QULI_PENCI
ID QULI_PENCI Reviewed; 440 AA.
AC P0DUR8;
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=Indoleamine 2,3-dioxygenase qulI {ECO:0000303|PubMed:32663343};
DE Short=IDO qulI {ECO:0000303|PubMed:32663343};
DE EC=1.13.11.52 {ECO:0000269|PubMed:32663343};
DE AltName: Full=Quinolactacin A2 biosynthesis cluster protein I {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, CATALYTIC ACTIVITY, DISRUPTION PHENOTYPE, 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: Indoleamine 2,3-dioxygenase; part of the gene cluster that
CC mediates the biosynthesis of quinolactacin A2 (QUL A2), a fungal
CC alkaloid that features a quinolone-gamma-lactam hybrid, which is a
CC potential pharmacophore for the treatment of cancer and Alzheimer's
CC disease (PubMed:32663343). The quinolone-gamma-lactam hybrid scaffold
CC is synthesized from the combination of L-isoleucine (L-Ile) and the
CC nonproteinogenic amino acid L-kynurenine, followed by quinolone
CC 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 -!- CATALYTIC ACTIVITY:
CC Reaction=D-tryptophan + O2 = N-formyl-D-kynurenine;
CC Xref=Rhea:RHEA:14189, ChEBI:CHEBI:15379, ChEBI:CHEBI:57719,
CC ChEBI:CHEBI:60051; EC=1.13.11.52;
CC Evidence={ECO:0000269|PubMed:32663343};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-tryptophan + O2 = N-formyl-L-kynurenine;
CC Xref=Rhea:RHEA:24536, ChEBI:CHEBI:15379, ChEBI:CHEBI:57912,
CC ChEBI:CHEBI:58629; EC=1.13.11.52;
CC Evidence={ECO:0000250|UniProtKB:P14902};
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000250|UniProtKB:P14902};
CC Note=Binds 1 heme group per subunit. {ECO:0000250|UniProtKB:P14902};
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:32663343}.
CC -!- SUBUNIT: Monomer. {ECO:0000250|UniProtKB:P14902}.
CC -!- DISRUPTION PHENOTYPE: Does not completely abolish the production of
CC quinolactacin A2, but leasd to substantial attenuation of the titer to
CC about 5%. {ECO:0000269|PubMed:32663343}.
CC -!- SIMILARITY: Belongs to the indoleamine 2,3-dioxygenase family.
CC {ECO:0000305}.
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DR SMR; P0DUR8; -.
DR GO; GO:0051213; F:dioxygenase activity; IEA:UniProtKB-KW.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0019441; P:tryptophan catabolic process to kynurenine; IEA:InterPro.
DR InterPro; IPR000898; Indolamine_dOase.
DR InterPro; IPR037217; Trp/Indoleamine_2_3_dOase-like.
DR PANTHER; PTHR28657; PTHR28657; 1.
DR Pfam; PF01231; IDO; 1.
DR SUPFAM; SSF140959; SSF140959; 1.
PE 1: Evidence at protein level;
KW Dioxygenase; Heme; Iron; Metal-binding; Oxidoreductase.
FT CHAIN 1..440
FT /note="Indoleamine 2,3-dioxygenase qulI"
FT /id="PRO_0000453482"
FT BINDING 347
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /ligand_part="Fe"
FT /ligand_part_id="ChEBI:CHEBI:18248"
FT /note="proximal binding residue"
FT /evidence="ECO:0000250|UniProtKB:P14902"
SQ SEQUENCE 440 AA; 49642 MW; 560E28BE0775F4F8 CRC64;
MKHFRDLDLS SYSLSSVSGF LPERPALERL PNPYYDHWED LSRNLPQLVA SDTLKDKLER
LPILSTALLD SEEEWRRAYV VLSFLSQGYI WSGDQPRRNL PIAIAAPLRR VSEYLTIMPC
GTFAAYCLWN VIPSPKFGNP QINPEDFIST CTFTGSKEEE WFYVISVAIE ARGGRLIPKI
LDAIDAVKEN DTPRVRSFLE AFITCVDGII LVLDRMGENL SQEFFYHRLR PYLRGGKNMA
QVGLPDGIFY PLCQCEGGEG EWLAYSGGSN AQSSLIQLMD ITLGTCQNVE FIKEMRNYMP
GPHREFLELM TSVSNIRPYI LSLGNDSDVR SLYDKAVLRL AALRDCHLRV VARYILIPAG
KKNPSGHRQL QERGRGTGGT DIMKFLRETR NNTLSACCEQ SKGSTVVQTY PKRCETCGSG
PIDRTTLIKK ATVVINEIEC
