ASR2_SARSH
ID ASR2_SARSH Reviewed; 516 AA.
AC A0A2U8U2M8;
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=Cytochrome P450 monooxygenase asR2 {ECO:0000303|PubMed:29773797};
DE EC=1.-.-.- {ECO:0000269|PubMed:29773797};
DE AltName: Full=Xenovulene A biosynthesis cluster protein R2 {ECO:0000303|PubMed:29773797};
GN Name=asR2 {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, CATALYTIC ACTIVITY,
RP 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: Cytochrome P450 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=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000250|UniProtKB:P04798};
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 -!- 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 cytochrome P450 family. {ECO:0000305}.
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DR EMBL; MG736817; AWM95791.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A2U8U2M8; -.
DR SMR; A0A2U8U2M8; -.
DR UniPathway; UPA00213; -.
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 GO; GO:0016114; P:terpenoid biosynthetic process; IEA:UniProtKB-UniPathway.
DR Gene3D; 1.10.630.10; -; 1.
DR InterPro; IPR001128; Cyt_P450.
DR InterPro; IPR017972; Cyt_P450_CS.
DR InterPro; IPR002403; Cyt_P450_E_grp-IV.
DR InterPro; IPR036396; Cyt_P450_sf.
DR Pfam; PF00067; p450; 1.
DR PRINTS; PR00465; EP450IV.
DR PRINTS; PR00385; P450.
DR SUPFAM; SSF48264; SSF48264; 1.
DR PROSITE; PS00086; CYTOCHROME_P450; 1.
PE 1: Evidence at protein level;
KW Glycoprotein; Heme; Iron; Membrane; Metal-binding; Monooxygenase;
KW Oxidoreductase; Transmembrane; Transmembrane helix.
FT CHAIN 1..516
FT /note="Cytochrome P450 monooxygenase asR2"
FT /id="PRO_0000449188"
FT TRANSMEM 9..29
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 461
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 248
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 273
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 516 AA; 59132 MW; 0BA758E8E6B42878 CRC64;
MALAQQFQLN SITFSLLVFL GFVGVSQLIR IYWRLRYIPG PFWAKFTDVQ RVFWVQTQRA
HEIHRDAHGK YGDIVRFGPN MVSVADPAWI KTIYPMRPGF PKGEFYRALM PYSRQGGALP
AVFTTRDENL HKMLKSPVAP LFSLSNVLTL ESHVDATIKV LVEQWDRRFL DSQDSIDLAD
WLSFFAFDVM GTLTFSKRYG FLEEGKDVGG MINTIFTFLK TAAPMTQVPW FDNIWIKNSF
AASFRKSNGS SILQIVGKHT SERLKASKSQ DMNGSAMSVT KDRDMLDQFI GLAAKNPDLP
PWCVTAWTFS NVAAGSDSTA AVMKKVFHSL LSHPNTLQRL MDELIQAQKT NKNMKETPFP
SWRDICDLPY LDACILEGIR LHPPFCLPFE RVVPKGGIMI GKTYIPEDTL IGMSPWVINH
HKPTFGEDAE DWNPNRWMGP EEEKQKREAA ILTFGAGKRI CLGKQIAMLE LKKIVATLLL
TYEFEILDPE RYEVENWWFF RQHGIDVRVR RRSDKE
