Aspergillus subgen. Fumigati.
OX NCBI_TaxID=330879;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC MYA-4609 / Af293 / CBS 101355 / FGSC A1100;
RX PubMed=16372009; DOI=10.1038/nature04332;
RA Nierman W.C., Pain A., Anderson M.J., Wortman J.R., Kim H.S., Arroyo J.,
RA Berriman M., Abe K., Archer D.B., Bermejo C., Bennett J.W., Bowyer P.,
RA Chen D., Collins M., Coulsen R., Davies R., Dyer P.S., Farman M.L.,
RA Fedorova N., Fedorova N.D., Feldblyum T.V., Fischer R., Fosker N.,
RA Fraser A., Garcia J.L., Garcia M.J., Goble A., Goldman G.H., Gomi K.,
RA Griffith-Jones S., Gwilliam R., Haas B.J., Haas H., Harris D.E.,
RA Horiuchi H., Huang J., Humphray S., Jimenez J., Keller N., Khouri H.,
RA Kitamoto K., Kobayashi T., Konzack S., Kulkarni R., Kumagai T., Lafton A.,
RA Latge J.-P., Li W., Lord A., Lu C., Majoros W.H., May G.S., Miller B.L.,
RA Mohamoud Y., Molina M., Monod M., Mouyna I., Mulligan S., Murphy L.D.,
RA O'Neil S., Paulsen I., Penalva M.A., Pertea M., Price C., Pritchard B.L.,
RA Quail M.A., Rabbinowitsch E., Rawlins N., Rajandream M.A., Reichard U.,
RA Renauld H., Robson G.D., Rodriguez de Cordoba S., Rodriguez-Pena J.M.,
RA Ronning C.M., Rutter S., Salzberg S.L., Sanchez M., Sanchez-Ferrero J.C.,
RA Saunders D., Seeger K., Squares R., Squares S., Takeuchi M., Tekaia F.,
RA Turner G., Vazquez de Aldana C.R., Weidman J., White O., Woodward J.R.,
RA Yu J.-H., Fraser C.M., Galagan J.E., Asai K., Machida M., Hall N.,
RA Barrell B.G., Denning D.W.;
RT "Genomic sequence of the pathogenic and allergenic filamentous fungus
RT Aspergillus fumigatus.";
RL Nature 438:1151-1156(2005).
RN [2]
RP FUNCTION, AND INDUCTION.
RX PubMed=25582336; DOI=10.1111/mmi.12926;
RA Macheleidt J., Scherlach K., Neuwirth T., Schmidt-Heck W., Strassburger M.,
RA Spraker J., Baccile J.A., Schroeder F.C., Keller N.P., Hertweck C.,
RA Heinekamp T., Brakhage A.A.;
RT "Transcriptome analysis of cyclic AMP-dependent protein kinase A-regulated
RT genes reveals the production of the novel natural compound fumipyrrole by
RT Aspergillus fumigatus.";
RL Mol. Microbiol. 96:148-162(2015).
RN [3]
RP FUNCTION, DISRUPTION PHENOTYPE, COFACTOR, CATALYTIC ACTIVITY, AND
RP BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=27065235; DOI=10.1038/nchembio.2061;
RA Baccile J.A., Spraker J.E., Le H.H., Brandenburger E., Gomez C., Bok J.W.,
RA Macheleidt J., Brakhage A.A., Hoffmeister D., Keller N.P., Schroeder F.C.;
RT "Plant-like biosynthesis of isoquinoline alkaloids in Aspergillus
RT fumigatus.";
RL Nat. Chem. Biol. 12:419-424(2016).
RN [4]
RP X-RAY CRYSTALLOGRAPHY (2.60 ANGSTROMS) IN COMPLEX WITH FAD, SUBUNIT,
RP COFACTOR, FUNCTION, CATALYTIC ACTIVITY, SUBSTRATE SPECIFICITY,
RP BIOPHYSICOCHEMICAL PROPERTIES, AND MUTAGENESIS OF ARG-63; ARG-66; TYR-121;
RP LYS-304; ASP-444 AND LYS-448.
RX PubMed=30194285; DOI=10.1074/jbc.ra118.004227;
RA Lahham M., Pavkov-Keller T., Fuchs M., Niederhauser J., Chalhoub G.,
RA Daniel B., Kroutil W., Gruber K., Macheroux P.;
RT "Oxidative cyclization of N-methyl-dopa by a fungal flavoenzyme of the
RT amine oxidase family.";
RL J. Biol. Chem. 293:17021-17032(2018).
CC -!- FUNCTION: Amino acid oxidase; part of the gene cluster that mediates
CC the biosynthesis of the isoquinoline alkaloids fumisoquin A, fumisoquin
CC B and fumisoquin C; as well as small amounts of fumipyrrole as a shunt
CC metabolite (PubMed:25582336, PubMed:27065235, PubMed:30194285). The
CC products of the cluster lead to a brown coloration and are important
CC for growth and conidiation (PubMed:25582336). The nonribosomal peptide
CC synthetase-like protein fsqF, which lacks a canonical condensation
CC domain, is required for addition of a serine-derived dehydroalanine
CC moiety to activated tyrosine but is not essential for the subsequent
CC steps leading to isoquinoline formation (PubMed:27065235). A different
CC enzyme, most likely the ATP-grasp enzyme fsqD, is responsible for
CC activation of tyrosine (Probable). Three additional enzymes encoded by
CC the fsq cluster, the N-methyltransferase fsqC, the phenol 2-
CC monooxygenase fsqG and the FAD-dependent oxidase fsqB, catalyze the
CC formation of the isoquinoline ring system in the fumisoquins
CC (PubMed:27065235, PubMed:30194285). FsqB converts the fspF thiolation
CC domain-bound (2S,4S,5S)-2-amino-6-(3,4-dihydroxyphenyl)-4-hydroxy-5-
CC (methylamino)hexanoyl into isoquinoline (PubMed:27065235,
CC PubMed:30194285). The cyclization most likely proceeds via a two-step
CC mechanism, beginning with FAD-dependent oxidation of the methyl group
CC to an iminium species followed by electrophilic attack on the
CC deprotonated phenol (Probable). {ECO:0000269|PubMed:25582336,
CC ECO:0000269|PubMed:27065235, ECO:0000269|PubMed:30194285,
CC ECO:0000305|PubMed:27065235}.
CC -!- FUNCTION: Is able to convert N-methyl-3,4-dihydroxy-DL-phenylalanine
CC (N-methyl-DOPA) directly into cyclic isoquinoline, in vitro
CC (PubMed:27065235, PubMed:30194285). The absence of the meta-hydroxyl
CC group, as in L-N-methyl-tyrosine, leads to a 25-fold lower rate of
CC reduction and the formation of the demethylated product L-tyrosine,
CC instead of a cyclic product (PubMed:30194285). Does not accept the D-
CC stereoisomer of N-methyltyrosine, in contrast to N-methyl-DOPA, for
CC which both stereoisomers are oxidized with similar rates
CC (PubMed:30194285). {ECO:0000269|PubMed:27065235,
CC ECO:0000269|PubMed:30194285}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(2S,4S,5S)-2-amino-6-(3,4-dihydroxyphenyl)-4-hydroxy-5-
CC (methylamino)hexanoyl-[peptidyl-carrier protein] + O2 = (2S,4S)-2-
CC amino-4-[(3S)-7,8-dihydroxy-1,2,3,4-tetrahydroisoquinolin-3-yl]-4-
CC hydroxybutanoyl-[peptidyl-carrier protein] + H2O2;
CC Xref=Rhea:RHEA:66628, Rhea:RHEA-COMP:17077, Rhea:RHEA-COMP:17078,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:16240, ChEBI:CHEBI:167304,
CC ChEBI:CHEBI:167307; Evidence={ECO:0000269|PubMed:27065235};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66629;
CC Evidence={ECO:0000269|PubMed:27065235};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=N-methyl-L-dopa + O2 = (3S)-7,8-dihydroxy-1,2,3,4-
CC tetrahydroisoquinoline-3-carboxylate + H2O2; Xref=Rhea:RHEA:66788,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:16240, ChEBI:CHEBI:167490,
CC ChEBI:CHEBI:167492; Evidence={ECO:0000269|PubMed:30194285};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66789;
CC Evidence={ECO:0000269|PubMed:30194285};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=N-methyl-D-dopa + O2 = (3R)-7,8-dihydroxy-1,2,3,4-
CC tetrahydroisoquinoline-3-carboxylate + H2O2; Xref=Rhea:RHEA:66792,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:16240, ChEBI:CHEBI:167491,
CC ChEBI:CHEBI:167493; Evidence={ECO:0000269|PubMed:30194285};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66793;
CC Evidence={ECO:0000269|PubMed:30194285};
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000269|PubMed:27065235, ECO:0000269|PubMed:30194285};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=142.5 uM for N-methyl-DOPA {ECO:0000269|PubMed:27065235};
CC KM=0.16 mM for rac-N-methyl-DOPA {ECO:0000269|PubMed:30194285};
CC KM=0.25 mM for L-N-methyl-DOPA {ECO:0000269|PubMed:30194285};
CC KM=2.1 mM for L-N-methyl-tyrosine {ECO:0000269|PubMed:30194285};
CC KM=1.6 mM for rac-N-methyl-meta-tyrosine
CC {ECO:0000269|PubMed:30194285};
CC pH dependence:
CC Optimum pH is 7.6. {ECO:0000269|PubMed:30194285};
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:27065235, ECO:0000269|PubMed:30194285}.
CC -!- SUBUNIT: Dimer. {ECO:0000269|PubMed:30194285}.
CC -!- INDUCTION: Expression is positively regulated by the fumisoquins
CC biosynthesis specific transcription factor fsqA (PubMed:25582336).
CC {ECO:0000269|PubMed:25582336, ECO:0000269|PubMed:27065235}.
CC -!- DISRUPTION PHENOTYPE: Leads to complete abolishment of isoquinoline
CC alkaloid production and accumulation of a series of benzyl pyrroles,
CC including fumipyrrole. {ECO:0000269|PubMed:27065235}.
CC -!- SIMILARITY: Belongs to the MSOX/MTOX family. {ECO:0000305}.
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DR EMBL; AAHF01000012; EAL85695.1; -; Genomic_DNA.
DR RefSeq; XP_747733.1; XM_742640.1.
DR PDB; 6GG2; X-ray; 2.60 A; A=1-497.
DR PDBsum; 6GG2; -.
DR AlphaFoldDB; Q4WD43; -.
DR SMR; Q4WD43; -.
DR STRING; 746128.CADAFUBP00009219; -.
DR EnsemblFungi; EAL85695; EAL85695; AFUA_6G03440.
DR GeneID; 3505180; -.
DR KEGG; afm:AFUA_6G03440; -.
DR VEuPathDB; FungiDB:Afu6g03440; -.
DR eggNOG; KOG2820; Eukaryota.
DR HOGENOM; CLU_007884_0_1_1; -.
DR InParanoid; Q4WD43; -.
DR OMA; CDHAFKF; -.
DR OrthoDB; 752680at2759; -.
DR Proteomes; UP000002530; Chromosome 6.
DR GO; GO:0050660; F:flavin adenine dinucleotide binding; IEA:InterPro.
DR GO; GO:0050031; F:L-pipecolate oxidase activity; IBA:GO_Central.
DR GO; GO:0051699; F:proline oxidase activity; IBA:GO_Central.
DR GO; GO:0008115; F:sarcosine oxidase activity; IBA:GO_Central.
DR Gene3D; 3.50.50.60; -; 3.
DR InterPro; IPR006076; FAD-dep_OxRdtase.
DR InterPro; IPR036188; FAD/NAD-bd_sf.
DR InterPro; IPR045170; MTOX.
DR PANTHER; PTHR10961; PTHR10961; 1.
DR Pfam; PF01266; DAO; 1.
DR SUPFAM; SSF51905; SSF51905; 1.
PE 1: Evidence at protein level;
KW 3D-structure; FAD; Flavoprotein; Oxidoreductase; Reference proteome.
FT CHAIN 1..497
FT /note="Amino acid oxidase fsqB"
FT /evidence="ECO:0000255"
FT /id="PRO_0000438869"
FT REGION 98..182
FT /note="Substrate binding"
FT /evidence="ECO:0000269|PubMed:30194285,
FT ECO:0007744|PDB:6GG2"
FT REGION 259..418
FT /note="Substrate binding"
FT /evidence="ECO:0000269|PubMed:30194285,
FT ECO:0007744|PDB:6GG2"
FT BINDING 1..97
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:30194285,
FT ECO:0007744|PDB:6GG2"
FT BINDING 14
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:30194285,
FT ECO:0007744|PDB:6GG2"
FT BINDING 38
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:30194285,
FT ECO:0007744|PDB:6GG2"
FT BINDING 53
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:30194285,
FT ECO:0007744|PDB:6GG2"
FT BINDING 57
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:30194285,
FT ECO:0007744|PDB:6GG2"
FT BINDING 58
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:30194285,
FT ECO:0007744|PDB:6GG2"
FT BINDING 183..257
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:30194285,
FT ECO:0007744|PDB:6GG2"
FT BINDING 211
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:30194285,
FT ECO:0007744|PDB:6GG2"
FT BINDING 419..496
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:30194285,
FT ECO:0007744|PDB:6GG2"
FT BINDING 448
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:30194285,
FT ECO:0007744|PDB:6GG2"
FT MOD_RES 414
FT /note="S-8alpha-FAD cysteine"
FT /evidence="ECO:0000269|PubMed:30194285,
FT ECO:0007744|PDB:6GG2"
FT MUTAGEN 63
FT /note="R->M: Severely compromises enzymatic activity."
FT /evidence="ECO:0000269|PubMed:30194285"
FT MUTAGEN 66
FT /note="R->M: Severely compromises enzymatic activity."
FT /evidence="ECO:0000269|PubMed:30194285"
FT MUTAGEN 121
FT /note="Y->F: Severely compromises enzymatic activity."
FT /evidence="ECO:0000269|PubMed:30194285"
FT MUTAGEN 304
FT /note="K->A: Severely compromises enzymatic activity."
FT /evidence="ECO:0000269|PubMed:30194285"
FT MUTAGEN 444
FT /note="D->A: Severely compromises enzymatic activity."
FT /evidence="ECO:0000269|PubMed:30194285"
FT MUTAGEN 448
FT /note="K->A: Impairs interaction with FAD and compromises
FT enzymatic activity."
FT /evidence="ECO:0000269|PubMed:30194285"
FT STRAND 5..10
FT /evidence="ECO:0007829|PDB:6GG2"
FT HELIX 14..25
FT /evidence="ECO:0007829|PDB:6GG2"
FT HELIX 27..29
FT /evidence="ECO:0007829|PDB:6GG2"
FT STRAND 30..40
FT /evidence="ECO:0007829|PDB:6GG2"
FT STRAND 63..65
FT /evidence="ECO:0007829|PDB:6GG2"
FT HELIX 73..85
FT /evidence="ECO:0007829|PDB:6GG2"
FT TURN 86..94
FT /evidence="ECO:0007829|PDB:6GG2"
FT STRAND 95..97
FT /evidence="ECO:0007829|PDB:6GG2"
FT STRAND 100..107
FT /evidence="ECO:0007829|PDB:6GG2"
FT HELIX 120..132
FT /evidence="ECO:0007829|PDB:6GG2"
FT HELIX 136..139
FT /evidence="ECO:0007829|PDB:6GG2"
FT HELIX 146..152
FT /evidence="ECO:0007829|PDB:6GG2"
FT STRAND 161..163
FT /evidence="ECO:0007829|PDB:6GG2"
FT STRAND 173..181
FT /evidence="ECO:0007829|PDB:6GG2"
FT STRAND 183..185
FT /evidence="ECO:0007829|PDB:6GG2"
FT HELIX 187..201
FT /evidence="ECO:0007829|PDB:6GG2"
FT STRAND 205..208
FT /evidence="ECO:0007829|PDB:6GG2"
FT STRAND 211..216
FT /evidence="ECO:0007829|PDB:6GG2"
FT STRAND 218..228
FT /evidence="ECO:0007829|PDB:6GG2"
FT STRAND 233..235
FT /evidence="ECO:0007829|PDB:6GG2"
FT STRAND 237..241
FT /evidence="ECO:0007829|PDB:6GG2"
FT HELIX 244..246
FT /evidence="ECO:0007829|PDB:6GG2"
FT HELIX 247..251
FT /evidence="ECO:0007829|PDB:6GG2"
FT STRAND 258..268
FT /evidence="ECO:0007829|PDB:6GG2"
FT HELIX 271..279
FT /evidence="ECO:0007829|PDB:6GG2"
FT STRAND 284..287
FT /evidence="ECO:0007829|PDB:6GG2"
FT TURN 288..291
FT /evidence="ECO:0007829|PDB:6GG2"
FT STRAND 292..295
FT /evidence="ECO:0007829|PDB:6GG2"
FT STRAND 301..307
FT /evidence="ECO:0007829|PDB:6GG2"
FT HELIX 310..319
FT /evidence="ECO:0007829|PDB:6GG2"
FT HELIX 331..337
FT /evidence="ECO:0007829|PDB:6GG2"
FT TURN 341..344
FT /evidence="ECO:0007829|PDB:6GG2"
FT STRAND 357..359
FT /evidence="ECO:0007829|PDB:6GG2"
FT HELIX 362..380
FT /evidence="ECO:0007829|PDB:6GG2"
FT TURN 382..385
FT /evidence="ECO:0007829|PDB:6GG2"
FT HELIX 398..405
FT /evidence="ECO:0007829|PDB:6GG2"
FT STRAND 410..418
FT /evidence="ECO:0007829|PDB:6GG2"
FT STRAND 420..422
FT /evidence="ECO:0007829|PDB:6GG2"
FT STRAND 425..428
FT /evidence="ECO:0007829|PDB:6GG2"
FT HELIX 430..432
FT /evidence="ECO:0007829|PDB:6GG2"
FT STRAND 435..440
FT /evidence="ECO:0007829|PDB:6GG2"
FT HELIX 447..449
FT /evidence="ECO:0007829|PDB:6GG2"
FT HELIX 450..463
FT /evidence="ECO:0007829|PDB:6GG2"
FT TURN 464..466
FT /evidence="ECO:0007829|PDB:6GG2"
FT HELIX 480..486
FT /evidence="ECO:0007829|PDB:6GG2"
FT HELIX 491..493
FT /evidence="ECO:0007829|PDB:6GG2"
SQ SEQUENCE 497 AA; 54929 MW; C4BBC46356D6A74D CRC64;
MSIPNSFIIV GSGVFGLSLA YALSLDDRFA DKKIILVDRW NFEPPNATGS VHNPAAANAD
TSRVIRRDYP HGPYASLALE AMKHWRGKFG ENNRYVNQRL LFSGEGSSLT TPPKALETVN
YIKKAYAISC ELTPGGRDAV QVLDSLDEVR AFLGNTPSHP PHLPVNKDPA ARDLRGYVSN
DCGWADAGAS IEWLRQEVLR LGRVECVVGE VESLVYSDDQ RAVKGVKLVD GKVLTAELTV
IAAGARSSHI LGIPKLCDVY SEFVAYIQLT KEEADELRRR QWPILVNCHR GVFAVGPDHD
NCLKFGHFSY SGIVDVLREA SIQVPTRPDG WEAQQKYWSD PRFAFGGEVK VSALGDVDDY
ENPAAQRALA DYRLFLLELL GPTGLQGVDT LGLDQSDNLL NNIANRPFTR VRKCWYNDTP
ALDFVVDYHP SYGKTLFVAT GGCDHAFKFL PIIGEKTLAL ILRNRGDSAV SLPAGVEPSL
EELSELWRFP VELLQDN
