ID FSQF_ASPFU Reviewed; 1480 AA.
AC Q4WD47;
DT 15-FEB-2017, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2005, sequence version 1.
DT 24-JAN-2024, entry version 117.
DE RecName: Full=Nonribosomal peptide synthetase-like enzyme fsqF {ECO:0000303|PubMed:25582336};
DE EC=6.3.2.- {ECO:0000305|PubMed:27065235};
DE AltName: Full=Fumipyrrole biosynthesis protein E {ECO:0000303|PubMed:25582336};
DE AltName: Full=Fumisoquins biosynthesis protein F {ECO:0000303|PubMed:27065235};
GN Name=fsqF {ECO:0000303|PubMed:27065235};
GN Synonyms=fmpE {ECO:0000303|PubMed:25582336}; ORFNames=AFUA_6G03480;
OS Aspergillus fumigatus (strain ATCC MYA-4609 / CBS 101355 / FGSC A1100 /
OS Af293) (Neosartorya fumigata).
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 / CBS 101355 / FGSC A1100 / Af293;
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, DISRUPTION PHENOTYPE, INDUCTION, AND PATHWAY.
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, DOMAIN, AND DISRUPTION PHENOTYPE.
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 FUNCTION.
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: Nonribosomal peptide synthetase-like enzyme; part of the gene
CC cluster that mediates the biosynthesis of the isoquinoline alkaloids
CC fumisoquin A, fumisoquin B and fumisoquin C; as well as small amounts
CC of fumipyrrole as a shunt metabolite (PubMed:25582336,
CC PubMed:27065235). The products of the cluster lead to a brown
CC coloration and are important for growth and conidiation
CC (PubMed:25582336). The nonribosomal peptide synthetase-like protein
CC fsqF, which lacks a canonical condensation domain, is required for
CC addition of a serine-derived dehydroalanine moiety to activated
CC tyrosine but is not essential for the subsequent steps leading to
CC isoquinoline formation (PubMed:27065235). A different enzyme, most
CC likely the ATP-grasp enzyme fsqD, is responsible for activation of
CC tyrosine (Probable). Three additional enzymes encoded by the fsq
CC cluster, the N-methyltransferase fsqC, the phenol 2-monooxygenase fsqG
CC and the FAD-dependent oxidase fsqB, catalyze the formation of the
CC isoquinoline ring system in the fumisoquins (PubMed:27065235,
CC PubMed:30194285). FsqB converts the fspF thiolation domain-bound
CC (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 -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:25582336}.
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 -!- DOMAIN: FsqF lacks the condensation domain that is essential for
CC canonical peptide bond formation, and bioinformatic analysis of the
CC vicinity of fsqF did not reveal any genes that could code for a second
CC NRPS or free-standing condensation domain.
CC {ECO:0000305|PubMed:27065235}.
CC -!- DISRUPTION PHENOTYPE: Prevents the production of fumipyrrole and leads
CC to reduced growth and sporulation, but does not affect virulence in
CC infected mice (PubMed:25582336). Abolishes completely the production of
CC isoquinolines as well as of pyrroles and leads to the production of a
CC single brightly red shunt metabolite, the anthranilic acid-substituted
CC isoquinoline (PubMed:27065235). {ECO:0000269|PubMed:25582336,
CC ECO:0000269|PubMed:27065235}.
CC -!- SIMILARITY: Belongs to the NRP synthetase family. {ECO:0000305}.
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DR EMBL; AAHF01000012; EAL85691.1; -; Genomic_DNA.
DR RefSeq; XP_747729.1; XM_742636.1.
DR AlphaFoldDB; Q4WD47; -.
DR SMR; Q4WD47; -.
DR STRING; 330879.Q4WD47; -.
DR EnsemblFungi; EAL85691; EAL85691; AFUA_6G03480.
DR GeneID; 3505176; -.
DR KEGG; afm:AFUA_6G03480; -.
DR eggNOG; KOG1178; Eukaryota.
DR eggNOG; KOG1549; Eukaryota.
DR HOGENOM; CLU_000022_60_8_1; -.
DR InParanoid; Q4WD47; -.
DR OMA; ASTWDIF; -.
DR OrthoDB; 2209130at2759; -.
DR Proteomes; UP000002530; Chromosome 6.
DR GO; GO:0016874; F:ligase activity; IEA:UniProtKB-KW.
DR GO; GO:1901566; P:organonitrogen compound biosynthetic process; IEA:UniProt.
DR GO; GO:0044550; P:secondary metabolite biosynthetic process; IEA:UniProt.
DR CDD; cd05918; A_NRPS_SidN3_like; 1.
DR Gene3D; 3.30.300.30; -; 1.
DR Gene3D; 1.10.1200.10; ACP-like; 1.
DR Gene3D; 3.90.1150.10; Aspartate Aminotransferase, domain 1; 1.
DR Gene3D; 3.40.50.12780; N-terminal domain of ligase-like; 1.
DR Gene3D; 3.40.50.720; NAD(P)-binding Rossmann-like Domain; 1.
DR Gene3D; 3.40.640.10; Type I PLP-dependent aspartate aminotransferase-like (Major domain); 1.
DR InterPro; IPR010071; AA_adenyl_domain.
DR InterPro; IPR036736; ACP-like_sf.
DR InterPro; IPR000192; Aminotrans_V_dom.
DR InterPro; IPR045851; AMP-bd_C_sf.
DR InterPro; IPR020845; AMP-binding_CS.
DR InterPro; IPR000873; AMP-dep_Synth/Lig_com.
DR InterPro; IPR042099; ANL_N_sf.
DR InterPro; IPR013120; Far_NAD-bd.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR015424; PyrdxlP-dep_Trfase.
DR InterPro; IPR015421; PyrdxlP-dep_Trfase_major.
DR InterPro; IPR015422; PyrdxlP-dep_Trfase_small.
DR InterPro; IPR010080; Thioester_reductase-like_dom.
DR NCBIfam; TIGR01733; AA-adenyl-dom; 1.
DR NCBIfam; TIGR01746; Thioester-redct; 1.
DR PANTHER; PTHR44845; CARRIER DOMAIN-CONTAINING PROTEIN; 1.
DR PANTHER; PTHR44845:SF4; NONRIBOSOMAL PEPTIDE SYNTHASE INPA; 1.
DR Pfam; PF00266; Aminotran_5; 1.
DR Pfam; PF00501; AMP-binding; 1.
DR Pfam; PF07993; NAD_binding_4; 1.
DR Pfam; PF00550; PP-binding; 1.
DR SUPFAM; SSF56801; Acetyl-CoA synthetase-like; 1.
DR SUPFAM; SSF47336; ACP-like; 1.
DR SUPFAM; SSF51735; NAD(P)-binding Rossmann-fold domains; 1.
DR SUPFAM; SSF53383; PLP-dependent transferases; 1.
DR PROSITE; PS00455; AMP_BINDING; 1.
DR PROSITE; PS50075; CARRIER; 1.
PE 2: Evidence at transcript level;
KW Ligase; Phosphopantetheine; Phosphoprotein; Reference proteome.
FT CHAIN 1..1480
FT /note="Nonribosomal peptide synthetase-like enzyme fsqF"
FT /id="PRO_0000438873"
FT DOMAIN 662..741
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 31..59
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 132..527
FT /note="Adenylation domain"
FT /evidence="ECO:0000255"
FT REGION 739..773
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 780..1003
FT /note="NAD-binding domain"
FT /evidence="ECO:0000255"
FT REGION 1100..1465
FT /note="Aminotransferase domain"
FT /evidence="ECO:0000255"
FT MOD_RES 700
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 1480 AA; 163306 MW; 45137566A9EAC7BE CRC64;
MLLQDVHHRE QLDDDVENAF SKINGTARQA SPFADEPSID VPSTHLPVVT PRSKTANDRT
GLAKSLPYAS LGASRSTIDE QDVLIQTWAI LLHQYAVSDT VAFAIIGKSD PSGYSGRRAS
TQVVCLPHLF LDSARATPHA PAVHGWDGRL TYAELDQLSN SVARQLLRRG VRKGQFVPFS
FEKSIWMVVA IIGILRAGGV VASIDPSQPQ SRAREIIQET GATVIVASTA QASVFAGLVD
TVVPIADDTV HPAANDTGLH PSLPPVHPED PAVVIFTSGS TGKPKGIVIQ HGAVTTRMVA
EGRAFQYHGA RTLQFAASTW DIFMTDIFTT LAFNGCVCIP SEEDRRFNLA RFCAEYDVSL
ALITPSLANL LEPTGFPTLK TLIFGGEALK EEVTRKWEAV DGISLHQGYG PAETGPCVAG
RLAERPEILG YALDNSVCVL VDPSNPNRLV PLGAVGELVV GGPSLLREYI NDPRKTEAAV
IENPPWALDL MTPVRRFYRT GDLLRYSVDT LDGRLEFVGR TDDQVKYHGQ RIELGEIEHH
LSRLPGVEAC VVVLAKAGFF KDRLVAVVQA GKSSGGSSYG TQLSLRSDPN ITITHMRRFL
SSRLPEFMIP NELLVVQELP HNNSMKLDRG RVAKWVADMQ SQPSEAVPKP HTRGNELLAH
ESTARTIARE YARIVAGDSV ARRREYEDRD FNLQEGGIDS IQIMSLSMFL TEHFGFQVPM
ADILSSRATV RSIASLIDAN SSPGRGQPLN TQETARLPLR SNGPAPSQQA LERNGSRVFL
TGASGFLGIE ILRQLLARPK THVYALVRGS SESQARERLV QKAISAGWWQ DAYRTRLHVW
HGDLTQPQLG LSQLQWQMLQ GKASPSIDAI IHNGAKVHYS QDYETLKKTN VSPTVELLKA
VHDREEPLHS FVFVSGGQQL SFDDREDEKN AAKSLKGSGY ARSKAVSEQI VRRFANQKGS
KARHVRIVKP GFIIGDAERG LANQSDFIWR LIAACVELGF YNGDEADSWL FISDITRVAQ
VILHSVFEDD SQPVTKVLDG LRFKTLWALL QDKFGFELQP LSRREWLARL KHSVATKKEK
HVLLREQFPA LHHGVVPFNN AAGTVVHREA AESTHRYMTS FPYELGRDDP ASAAKTQRLQ
DRFAELAAFM NADPDEIAFG QSTTFLLRSL GQALKPLLNS DCEIIVSILC HEGSAAAWVA
LAKDLGIAIK WWAPPPGDDP VLSLDTLRPL LTPKTRLVAC NHVSNVVGTI HPIRQVADLV
HRIPGAVLVV DGVAWAPHRP IDVKALDVDF YCFSWYKVFG PHVAQLYGRR SAQKRALAGI
SHFFLSEMPG LDWRLRLGAN SFELEEALVP ITRYLKRVGW DNIIAQETVL QDVFLAYLRR
RPRVFRIFGE QSSDPAKRVP VITFEVIGHS STVVANKVNQ RGRFRVVSGN CWAPRPTHDV
LGLGADGLIR VSFVHYNTVA EVQEFCTELD SVLETLNAGI
//
