ASR6_SARSH
ID ASR6_SARSH Reviewed; 430 AA.
AC A0A2U8U2L5;
DT 26-FEB-2020, integrated into UniProtKB/Swiss-Prot.
DT 12-SEP-2018, sequence version 1.
DT 25-MAY-2022, entry version 12.
DE RecName: Full=Alpha-humulene synthase asR6 {ECO:0000303|PubMed:29773797};
DE EC=4.2.3.104 {ECO:0000269|PubMed:29773797};
DE AltName: Full=Xenovulene A biosynthesis cluster protein R6 {ECO:0000303|PubMed:29773797};
GN Name=asR6 {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 COFACTOR, 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: Alpha-humulene synthase; 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 -!- CATALYTIC ACTIVITY:
CC Reaction=(2E,6E)-farnesyl diphosphate = alpha-humulene + diphosphate;
CC Xref=Rhea:RHEA:31895, ChEBI:CHEBI:5768, ChEBI:CHEBI:33019,
CC ChEBI:CHEBI:175763; EC=4.2.3.104;
CC Evidence={ECO:0000269|PubMed:29773797};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:31896;
CC Evidence={ECO:0000269|PubMed:29773797};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:29773797};
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 -!- 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 terpene synthase family. Alpha-humulene
CC synthase eupE subfamily. {ECO:0000305}.
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DR EMBL; MG736817; AWM95795.1; -; Genomic_DNA.
DR PDB; 7OC4; X-ray; 2.03 A; A/B=1-430.
DR PDB; 7OC5; X-ray; 2.01 A; A/B=1-430.
DR PDB; 7OC6; X-ray; 2.01 A; A=1-430.
DR PDBsum; 7OC4; -.
DR PDBsum; 7OC5; -.
DR PDBsum; 7OC6; -.
DR AlphaFoldDB; A0A2U8U2L5; -.
DR SMR; A0A2U8U2L5; -.
DR UniPathway; UPA00213; -.
DR GO; GO:0080017; F:alpha-humulene synthase activity; IEA:UniProtKB-EC.
DR GO; GO:0016114; P:terpenoid biosynthetic process; IEA:UniProtKB-UniPathway.
PE 1: Evidence at protein level;
KW 3D-structure; Lyase; Magnesium.
FT CHAIN 1..430
FT /note="Alpha-humulene synthase asR6"
FT /id="PRO_0000449161"
FT HELIX 14..25
FT /evidence="ECO:0007829|PDB:7OC5"
FT HELIX 42..44
FT /evidence="ECO:0007829|PDB:7OC5"
FT HELIX 59..61
FT /evidence="ECO:0007829|PDB:7OC5"
FT HELIX 68..73
FT /evidence="ECO:0007829|PDB:7OC5"
FT HELIX 87..89
FT /evidence="ECO:0007829|PDB:7OC5"
FT HELIX 90..103
FT /evidence="ECO:0007829|PDB:7OC5"
FT TURN 109..112
FT /evidence="ECO:0007829|PDB:7OC5"
FT HELIX 124..142
FT /evidence="ECO:0007829|PDB:7OC5"
FT HELIX 148..150
FT /evidence="ECO:0007829|PDB:7OC5"
FT HELIX 151..161
FT /evidence="ECO:0007829|PDB:7OC5"
FT HELIX 162..164
FT /evidence="ECO:0007829|PDB:7OC5"
FT HELIX 170..175
FT /evidence="ECO:0007829|PDB:7OC5"
FT HELIX 185..194
FT /evidence="ECO:0007829|PDB:7OC5"
FT HELIX 199..221
FT /evidence="ECO:0007829|PDB:7OC5"
FT HELIX 225..229
FT /evidence="ECO:0007829|PDB:7OC5"
FT HELIX 233..244
FT /evidence="ECO:0007829|PDB:7OC5"
FT HELIX 246..257
FT /evidence="ECO:0007829|PDB:7OC5"
FT STRAND 260..262
FT /evidence="ECO:0007829|PDB:7OC6"
FT HELIX 267..295
FT /evidence="ECO:0007829|PDB:7OC5"
FT HELIX 305..326
FT /evidence="ECO:0007829|PDB:7OC5"
FT HELIX 331..339
FT /evidence="ECO:0007829|PDB:7OC5"
FT HELIX 341..347
FT /evidence="ECO:0007829|PDB:7OC5"
FT HELIX 349..355
FT /evidence="ECO:0007829|PDB:7OC5"
FT TURN 356..358
FT /evidence="ECO:0007829|PDB:7OC5"
FT HELIX 365..371
FT /evidence="ECO:0007829|PDB:7OC5"
FT HELIX 372..374
FT /evidence="ECO:0007829|PDB:7OC5"
FT HELIX 377..379
FT /evidence="ECO:0007829|PDB:7OC5"
FT HELIX 382..384
FT /evidence="ECO:0007829|PDB:7OC5"
FT HELIX 389..391
FT /evidence="ECO:0007829|PDB:7OC5"
SQ SEQUENCE 430 AA; 48387 MW; C1B95D04415D078B CRC64;
MPVTTPTKMA TLTTKQMWQT IKDYFGDGFV TGSAPISYNV HTCDMQLQPD SGIHAASDGI
HYGVQISEDS MPLFSIMGDT AAPPCTCHRV DEIVKHIDEF LERAPEALPD DGAITSGKPC
DTNPDQVSLY AMRDSLSWWV HWGGNLRPEH YWKQIYIGFA AIPDDVQISP REFLDGTYRY
LGHTWDDCLS GLEEEGVSPD EIEFANMCMW RQMLTQWLEK ADPELLPLLK GKISLMLQYR
VLTANTLGCL ALFMNATADP KDGPIHYADS SYEMEIASVA QCVTLDMAKE AMGILQGERT
EVVAGDRAQR KRELRWIYVR CMQILESQPH AHMLRRYGSA GLHYVPMMDR YLERVSGHTR
FPIRDGAARI LERFINRAEL PKESEDINPN GRSLKVSAKM NGNGQLHHEV NGNAKLHLEA
ERPDVTTAVG
