FMQD_ASPFU
ID FMQD_ASPFU Reviewed; 497 AA.
AC Q4WLW6;
DT 20-JUN-2018, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2005, sequence version 1.
DT 03-AUG-2022, entry version 87.
DE RecName: Full=FAD-linked oxidoreductase fmqD {ECO:0000303|PubMed:21899262};
DE EC=1.-.-.- {ECO:0000269|PubMed:21899262};
DE AltName: Full=Fumiquinazoline biosynthesis cluster protein D {ECO:0000303|PubMed:24612080};
DE Flags: Precursor;
GN Name=fmqD {ECO:0000303|PubMed:24612080}; ORFNames=AFUA_6G12070;
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.
RX PubMed=20225828; DOI=10.1021/bi100198y;
RA Ames B.D., Walsh C.T.;
RT "Anthranilate-activating modules from fungal nonribosomal peptide assembly
RT lines.";
RL Biochemistry 49:3351-3365(2010).
RN [3]
RP FUNCTION.
RX PubMed=20804163; DOI=10.1021/bi1012029;
RA Ames B.D., Liu X., Walsh C.T.;
RT "Enzymatic processing of fumiquinazoline F: a tandem oxidative-acylation
RT strategy for the generation of multicyclic scaffolds in fungal indole
RT alkaloid biosynthesis.";
RL Biochemistry 49:8564-8576(2010).
RN [4]
RP FUNCTION, SUBCELLULAR LOCATION, CATALYTIC ACTIVITY, AND PATHWAY.
RX PubMed=21899262; DOI=10.1021/bi201302w;
RA Ames B.D., Haynes S.W., Gao X., Evans B.S., Kelleher N.L., Tang Y.,
RA Walsh C.T.;
RT "Complexity generation in fungal peptidyl alkaloid biosynthesis: oxidation
RT of fumiquinazoline A to the heptacyclic hemiaminal fumiquinazoline C by the
RT flavoenzyme Af12070 from Aspergillus fumigatus.";
RL Biochemistry 50:8756-8769(2011).
RN [5]
RP FUNCTION, DISRUPTION PHENOTYPE, INDUCTION, SUBCELLULAR LOCATION, AND
RP PATHWAY.
RX PubMed=24612080; DOI=10.1111/cmi.12284;
RA Lim F.Y., Ames B., Walsh C.T., Keller N.P.;
RT "Co-ordination between BrlA regulation and secretion of the oxidoreductase
RT FmqD directs selective accumulation of fumiquinazoline C to conidial
RT tissues in Aspergillus fumigatus.";
RL Cell. Microbiol. 16:1267-1283(2014).
RN [6]
RP FUNCTION, AND INDUCTION.
RX PubMed=33705521; DOI=10.1093/genetics/iyab036;
RA Rocha M.C., Fabri J.H.T.M., da Silva L.P., Angolini C.F.F., Bertolini M.C.,
RA da Cunha A.F., Valiante V., Goldman G.H., Fill T.P., Malavazi I.;
RT "Transcriptional control of the production of Aspergillus fumigatus
RT conidia-borne secondary metabolite fumiquinazoline C important for
RT phagocytosis protection.";
RL Genetics 0:0-0(2021).
CC -!- FUNCTION: FAD-linked oxidoreductase; part of the gene cluster that
CC mediates the biosynthesis of the antitumor fumiquinazolines that confer
CC a dual-usage capability to defend against phagocytes in the environment
CC and animal hosts (PubMed:20225828, PubMed:20804163, PubMed:21899262,
CC PubMed:24612080, PubMed:33705521). The simplest member is
CC fumiquinazoline F (FQF) with a 6-6-6 tricyclic core derived from
CC anthranilic acid (Ant), tryptophan (Trp), and alanine (Ala)
CC (PubMed:20225828). The trimodular NRPS fmqA is responsible for FQF
CC formation (PubMed:20225828). Modules 1, 2 and 3 of fmqA are predicted
CC to activate and load Ant, Trp and Ala, respectively, providing for the
CC assembly of an Ant-Trp-Ala-S-enzyme intermediate that would undergo
CC double cyclization for chain release and generation of the tricyclic 6-
CC 6-6 product fumiquinazoline F (PubMed:20225828). The presence of an E
CC domain predicted for module 2 of fmqA is consistent with epimerization
CC of L-Trp to D-Trp during assembly to generate the R-stereocenter at C14
CC of FQF (PubMed:20225828). The FAD-dependent monooxygenase fmqB and the
CC monomodular NRPS fmqC then maturate FQF to FQA (PubMed:20804163). FmqB
CC oxidizes the 2',3'-double bond of the indole side chain of FQF, and
CC fmqC activates L-Ala as the adenylate, installs it as the pantetheinyl
CC thioester on its carrier protein domain, and acylates the oxidized
CC indole for subsequent intramolecular cyclization to create the 6-5-5-
CC imidazolindolone of FQA (PubMed:20804163). The FAD-linked
CC oxidoreductase fmqD introduces a third layer of scaffold complexity by
CC converting FQA to the spirohemiaminal FQC, presumably by catalyzing the
CC formation of a transient imine within the pyrazinone ring
CC (PubMed:21899262). FQC subsequently converts nonenzymatically to the
CC known cyclic aminal FQD (PubMed:21899262).
CC {ECO:0000269|PubMed:20225828, ECO:0000269|PubMed:20804163,
CC ECO:0000269|PubMed:21899262, ECO:0000269|PubMed:24612080,
CC ECO:0000269|PubMed:33705521}.
CC -!- PATHWAY: Alkaloid biosynthesis. {ECO:0000269|PubMed:21899262,
CC ECO:0000269|PubMed:24612080}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:24612080,
CC ECO:0000305|PubMed:21899262}. Secreted, cell wall
CC {ECO:0000269|PubMed:24612080}. Note=Localizes to the cell wall of the
CC conidia and In to both the cell wall and septa in the hyphae
CC (PubMed:24612080). {ECO:0000269|PubMed:24612080}.
CC -!- INDUCTION: Expression is positively regulated by brlA, a conidiation-
CC specific transcription factor involved in the early stage of asexual
CC development and necessary for conidiophore formation (PubMed:24612080).
CC Expression is also induced by the cell wall integrity (CWI) signaling
CC pathway that includes the mitogen-activated protein kinase mpkA and the
CC transcription factor rlmA (PubMed:33705521). Expression is negatively
CC regulated by the transcription factor sebA (PubMed:33705521).
CC {ECO:0000269|PubMed:24612080, ECO:0000269|PubMed:33705521}.
CC -!- DISRUPTION PHENOTYPE: Leads to a significant decrease but not complete
CC loss of fumiquinazoline C production and accumulates fumiquinazoline A
CC (PubMed:24612080). {ECO:0000269|PubMed:24612080}.
CC -!- SIMILARITY: Belongs to the oxygen-dependent FAD-linked oxidoreductase
CC family. {ECO:0000305}.
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DR EMBL; AAHF01000006; EAL89048.1; -; Genomic_DNA.
DR RefSeq; XP_751086.1; XM_745993.1.
DR AlphaFoldDB; Q4WLW6; -.
DR SMR; Q4WLW6; -.
DR STRING; 746128.CADAFUBP00007609; -.
DR EnsemblFungi; EAL89048; EAL89048; AFUA_6G12070.
DR GeneID; 3508391; -.
DR KEGG; afm:AFUA_6G12070; -.
DR eggNOG; ENOG502SJ3M; Eukaryota.
DR HOGENOM; CLU_018354_0_0_1; -.
DR InParanoid; Q4WLW6; -.
DR OMA; ITSATYE; -.
DR OrthoDB; 350817at2759; -.
DR BioCyc; MetaCyc:MON-18844; -.
DR Proteomes; UP000002530; Chromosome 6.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0071949; F:FAD binding; IEA:InterPro.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR GO; GO:1900781; P:fumiquinazoline C biosynthetic process; IDA:GO_Central.
DR Gene3D; 3.30.465.10; -; 1.
DR InterPro; IPR012951; BBE.
DR InterPro; IPR016166; FAD-bd_PCMH.
DR InterPro; IPR036318; FAD-bd_PCMH-like_sf.
DR InterPro; IPR016169; FAD-bd_PCMH_sub2.
DR InterPro; IPR016164; FAD-linked_Oxase-like_C.
DR InterPro; IPR006094; Oxid_FAD_bind_N.
DR Pfam; PF08031; BBE; 1.
DR Pfam; PF01565; FAD_binding_4; 1.
DR SUPFAM; SSF55103; SSF55103; 1.
DR SUPFAM; SSF56176; SSF56176; 1.
DR PROSITE; PS51387; FAD_PCMH; 1.
PE 1: Evidence at protein level;
KW Cell wall; FAD; Flavoprotein; Glycoprotein; Oxidoreductase;
KW Reference proteome; Secreted; Signal.
FT SIGNAL 1..17
FT /evidence="ECO:0000255"
FT CHAIN 18..497
FT /note="FAD-linked oxidoreductase fmqD"
FT /id="PRO_5004245690"
FT DOMAIN 68..243
FT /note="FAD-binding PCMH-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00718"
FT CARBOHYD 99
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 261
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 288
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 497 AA; 54550 MW; CE0BBDD296FDFED8 CRC64;
MQYIPFLISG LVPVALSKSL FEATSNTRID GNDIAAIFGP VLTPEAHIFL PSDGDYDDNV
MARWSTFNDP SYVATVKPAT ETDVQAIREY QVSTAASHNI TFFATGGGHG VKLNFGNVQN
AINIELSLLD FIDLDLDNEV VTIGPGVENA QLYDLLSSVG KETALTGERC VNTIGPTLGG
GLGPLYGIRG PQVDSLVSAR LVTASGDVIT VSRSENRDLF WAIRGAGANF GIVTSATYRI
YDQTNGGMAV SAQFAFAPAV NRSVFDLMES MNDEYPPGMS GGMILSYNHT TNEPSVQWNL
LFMGSNEDAQ PWLDKIQALG PIDSSIRNVP WHRRDEPEVP YCERGQHYIL YNLNLRRTDA
ATLQSYFDSF VDFSSKNPWF DCDLMYERQA TDAALAVPLS ERGVGPWRDS KINANFLVVT
PSEEYDEAAD AFVRPFMDRF QAVMGFDTLH VYVNEALGDE GPASWYGEEN LPRLVALKQQ
WDPENKFGAG APIPLSL
