ID   UCSH_ACRSP              Reviewed;         409 AA.
AC   A0A411KUQ1;
DT   12-AUG-2020, integrated into UniProtKB/Swiss-Prot.
DT   08-MAY-2019, sequence version 1.
DT   25-MAY-2022, entry version 10.
DE   RecName: Full=Diels-Alderase ucsH {ECO:0000303|PubMed:29373009};
DE            EC=5.5.1.- {ECO:0000269|PubMed:29373009};
DE   AltName: Full=UCS1025A pyrrolizidinone biosynthesis cluster protein H {ECO:0000303|PubMed:29373009};
GN   Name=ucsH {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, AND
RP   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: Diels-Alderase; part of the gene cluster that mediates the
CC       biosynthesis of UCS1025A, a member of the pyrrolizidinone family that
CC       acts as a strong telomerase inhibitor and displays potent antibacterial
CC       and antitumor properties (PubMed:29373009). These compounds share a
CC       hemiaminal-containing pyrrolizidinone core fused with a gamma-lactone,
CC       giving a 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   -!- PATHWAY: Mycotoxin biosynthesis. {ECO:0000269|PubMed:29373009}.
CC   -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass membrane
CC       protein {ECO:0000255}.
CC   -!- DISRUPTION PHENOTYPE: Abolishes the production of UCS1025A.
CC       {ECO:0000269|PubMed:29373009}.
CC   -!- SIMILARITY: Belongs to the Diels-Alderase family. {ECO:0000305}.
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DR   EMBL; MH375771; QBC88152.1; -; Genomic_DNA.
DR   AlphaFoldDB; A0A411KUQ1; -.
DR   SMR; A0A411KUQ1; -.
DR   GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR   GO; GO:0016853; F:isomerase activity; IEA:UniProtKB-KW.
PE   3: Inferred from homology;
KW   Isomerase; Membrane; Transmembrane; Transmembrane helix.
FT   CHAIN           1..409
FT                   /note="Diels-Alderase ucsH"
FT                   /id="PRO_0000450538"
FT   TRANSMEM        386..406
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
SQ   SEQUENCE   409 AA;  44901 MW;  86230F2D06151726 CRC64;
     MARINRQTAY QKAQEIEFST SSADPLAAWR ISGIKGTAWE QWYFDSIADD GKSGIVLTMA
     RDASYTVLGR GVLRVELDVT FEDGSHHNHV DWMNEAIVED RSSPKSTGTI DGVWTAPGKS
     IRFQIAADGS AAKVEVDTPE TKGHFTLAAL SPPMYPNGET QNELESQGKV ASTELLPKIH
     LVQVIPTATF EGDLMVNGRL LRFRGIGGHM HAWAQGAWFD TTLGWKVARG VAGPFSVTLM
     EYTDMEGIVH SSGYVVEDGV KRFGGLETYA TPRSSATSQQ VLKYRDEDRK GKQTVRWTPT
     YNTGFAGRFG DSSTGAILQF SSADSGETYR FELTHRRKAF EFLFGSSDSG LTAFLGEIKG
     GKIGSEVYEG VQASNVCVLP QGWTKIYFFI CMLLAVVTFG YINILETNT