FMQC_ASPFU
ID FMQC_ASPFU Reviewed; 1160 AA.
AC Q4WLW8;
DT 18-APR-2012, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2005, sequence version 1.
DT 03-AUG-2022, entry version 101.
DE RecName: Full=Nonribosomal peptide synthetase fmqC {ECO:0000303|PubMed:16962256};
DE EC=6.3.2.- {ECO:0000269|PubMed:20804163};
DE AltName: Full=Fumiquinazoline biosynthesis cluster protein C {ECO:0000303|PubMed:24612080};
GN Name=fmqC {ECO:0000303|PubMed:24612080};
GN Synonyms=NRPS11 {ECO:0000303|PubMed:16962256},
GN pesL {ECO:0000303|PubMed:17464044}; ORFNames=AFUA_6G12050;
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 NOMENCLATURE.
RX PubMed=16962256; DOI=10.1016/j.gene.2006.07.008;
RA Cramer R.A. Jr., Stajich J.E., Yamanaka Y., Dietrich F.S., Steinbach W.J.,
RA Perfect J.R.;
RT "Phylogenomic analysis of non-ribosomal peptide synthetases in the genus
RT Aspergillus.";
RL Gene 383:24-32(2006).
RN [3]
RP REVIEW ON FUNCTION, AND DOMAIN.
RX PubMed=17464044; DOI=10.1099/mic.0.2006/006908-0;
RA Stack D., Neville C., Doyle S.;
RT "Nonribosomal peptide synthesis in Aspergillus fumigatus and other fungi.";
RL Microbiology 153:1297-1306(2007).
RN [4]
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 [5]
RP FUNCTION, DOMAIN, CATALYTIC ACTIVITY, AND PATHWAY.
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 [6]
RP FUNCTION.
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 [7]
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 [8]
RP FUNCTION, INDUCTION, INTERACTION WITH MPKA, AND PHOSPHORYLATION.
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: Nonribosomal peptide synthetase; part of the gene cluster
CC that mediates the biosynthesis of the antitumor fumiquinazolines that
CC confer a dual-usage capability to defend against phagocytes in the
CC environment and animal hosts (PubMed:20225828, PubMed:20804163,
CC PubMed:21899262, PubMed:24612080, PubMed:33705521). The simplest member
CC is 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:20804163,
CC ECO:0000269|PubMed:24612080}.
CC -!- SUBUNIT: Interacts with the mitogen-activated protein kinase mpkA.
CC {ECO:0000269|PubMed:33705521}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {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 -!- DOMAIN: NRP synthetases are composed of discrete domains (adenylation
CC (A), thiolation (T) or peptidyl carrier protein (PCP) and condensation
CC (C) domains) which when grouped together are referred to as a single
CC module (PubMed:17464044). Each module is responsible for the
CC recognition (via the A domain) and incorporation of a single amino acid
CC into the growing peptide product (PubMed:17464044). Thus, an NRP
CC synthetase is generally composed of one or more modules and can
CC terminate in a thioesterase domain (TE) that releases the newly
CC synthesized peptide from the enzyme (PubMed:17464044). Occasionally,
CC epimerase (E) domains (responsible for L- to D- amino acid conversion)
CC are present within the NRP synthetase (PubMed:17464044). NRPS11 has the
CC following architecture: A-T-C (PubMed:17464044, PubMed:20804163).
CC {ECO:0000305|PubMed:17464044, ECO:0000305|PubMed:20804163}.
CC -!- PTM: Phosphorylated by mpkA during conidiogenesis.
CC {ECO:0000269|PubMed:33705521}.
CC -!- DISRUPTION PHENOTYPE: Abolishes the production of fumiquinazoline A and
CC C but does not accumulate fumiquinazoline F (PubMed:24612080).
CC {ECO:0000269|PubMed:24612080}.
CC -!- SIMILARITY: Belongs to the NRP synthetase family. {ECO:0000305}.
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DR EMBL; AAHF01000006; EAL89046.1; -; Genomic_DNA.
DR RefSeq; XP_751084.1; XM_745991.1.
DR AlphaFoldDB; Q4WLW8; -.
DR SMR; Q4WLW8; -.
DR STRING; 746128.CADAFUBP00007607; -.
DR EnsemblFungi; EAL89046; EAL89046; AFUA_6G12050.
DR GeneID; 3508389; -.
DR KEGG; afm:AFUA_6G12050; -.
DR VEuPathDB; FungiDB:Afu6g12050; -.
DR eggNOG; KOG1178; Eukaryota.
DR HOGENOM; CLU_000022_60_3_1; -.
DR InParanoid; Q4WLW8; -.
DR OMA; GITHENR; -.
DR OrthoDB; 4243at2759; -.
DR BioCyc; MetaCyc:MON-18833; -.
DR Proteomes; UP000002530; Chromosome 6.
DR GO; GO:0005737; C:cytoplasm; IDA:AspGD.
DR GO; GO:0016874; F:ligase activity; IEA:UniProtKB-KW.
DR GO; GO:0031177; F:phosphopantetheine binding; IBA:GO_Central.
DR GO; GO:0043041; P:amino acid activation for nonribosomal peptide biosynthetic process; IBA:GO_Central.
DR GO; GO:0008218; P:bioluminescence; IEA:UniProtKB-KW.
DR GO; GO:1900809; P:fumigaclavine C biosynthetic process; IMP:AspGD.
DR GO; GO:1900778; P:fumiquinazoline A biosynthetic process; IDA:AspGD.
DR GO; GO:1900781; P:fumiquinazoline C biosynthetic process; IDA:GO_Central.
DR GO; GO:0019184; P:nonribosomal peptide biosynthetic process; ISM:AspGD.
DR GO; GO:0019748; P:secondary metabolic process; NAS:AspGD.
DR GO; GO:0044550; P:secondary metabolite biosynthetic process; IDA:AspGD.
DR Gene3D; 1.10.1200.10; -; 1.
DR Gene3D; 3.30.300.30; -; 1.
DR Gene3D; 3.30.559.10; -; 1.
DR Gene3D; 3.40.50.12780; -; 1.
DR InterPro; IPR010071; AA_adenyl_domain.
DR InterPro; IPR036736; ACP-like_sf.
DR InterPro; IPR045851; AMP-bd_C_sf.
DR InterPro; IPR000873; AMP-dep_Synth/Lig.
DR InterPro; IPR042099; ANL_N_sf.
DR InterPro; IPR023213; CAT-like_dom_sf.
DR InterPro; IPR001242; Condensatn.
DR InterPro; IPR009081; PP-bd_ACP.
DR Pfam; PF00501; AMP-binding; 1.
DR Pfam; PF00668; Condensation; 1.
DR Pfam; PF00550; PP-binding; 1.
DR SUPFAM; SSF47336; SSF47336; 1.
DR TIGRFAMs; TIGR01733; AA-adenyl-dom; 1.
DR PROSITE; PS50075; CARRIER; 1.
PE 1: Evidence at protein level;
KW Cytoplasm; Ligase; Luminescence; Phosphopantetheine; Phosphoprotein;
KW Photoprotein; Reference proteome; Repeat; Virulence.
FT CHAIN 1..1160
FT /note="Nonribosomal peptide synthetase fmqC"
FT /id="PRO_0000416552"
FT DOMAIN 642..719
FT /note="Carrier"
FT /evidence="ECO:0000255, ECO:0000255|PROSITE-
FT ProRule:PRU00258, ECO:0000305|PubMed:17464044,
FT ECO:0000305|PubMed:20804163"
FT REGION 132..520
FT /note="Adenylation"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:17464044,
FT ECO:0000305|PubMed:20804163"
FT REGION 749..1025
FT /note="Condensation"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:17464044,
FT ECO:0000305|PubMed:20804163"
FT MOD_RES 679
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 1160 AA; 128744 MW; FAA8BE224F567D84 CRC64;
MPDLIQTKSV VLGYGVKMVL APAKAARSLL IREEAVWRFS LPRVLSTPTT MLETTEPIAH
ASELDKPSIV VTNTEVDSED NTSSVLGRYI PQKCLQNARL AAVNSCVNEI FEARFRERPD
APAVCAWDGS YTYRELNDRS SALAHKLRRR GVQAEVLVAL LFEKSKFSVV AMHAVIKAGG
AFQLWDPSLP VARLGGMFAE SKAHLVLASA ANARLAAEIS ENVMVVDESL VPPWESAPLN
PGTQPENALY CVFTSGSTGK PKGFLMDHRA FCTCALGVGE LLGLNGASRL IQFSANSFDL
ATFDHILPFL CGACLCIPSE EERKGDLTRA FNRYRATHAV LTPTVSRLLE PEKLTTLQVL
LLAGEAPSRE DIRRWASTVG LLNGYSPAEA GCITIVNPSL QESHPSKIGF PVSVVPWVVD
PDDCNRLVPA GEVGELVLQG HTLARGYFGR PDQSKAAFIP TPAWVRQFGY ETYGRLYRTG
DLVRFDAEDE SLVYIGRKDS QVKIRGQRLE LGEVEHALQQ FFPRPQIVVV ELLTAEDREP
ALVGFVYQPG SSQHMPAPPQ HQDNSLFLVA DDQFCADAQK ALASLRDILP PYMIPSDLLR
ISHLPMVPSG KTDRRLIRMR AVDLAPEERR KYSSVLGQSR DQPVTQLEES LLGLWATCLK
LPPSQIGVLD NFFHLGGGSL EAIHLAAEAR NMGFAELSSA AVFQCPTIRE MAGMLDGVTA
SVQEQDPRGC TSFQLESSLV AELLRKSQCT LEDLQEGFLP LTPFQEKTAK MKPMHLLLDI
PGIDHSRLEA AWALVLEKHI SFRSIYVEHQ GRVYQAFLRQ PDTVSIPIRW CDEPVHECAA
RFCEQDVDLI LDGRPWWSMT RINNKIDSVL VLRLTHAQWD ALTLDVLFKD FMAAYESREL
SRRDLEFPAY MRFRLRHNAS PATVRFWSTF LHGSRLTQPL LLDGAAEVDP GNEAMVFVSQ
QIPMLTPPHG ITLGSVFRAA WAFVLARYTG QEDVVFGEFV EGRSLLVKSV EKVTGCAAAE
TPMRIVVSPT ASVRDLLKHS QEQYVARIPY ETCELEDIVP SSTSWPTDTT FNHILVIQHE
PVLPPVALDG RPCPHRWAFH GRLEDVYVQM VFGPDTLHVG MSGPEIRLSR TIATQLVEKL
ASTITQFNDR PEALLSEITV
