UCSI_ACRSP
ID UCSI_ACRSP Reviewed; 292 AA.
AC A0A411KUQ9;
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=Medium chain reductase/dehydrogenase ucsI {ECO:0000303|PubMed:29373009};
DE EC=1.-.-.- {ECO:0000305|PubMed:29373009};
DE AltName: Full=UCS1025A pyrrolizidinone biosynthesis cluster protein I {ECO:0000303|PubMed:29373009};
GN Name=ucsI {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, 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: Medium chain reductase/dehydrogenase; part of the gene
CC cluster that mediates the biosynthesis of UCS1025A, a member of the
CC pyrrolizidinone family that acts as a strong telomerase inhibitor and
CC displays potent antibacterial and antitumor properties
CC (PubMed:29373009). These compounds share a hemiaminal-containing
CC pyrrolizidinone core fused with a gamma-lactone, giving a
CC furopyrrolizidine that is connected to a decalin fragment
CC (PubMed:29373009). The polyketide synthase module (PKS) of the PKS-NRPS
CC ucsA is responsible for the synthesis of the polyketide backbone via
CC the condensation of an acetyl-CoA starter unit with 6 malonyl-CoA units
CC (PubMed:29373009). The downstream nonribosomal peptide synthetase
CC (NRPS) module then amidates the carboxyl end of the polyketide with a
CC 2S,3S-methylproline derived from L-isoleucine by the 2-oxoglutarate-
CC dependent dioxygenase ucsF which converts L-isoleucine to (4S,5S)-4-
CC methylpyrroline-5-carboxylate that is further converted to 2S,3S-
CC 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=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000250|UniProtKB:P27867};
CC Note=Binds 1 zinc ion per subunit. {ECO:0000250|UniProtKB:P27867};
CC -!- PATHWAY: Mycotoxin biosynthesis. {ECO:0000305|PubMed:29373009}.
CC -!- SIMILARITY: Belongs to the zinc-containing alcohol dehydrogenase
CC family. {ECO:0000305}.
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DR EMBL; MH375772; QBC88153.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A411KUQ9; -.
DR SMR; A0A411KUQ9; -.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR InterPro; IPR013149; ADH-like_C.
DR InterPro; IPR013154; ADH_N.
DR InterPro; IPR002328; ADH_Zn_CS.
DR InterPro; IPR011032; GroES-like_sf.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR Pfam; PF08240; ADH_N; 1.
DR Pfam; PF00107; ADH_zinc_N; 1.
DR SUPFAM; SSF50129; SSF50129; 1.
DR SUPFAM; SSF51735; SSF51735; 1.
DR PROSITE; PS00059; ADH_ZINC; 1.
PE 3: Inferred from homology;
KW Metal-binding; NAD; Oxidoreductase; Zinc.
FT CHAIN 1..292
FT /note="Medium chain reductase/dehydrogenase ucsI"
FT /id="PRO_0000450539"
FT BINDING 43
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:P27867"
FT BINDING 49
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P27867"
FT BINDING 65
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:P27867"
FT BINDING 66
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:P27867"
FT BINDING 184..189
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:P27867"
FT BINDING 208
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:P27867"
FT BINDING 213
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:P27867"
FT BINDING 276..278
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:P27867"
SQ SEQUENCE 292 AA; 30635 MW; A77B13446488CC38 CRC64;
MSPTDMKAVV FYGPHSIAIE SRPIPKVQHD KDIVVKVSAS GLCGSDLHYF RGHEVVDSAG
FIMGHEFVGE VVEAGRAVTT VRPGDKVVSP FTVSCGDCFY CKLQNSSRCV HCQVFGSNGL
DGAQAEYVRV PLADSTVVRA PPGLSDDALI LMADIFPTGF FGARNAMAGL GAQDPTEAVV
VVIGCGPVGL CAIVSALEYR PRVVFAIDSV DSRLGLAEKL GARPLDLKKG VPSIISAVQE
VTEGRGADAV VEVVGQGPAL RTAYDIIRPF GSISSIGAHH SAMPFSATDG YE
