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ASL6_SARSH
ID   ASL6_SARSH              Reviewed;         423 AA.
AC   A0A2U8U2L0;
DT   26-FEB-2020, integrated into UniProtKB/Swiss-Prot.
DT   12-SEP-2018, sequence version 1.
DT   03-AUG-2022, entry version 11.
DE   RecName: Full=FAD-dependent monooxygenase asL6 {ECO:0000303|PubMed:29773797};
DE            EC=1.14.13.- {ECO:0000305|PubMed:29773797};
DE   AltName: Full=Xenovulene A biosynthesis cluster protein L6 {ECO:0000303|PubMed:29773797};
GN   Name=asL6 {ECO:0000303|PubMed:29773797};
OS   Sarocladium schorii (Acremonium strictum (strain IMI 501407)).
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Sordariomycetes;
OC   Hypocreomycetidae; Hypocreales; Sarocladiaceae; Sarocladium;
OC   unclassified Sarocladium.
OX   NCBI_TaxID=2203296;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], INDUCTION, FUNCTION, DISRUPTION
RP   PHENOTYPE, AND PATHWAY.
RX   PubMed=29773797; DOI=10.1038/s41467-018-04364-9;
RA   Schor R., Schotte C., Wibberg D., Kalinowski J., Cox R.J.;
RT   "Three previously unrecognised classes of biosynthetic enzymes revealed
RT   during the production of xenovulene A.";
RL   Nat. Commun. 9:1963-1963(2018).
RN   [2]
RP   BIOTECHNOLOGY.
RX   PubMed=9262310;
RA   Thomas P., Sundaram H., Krishek B.J., Chazot P., Xie X., Bevan P.,
RA   Brocchini S.J., Latham C.J., Charlton P., Moore M., Lewis S.J.,
RA   Thornton D.M., Stephenson F.A., Smart T.G.;
RT   "Regulation of neuronal and recombinant GABA(A) receptor ion channels by
RT   xenovulene A, a natural product isolated from Acremonium strictum.";
RL   J. Pharmacol. Exp. Ther. 282:513-520(1997).
RN   [3]
RP   FUNCTION.
RX   PubMed=17912413; DOI=10.1039/b708614h;
RA   Bailey A.M., Cox R.J., Harley K., Lazarus C.M., Simpson T.J., Skellam E.;
RT   "Characterisation of 3-methylorcinaldehyde synthase (MOS) in Acremonium
RT   strictum: first observation of a reductive release mechanism during
RT   polyketide biosynthesis.";
RL   Chem. Commun. (Camb.) 39:4053-4055(2007).
RN   [4]
RP   FUNCTION.
RX   PubMed=20552126; DOI=10.1039/c0cc01162b;
RA   Fisch K.M., Skellam E., Ivison D., Cox R.J., Bailey A.M., Lazarus C.M.,
RA   Simpson T.J.;
RT   "Catalytic role of the C-terminal domains of a fungal non-reducing
RT   polyketide synthase.";
RL   Chem. Commun. (Camb.) 46:5331-5333(2010).
CC   -!- FUNCTION: FAD-dependent monooxygenase; part of the gene cluster that
CC       mediates the biosynthesis of xenovulene A, an unusual meroterpenoid
CC       that has potent inhibitory effects on the human gamma-aminobutyrate A
CC       (GABAA) benzodiazepine receptor (PubMed:29773797). The first step of
CC       xenovulene A biosynthesis is the biosynthesis of 3-methylorcinaldehyde
CC       performed by the non-reducing polyketide synthase aspks1
CC       (PubMed:17912413, PubMed:29773797, PubMed:20552126). The salicylate
CC       hydroxylase asL1 then catalyzes the oxidative dearomatization of 3-
CC       methylorcinaldehyde to yield a dearomatized hydroxycyclohexadione
CC       (PubMed:29773797). The 2-oxoglutarate-dependent dioxygenase asL3
CC       further catalyzes the oxidative ring expansion to provide the first
CC       tropolone metabolite (PubMed:29773797). The cytochrome P450
CC       monooxygenase asR2 allows the synthesis of tropolone hemiacetal
CC       (PubMed:29773797). In parallel, a previously unrecognised class of
CC       terpene cyclase, asR6, produces alpha-humulene from
CC       farnesylpyrophosphate (FPP) (PubMed:29773797). The putative Diels-
CC       Alderase asR5 probably catalyzes the formation of the tropolone-
CC       humulene skeleton by linking humulene and the polyketide moiety
CC       (PubMed:29773797). Oxidative-ring contractions catalyzed by asL4 and
CC       asL6 then processively remove carbon atoms from the polyketide to yield
CC       xenovulene A (PubMed:29773797). {ECO:0000269|PubMed:17912413,
CC       ECO:0000269|PubMed:20552126, ECO:0000269|PubMed:29773797}.
CC   -!- COFACTOR:
CC       Name=FAD; Xref=ChEBI:CHEBI:57692;
CC         Evidence={ECO:0000250|UniProtKB:D3HKY4};
CC       Note=Binds 1 FAD per subunit. {ECO:0000250|UniProtKB:D3HKY4};
CC   -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC       {ECO:0000269|PubMed:29773797}.
CC   -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass membrane
CC       protein {ECO:0000255}.
CC   -!- INDUCTION: Expression is significantly up-regulated under xenovulene A
CC       producing condition. {ECO:0000269|PubMed:29773797}.
CC   -!- DISRUPTION PHENOTYPE: Severely reduces, but does not abolish xenovulene
CC       A biosynthesis. {ECO:0000269|PubMed:29773797}.
CC   -!- BIOTECHNOLOGY: Xenovulene A is a natural product exhibiting little
CC       structural resemblance with classical benzodiazepines yet is able to
CC       displace high-affinity ligand binding to the benzodiazepine site of the
CC       gamma-aminobutyrate A (GABAA) receptor and could be potentially used as
CC       an anti-depressant with reduced addictive properties.
CC       {ECO:0000269|PubMed:9262310}.
CC   -!- SIMILARITY: Belongs to the aromatic-ring hydroxylase family.
CC       {ECO:0000305}.
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DR   EMBL; MG736817; AWM95784.1; -; Genomic_DNA.
DR   AlphaFoldDB; A0A2U8U2L0; -.
DR   SMR; A0A2U8U2L0; -.
DR   UniPathway; UPA00213; -.
DR   GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR   GO; GO:0071949; F:FAD binding; IEA:InterPro.
DR   GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR   GO; GO:0044550; P:secondary metabolite biosynthetic process; IEA:UniProt.
DR   GO; GO:0016114; P:terpenoid biosynthetic process; IEA:UniProtKB-UniPathway.
DR   Gene3D; 3.50.50.60; -; 1.
DR   InterPro; IPR002938; FAD-bd.
DR   InterPro; IPR036188; FAD/NAD-bd_sf.
DR   Pfam; PF01494; FAD_binding_3; 1.
DR   SUPFAM; SSF51905; SSF51905; 1.
PE   1: Evidence at protein level;
KW   FAD; Flavoprotein; Membrane; NADP; Nucleotide-binding; Oxidoreductase;
KW   Transmembrane; Transmembrane helix.
FT   CHAIN           1..423
FT                   /note="FAD-dependent monooxygenase asL6"
FT                   /id="PRO_0000449183"
FT   TRANSMEM        371..391
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   BINDING         10..13
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000250|UniProtKB:D3HKY4"
FT   BINDING         34..35
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000250|UniProtKB:D3HKY4"
FT   BINDING         108
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000250|UniProtKB:D3HKY4"
FT   BINDING         290
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000250|UniProtKB:D3HKY4"
FT   BINDING         312
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000250|UniProtKB:D3HKY4"
SQ   SEQUENCE   423 AA;  46998 MW;  A7D2777CC8B2A0F8 CRC64;
     MTVKILVSGA GVAGTALVNF LCRSKHEYDI TVVERAPALR AAGSQLDLKS FGAPLMRKLG
     LIEKVREKSI HETAFTFVDS KGREWARFPV NEAGKGYEGI TSEFEIMRAD LVAVLYEASK
     EVSANPFMKG PQKLRYVFGK HGVHFTQGNS KVNVVFSDGS SDDYDLVVGA DGQYSMTRRL
     LWEPEKGSGD TTLKYTGVTA GFFQMPKSED EADSTLFKNC LQAGPRGLCL RCAHKDFTQA
     MLGIPTTDEH KQVFKKPLEQ QKQMWEESVG SFKWQGQRVL AELRKSDDFY MTPVAQVKVD
     RWSKGRVVLV GDAGYCPSVM TGRGTTVSLV GAYVLAGELA KHGDNIDAAL ESYEKVLRPF
     ITTAQEIPSM GMGMFQSKFG VGVFYVLLAI ISKLKIDRLL QALMKEEKET WELPEYPELE
     FEA
 
 
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