UCSK_ACRSP
ID UCSK_ACRSP Reviewed; 526 AA.
AC A0A411KUQ5;
DT 12-AUG-2020, integrated into UniProtKB/Swiss-Prot.
DT 08-MAY-2019, sequence version 1.
DT 03-AUG-2022, entry version 11.
DE RecName: Full=Cytochrome P450 monooxygenase ucsK {ECO:0000303|PubMed:29373009};
DE EC=1.-.-.- {ECO:0000269|PubMed:29373009};
DE AltName: Full=UCS1025A pyrrolizidinone biosynthesis cluster protein K {ECO:0000303|PubMed:29373009};
GN Name=ucsK {ECO:0000303|PubMed:29373009};
OS Acremonium sp.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Sordariomycetes;
OC Hypocreomycetidae; Hypocreales; Hypocreales incertae sedis; Acremonium;
OC unclassified Acremonium.
OX NCBI_TaxID=2046025;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, DISRUPTION PHENOTYPE,
RP CATALYTIC ACTIVITY, AND PATHWAY.
RC STRAIN=KY4917;
RX PubMed=29373009; DOI=10.1021/jacs.8b00056;
RA Li L., Tang M.C., Tang S., Gao S., Soliman S., Hang L., Xu W., Ye T.,
RA Watanabe K., Tang Y.;
RT "Genome mining and assembly-line biosynthesis of the UCS1025A
RT pyrrolizidinone family of fungal alkaloids.";
RL J. Am. Chem. Soc. 140:2067-2071(2018).
CC -!- FUNCTION: Cytochrome P450 monooxygenase; part of the gene cluster that
CC mediates the biosynthesis of UCS1025A, a member of the pyrrolizidinone
CC family that acts as a strong telomerase inhibitor and displays potent
CC antibacterial and antitumor properties (PubMed:29373009). These
CC compounds share a hemiaminal-containing pyrrolizidinone core fused with
CC a gamma-lactone, giving a furopyrrolizidine that is connected to a
CC decalin fragment (PubMed:29373009). The polyketide synthase module
CC (PKS) of the PKS-NRPS ucsA is responsible for the synthesis of the
CC polyketide backbone via the condensation of an acetyl-CoA starter unit
CC with 6 malonyl-CoA units (PubMed:29373009). The downstream nonribosomal
CC peptide synthetase (NRPS) module then amidates the carboxyl end of the
CC polyketide with a 2S,3S-methylproline derived from L-isoleucine by the
CC 2-oxoglutarate-dependent dioxygenase ucsF which converts L-isoleucine
CC to (4S,5S)-4-methylpyrroline-5-carboxylate that is further converted to
CC 2S,3S-methylproline by the pyrroline-5-carboxylate reductase ucsG
CC (PubMed:29373009). Reductive release of the completed aminoacyl
CC polyketide from the assembly line can form the 3-pyrrolin-2-one
CC structure via an intramolecular Knoevenagel reaction (PubMed:29373009).
CC Because ucsA lacks a designated enoylreductase (ER) domain, the
CC required activity is provided the enoyl reductase ucsL
CC (PubMed:29373009). This keto acyclic precursor is the substrate of the
CC Diels-Alderase ucsH, that catalyzes the Diels-Alder cycloaddition
CC (PubMed:29373009). Oxidation of the 3S-methyl group to a carboxylate by
CC the cytochrome P450 monooxygenase ucsK allows an oxa-Michael
CC cyclization that might involve the reductase/dehydrogenase ucsI and
CC which furnishes the furopyrrolizidine (PubMed:29373009). The oxidase
CC ucsJ likely plays a critical role in stereoselective reduction of the
CC C5-C6 double bond to afford the required R-configured carboxylate group
CC (Probable). Further enolization and oxidation at C5 by an unidentified
CC enzyme affords the last intermediate that can undergo oxa-Michael
CC cyclization to yield UCS1025A (Probable). {ECO:0000269|PubMed:29373009,
CC ECO:0000305|PubMed:29373009}.
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000250|UniProtKB:P04798};
CC -!- PATHWAY: Mycotoxin biosynthesis. {ECO:0000269|PubMed:29373009}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass membrane
CC protein {ECO:0000255}.
CC -!- DISRUPTION PHENOTYPE: Leads to the accumulation of intermediate
CC diastereomers that are methylated at C6 of the pyrrolizidinone.
CC {ECO:0000269|PubMed:29373009}.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR EMBL; MH375774; QBC88155.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A411KUQ5; -.
DR SMR; A0A411KUQ5; -.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0004497; F:monooxygenase activity; IEA:UniProtKB-KW.
DR GO; GO:0016705; F:oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen; IEA:InterPro.
DR Gene3D; 1.10.630.10; -; 1.
DR InterPro; IPR001128; Cyt_P450.
DR InterPro; IPR002401; Cyt_P450_E_grp-I.
DR InterPro; IPR036396; Cyt_P450_sf.
DR Pfam; PF00067; p450; 1.
DR PRINTS; PR00463; EP450I.
DR PRINTS; PR00385; P450.
DR SUPFAM; SSF48264; SSF48264; 1.
PE 1: Evidence at protein level;
KW Glycoprotein; Heme; Iron; Membrane; Metal-binding; Monooxygenase;
KW Oxidoreductase; Transmembrane; Transmembrane helix.
FT CHAIN 1..526
FT /note="Cytochrome P450 monooxygenase ucsK"
FT /id="PRO_0000450542"
FT TRANSMEM 7..27
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 467
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /ligand_part="Fe"
FT /ligand_part_id="ChEBI:CHEBI:18248"
FT /note="axial binding residue"
FT /evidence="ECO:0000250|UniProtKB:P04798"
FT CARBOHYD 403
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 526 AA; 58960 MW; C8360EBFDBFAFC5E CRC64;
MALLNTPVLA AATAVSFGFY LAGLFVYRVF YHRLSHIPGP RLAAFTVYYQ SYYDFFPHQG
QFLWKLVELH KAYGPIIRIG PDEVHVNDAR FYKEMYGSSV HKRNKSPIWY WMDGLGAVGD
QSMFITLDHD HHRLRKAGLG TYFSKRKVQE LEPRVKEKVL LLRQRLLERA GRGAINLKDA
FGGMALDIIT QYCFNQCMGA LDRDDLGREW NQLMAAGVKI NPFARTFPTV ARTLLRLPKW
VLGVSGMVST TGEFLDLADR LSANARNEAI RDLQEGKYTL TDDADSRTVL HSMMRSDVLP
EHEKGERRLQ ADGMTLIAAG FDTTSRTLTV VFYHLLAKPA MRARVLEEIR TLMPTPSSPL
PTVAQLEQLP YLTCVIHEGT RLAHGVAGRL VRIAPEEDLV YHNSSDDTEY TIPRGATFGQ
SSYLVHTDES IYPNPHDFIP ERYWSDDGKP TDAERYLVAF GKGTRMCSGI NLAFAELYLT
IAALLGAVDM KLAPGTTEHD VSLVAELFVG VLPESPGVRV NVVGSL
