QULF_PENCI
ID QULF_PENCI Reviewed; 402 AA.
AC P0DUR7;
DT 29-SEP-2021, integrated into UniProtKB/Swiss-Prot.
DT 29-SEP-2021, sequence version 1.
DT 03-AUG-2022, entry version 4.
DE RecName: Full=FMN-dependent alpha-hydroxy acid dehydrogenase qulF {ECO:0000303|PubMed:32663343};
DE EC=1.13.12.- {ECO:0000269|PubMed:32663343};
DE AltName: Full=Quinolactacin A2 biosynthesis cluster protein F {ECO:0000303|PubMed:32663343};
GN Name=qulF {ECO:0000303|PubMed:32663343};
OS Penicillium citrinum.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium.
OX NCBI_TaxID=5077;
RN [1]
RP FUNCTION, DISRUPTION PHENOTYPE, CATALYTIC ACTIVITY, MUTAGENESIS OF HIS-289,
RP AND PATHWAY.
RX PubMed=32663343; DOI=10.1002/anie.202005770;
RA Zhao F., Liu Z., Yang S., Ding N., Gao X.;
RT "Quinolactacin biosynthesis involves non-ribosomal-peptide-synthetase-
RT catalyzed Dieckmann condensation to form the quinolone-gamma-lactam
RT hybrid.";
RL Angew. Chem. Int. Ed. 59:19108-19114(2020).
CC -!- FUNCTION: FMN-dependent alpha-hydroxy acid dehydrogenase; part of the
CC gene cluster that mediates the biosynthesis of quinolactacin A2 (QUL
CC A2), a fungal alkaloid that features a quinolone-gamma-lactam hybrid,
CC which is a potential pharmacophore for the treatment of cancer and
CC Alzheimer's disease (PubMed:32663343). The quinolone-gamma-lactam
CC hybrid scaffold is synthesized from the combination of L-isoleucine (L-
CC Ile) and the nonproteinogenic amino acid L-kynurenine, followed by
CC quinolone cyclization, oxidative decarboxylation, and lactam formation
CC (PubMed:32663343). Additionally, the N-methyl group is derived from
CC methionine, which might be catalyzed by an S-adenosylmethionine (SAM)-
CC dependent methyltransferase (PubMed:32663343). Bioconversion of L-
CC tryptophan to L-kynurenine could be catalyzed by the indoleamine-2,3-
CC dioxygenase (IDO) qulI to produce an unstable product, N-formyl-L-
CC kynurenine, followed by kynurenine formamidase catalyzed hydrolysis
CC (PubMed:32663343). QulM then acts as a methyltransferase that
CC methylates L-kynurenine at the N-4 position (PubMed:32663343). The FMN-
CC dependent alpha-hydroxy acid dehydrogenase qulF than functions as an
CC oxidative decarboxylase which converts N-methylkynurenine into 2-
CC aminobenzoylacetamide via 2 tandem reactions, including dehydrogenation
CC and decarboxylation (PubMed:32663343). An amidase located outside of
CC the qul gene cluster further produces the unstable beta-keto acid
CC precursor N-methyl-2-aminobenzoylacetate, which could be spontaneously
CC dehydrated to form N-methyl-4-hydroxy-2-quinolone (PubMed:32663343).
CC The NRPS qulB is able to incorporate N-methyl-2-aminobenzoylacetate and
CC efficiently compete with the spontaneous reaction (PubMed:32663343). By
CC further extending the beta-keto acid with L-Ile, qulA performs a
CC Dieckmann condensation to form the gamma-lactam ring and release a 4-
CC ketopyrrolidinone intermediate from the assembly line
CC (PubMed:32663343). This intermediate could plausibly further undergo a
CC spontaneous cyclization to yield the final quinolone-gamma-lactam
CC hybrid structure (PubMed:32663343). {ECO:0000269|PubMed:32663343}.
CC -!- COFACTOR:
CC Name=FMN; Xref=ChEBI:CHEBI:58210;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU00683,
CC ECO:0000269|PubMed:32663343};
CC -!- DISRUPTION PHENOTYPE: Impairs the production of quinolactacin A2 and
CC leads to the accumulatin of N-methylkynurenine.
CC {ECO:0000269|PubMed:32663343}.
CC -!- SIMILARITY: Belongs to the FMN-dependent alpha-hydroxy acid
CC dehydrogenase family. {ECO:0000255|PROSITE-ProRule:PRU00683}.
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DR SMR; P0DUR7; -.
DR GO; GO:0010181; F:FMN binding; IEA:InterPro.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR CDD; cd03332; LMO_FMN; 1.
DR Gene3D; 3.20.20.70; -; 1.
DR InterPro; IPR013785; Aldolase_TIM.
DR InterPro; IPR012133; Alpha-hydoxy_acid_DH_FMN.
DR InterPro; IPR000262; FMN-dep_DH.
DR InterPro; IPR037396; FMN_HAD.
DR InterPro; IPR008259; FMN_hydac_DH_AS.
DR InterPro; IPR037350; LMO_FMN.
DR Pfam; PF01070; FMN_dh; 1.
DR PIRSF; PIRSF000138; Al-hdrx_acd_dh; 1.
DR PROSITE; PS00557; FMN_HYDROXY_ACID_DH_1; 1.
DR PROSITE; PS51349; FMN_HYDROXY_ACID_DH_2; 1.
PE 1: Evidence at protein level;
KW Flavoprotein; FMN; Oxidoreductase.
FT CHAIN 1..402
FT /note="FMN-dependent alpha-hydroxy acid dehydrogenase qulF"
FT /id="PRO_0000453483"
FT DOMAIN 22..394
FT /note="FMN hydroxy acid dehydrogenase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00683"
FT ACT_SITE 289
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00683"
FT BINDING 48
FT /ligand="a 2-oxocarboxylate"
FT /ligand_id="ChEBI:CHEBI:35179"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00683"
FT BINDING 130
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00683"
FT BINDING 152
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00683"
FT BINDING 154
FT /ligand="a 2-oxocarboxylate"
FT /ligand_id="ChEBI:CHEBI:35179"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00683"
FT BINDING 189
FT /ligand="a 2-oxocarboxylate"
FT /ligand_id="ChEBI:CHEBI:35179"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00683"
FT BINDING 265
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00683"
FT BINDING 292
FT /ligand="a 2-oxocarboxylate"
FT /ligand_id="ChEBI:CHEBI:35179"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00683"
FT BINDING 320..324
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00683"
FT BINDING 343..344
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00683"
FT MUTAGEN 289
FT /note="H->A: Blocks the formatin of 2-
FT aminobenzoylacetamide."
FT /evidence="ECO:0000269|PubMed:32663343"
SQ SEQUENCE 402 AA; 44060 MW; BE0E7F123E29BF66 CRC64;
MPPVNFGSYQ TKIYHDGTNL NRLPAITTNP TLLEKHAREV LSSRAYSYIA GGAGEKSTME
ANRLAFRQWK LVPRVMRPMD DQSISVNLFG QEYKSPLIVG PVGVQGLFHR DKETGVAQVC
SELDVPYTLS TASSSSIEDV AAANQAGHRW FQLYWVHDEE ILLSLLKRAK ENGFTVLVVS
LDTWTLGWRP TDLDQGYFPF YAGIGNDVGF SDPVFRAKHE KKGGKIEDDI IGAANAWVSE
LDDRPHTWEQ VEFLRKHWQG PIVLKGIQHA DDARRALETG CEGLVVSNHG GRQVDGAIGS
LDALPDIVDA VGDKMTVMFD SGVRTGADVI KALCLGAKAV LVGRPVIYGL AIGGKEGAKS
VIECLLADLW QGMGLAGMRT VADCNRDCMR RISYPGDLKT ML
