ASL4_SARSH
ID ASL4_SARSH Reviewed; 430 AA.
AC A0A2U8U2L4;
DT 26-FEB-2020, integrated into UniProtKB/Swiss-Prot.
DT 12-SEP-2018, sequence version 1.
DT 03-AUG-2022, entry version 12.
DE RecName: Full=FAD-dependent monooxygenase asL4 {ECO:0000303|PubMed:29773797};
DE EC=1.14.13.- {ECO:0000269|PubMed:29773797};
DE AltName: Full=Xenovulene A biosynthesis cluster protein L4 {ECO:0000303|PubMed:29773797};
GN Name=asL4 {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: Flavin-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 -!- 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; AWM95786.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A2U8U2L4; -.
DR SMR; A0A2U8U2L4; -.
DR UniPathway; UPA00213; -.
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; NADP; Nucleotide-binding; Oxidoreductase.
FT CHAIN 1..430
FT /note="FAD-dependent monooxygenase asL4"
FT /id="PRO_0000449182"
FT BINDING 11..14
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:D3HKY4"
FT BINDING 33..34
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 278
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:D3HKY4"
SQ SEQUENCE 430 AA; 47733 MW; 4C979CB886EABB16 CRC64;
MPQLKVLING GGIAGNAIAF WLTKLGHDVT VLERFPALRT TGLQLDLRGH GIEVLKRMGL
DDAMKAKVIK EDGAQFVDTN GKVVAYFPAV DTSKGGVQAF TSEYEIMRGD ICRVFYAATK
DRATYKFGTS VESFEDLGDS IKVQLTDHTV DHYDLLIGAD GVTSSIRKMM LGPGVPDKFI
QFQNLYASYF TIPAPIKPDE KYMANIFIAP GSKLLMTRRD NPERLQVYMG GKAPGARLEN
ARRGDTAEEK LGIEEFMQGC GWRTSEMIDE LRKADDFYLE RLGMVKLDSW HRGRVALVGE
AAWCSSVLTG MGTTSCLVGA YCLAGEIAKH CGRGDQGEAK DDPMMVQKNL ANALAGYEEK
FMPFMHQVQD GLSAKTGTRT YMPSSQWGVT ILNWVIKIIA LLRLNMAGDW VIREAVRNWK
LPDYPELLKE
