PRO1_ARMGA
ID PRO1_ARMGA Reviewed; 345 AA.
AC P0DL13; A0A2H3CTI0; S5LSQ7;
DT 01-MAY-2013, integrated into UniProtKB/Swiss-Prot.
DT 22-APR-2020, sequence version 2.
DT 03-AUG-2022, entry version 23.
DE RecName: Full=Delta(6)-protoilludene synthase {ECO:0000303|PubMed:21148562};
DE EC=4.2.3.135 {ECO:0000269|PubMed:21148562};
DE AltName: Full=Melleolides biosynthesis cluster protein PRO1 {ECO:0000303|PubMed:21148562};
GN Name=PRO1 {ECO:0000303|PubMed:21148562}; ORFNames=ARMGADRAFT_1000221;
OS Armillaria gallica (Bulbous honey fungus) (Armillaria bulbosa).
OC Eukaryota; Fungi; Dikarya; Basidiomycota; Agaricomycotina; Agaricomycetes;
OC Agaricomycetidae; Agaricales; Physalacriaceae; Armillaria.
OX NCBI_TaxID=47427;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, COFACTOR,
RP BIOPHYSICOCHEMICAL PROPERTIES, SUBUNIT, AND PATHWAY.
RC STRAIN=FU02472;
RX PubMed=21148562; DOI=10.1074/jbc.m110.165845;
RA Engels B., Heinig U., Grothe T., Stadler M., Jennewein S.;
RT "Cloning and characterization of an Armillaria gallica cDNA encoding
RT protoilludene synthase, which catalyzes the first committed step in the
RT synthesis of antimicrobial melleolides.";
RL J. Biol. Chem. 286:6871-6878(2011).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Ar21-2;
RX PubMed=29085064; DOI=10.1038/s41559-017-0347-8;
RA Sipos G., Prasanna A.N., Walter M.C., O'Connor E., Balint B., Krizsan K.,
RA Kiss B., Hess J., Varga T., Slot J., Riley R., Boka B., Rigling D.,
RA Barry K., Lee J., Mihaltcheva S., LaButti K., Lipzen A., Waldron R.,
RA Moloney N.M., Sperisen C., Kredics L., Vagvoelgyi C., Patrignani A.,
RA Fitzpatrick D., Nagy I., Doyle S., Anderson J.B., Grigoriev I.V.,
RA Gueldener U., Muensterkoetter M., Nagy L.G.;
RT "Genome expansion and lineage-specific genetic innovations in the forest
RT pathogenic fungi Armillaria.";
RL Nat. Ecol. Evol. 1:1931-1941(2017).
RN [3]
RP BIOTECHNOLOGY.
RX PubMed=21376582; DOI=10.1016/j.bmcl.2011.02.026;
RA Bohnert M., Miethbauer S., Dahse H.M., Ziemen J., Nett M., Hoffmeister D.;
RT "In vitro cytotoxicity of melleolide antibiotics: structural and
RT mechanistic aspects.";
RL Bioorg. Med. Chem. Lett. 21:2003-2006(2011).
RN [4]
RP BIOTECHNOLOGY.
RX PubMed=23864890; DOI=10.1155/2013/459271;
RA Chi C.W., Chen C.C., Chen Y.J.;
RT "Therapeutic and radiosensitizing effects of armillaridin on human
RT esophageal cancer cells.";
RL Evid. Based Complement Alternat. Med. 2013:459271-459271(2013).
RN [5]
RP BIOTECHNOLOGY.
RX PubMed=25746621; DOI=10.1615/intjmedmushrooms.v17.i2.70;
RA Liu T.P., Chen C.C., Shiao P.Y., Shieh H.R., Chen Y.Y., Chen Y.J.;
RT "Armillaridin, a honey medicinal mushroom, Armillaria mellea (higher
RT basidiomycetes) component, inhibits differentiation and activation of human
RT macrophages.";
RL Int. J. Med. Mushrooms 17:161-168(2015).
RN [6]
RP BIOTECHNOLOGY.
RX PubMed=26952552; DOI=10.1016/j.jep.2016.02.044;
RA Li Z., Wang Y., Jiang B., Li W., Zheng L., Yang X., Bao Y., Sun L.,
RA Huang Y., Li Y.;
RT "Structure, cytotoxic activity and mechanism of protoilludane sesquiterpene
RT aryl esters from the mycelium of Armillaria mellea.";
RL J. Ethnopharmacol. 184:119-127(2016).
RN [7]
RP BIOTECHNOLOGY.
RX PubMed=27592257; DOI=10.1007/s13277-016-5208-6;
RA Chang W.H., Huang H.L., Huang W.P., Chen C.C., Chen Y.J.;
RT "Armillaridin induces autophagy-associated cell death in human chronic
RT myelogenous leukemia K562 cells.";
RL Tumor Biol. 37:14291-14300(2016).
RN [8]
RP MISCELLANEOUS.
RX PubMed=29614282; DOI=10.1016/j.cub.2018.01.026;
RA Sipos G., Anderson J.B., Nagy L.G.;
RT "Armillaria.";
RL Curr. Biol. 28:R297-R298(2018).
RN [9]
RP MISCELLANEOUS.
RX PubMed=30963893; DOI=10.1098/rspb.2018.2233;
RA Anderson J.B., Bruhn J.N., Kasimer D., Wang H., Rodrigue N., Smith M.L.;
RT "Clonal evolution and genome stability in a 2500-year-old fungal
RT individual.";
RL Proc. R. Soc. B 285:20182233-20182233(2018).
RN [10]
RP BIOTECHNOLOGY.
RX PubMed=31488037; DOI=10.1142/s0192415x19500708;
RA Leu Y.S., Chen Y.J., Chen C.C., Huang H.L.;
RT "Induction of autophagic death of human hepatocellular carcinoma cells by
RT armillaridin from Armillaria mellea.";
RL Am. J. Chin. Med. 47:1365-1380(2019).
RN [11]
RP MISCELLANEOUS.
RX PubMed=31746694; DOI=10.1094/pdis-06-19-1147-re;
RA Cromey M.G., Drakulic J., Beal E.J., Waghorn I.A.G., Perry J.N.,
RA Clover G.R.G.;
RT "Susceptibility of garden trees and shrubs to Armillaria root rot.";
RL Plant Dis. 104:483-492(2020).
CC -!- FUNCTION: Delta(6)-protoilludene synthase, part of the gene cluster
CC that mediates the biosynthesis of melleolides, a range of antifungal
CC and phytotoxic polyketide derivatives composed of an orsellinic acid
CC (OA) moiety esterified to various sesquiterpene alcohols
CC (PubMed:21148562). The first step in melleolides biosynthesis is
CC performed by the delta(6)-protoilludene synthase PRO1 which catalyzes
CC the cyclization of farnesyl diphosphate to protoilludene
CC (PubMed:21148562). The orsellinic acid synthase armB produces OA by
CC condensing acetyl-CoA with 3 malonyl-CoA units in a three-round chain
CC elongation reaction folowed by a C2-C7 ring closure (By similarity).
CC ArmB further catalyzes the trans-esterification of OA to the various
CC sesquiterpene alcohols resulting from the hydroxylation of
CC protoilludene (By similarity). The melleolides cluster also includes 5
CC cytochrome P450 monooxygenases, 4 NAD(+)-dependent oxidoreductases, one
CC flavin-dependent oxidoreductase, and one O-methyltransferase (By
CC similarity). The cytochrome P450 monooxygenases may be involved in
CC protoilludene hydroxylation to elaborate melleolides with multiple
CC alcohol groups, such as melleolide D, which carries alcohol
CC functionalities at C-4, C-5, C-10, and C-13 (By similarity). The role
CC of the NAD(+)-dependent enzymes remains unknown (By similarity).
CC Numerous melleolides, including arnamial, show 5'-O-methylation of the
CC aromatic moiety which may be catalyzed by the methyltransferase encoded
CC in the cluster (By similarity). The flavin-dependent oxidoreductase
CC might represent the dehydrogenase yielding the aldehyde in position 1
CC of arnamial and other melleolides (By similarity). Finally, several
CC halogenases, localized outside of the cluster, are able to catalyze the
CC transfer of a single chlorine atom to the melleolide backbone,
CC resulting in a 6'-chloromelleolide product (By similarity).
CC {ECO:0000250|UniProtKB:I3ZNU9, ECO:0000269|PubMed:21148562}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(2E,6E)-farnesyl diphosphate = Delta(6)-protoilludene +
CC diphosphate; Xref=Rhea:RHEA:34695, ChEBI:CHEBI:33019,
CC ChEBI:CHEBI:68655, ChEBI:CHEBI:175763; EC=4.2.3.135;
CC Evidence={ECO:0000269|PubMed:21148562};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000305|PubMed:21148562};
CC Note=Binds 3 Mg(2+) ions per subunit. {ECO:0000305|PubMed:21148562};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.53 uM for farnesyl diphosphate {ECO:0000269|PubMed:21148562};
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:21148562}.
CC -!- SUBUNIT: Monomer. {ECO:0000269|PubMed:21148562}.
CC -!- DOMAIN: The Asp-Asp-Xaa-Xaa-Asp/Glu (DDXXD/E) motif is important for
CC the catalytic activity, presumably through binding to Mg(2+).
CC {ECO:0000250}.
CC -!- BIOTECHNOLOGY: Melleolide sesquiterpene aryl esters are cytotoxic
CC secondary products with anti-cancer potential (PubMed:21376582,
CC PubMed:26952552). Armillaridin shows therapeutic and radiosensitizing
CC effects on human esophageal cancer cells (PubMed:23864890).
CC Armillaridin induces autophagy-associated cell death in human chronic
CC myelogenous leukemia as well as of hepatocellular carcinoma cells
CC (PubMed:27592257, PubMed:31488037). Armillaridin can also inhibit the
CC differentiation and activation of human macrophages and thus might have
CC potential to be developed as a biological response modifier for
CC inflammatory diseases (PubMed:25746621). {ECO:0000269|PubMed:21376582,
CC ECO:0000269|PubMed:23864890, ECO:0000269|PubMed:25746621,
CC ECO:0000269|PubMed:26952552, ECO:0000269|PubMed:27592257,
CC ECO:0000269|PubMed:31488037}.
CC -!- MISCELLANEOUS: Armillaria species are both devastating forest pathogens
CC and some of the largest and oldest terrestrial organisms on Earth
CC (PubMed:31746694) (Probable). They forage for hosts and achieve immense
CC colony sizes via rhizomorphs, root-like multicellular structures of
CC clonal dispersal (Probable). One genetic Armillaria gallica individual
CC localized in Michigan's Upper Peninsula stands out as exceptionally
CC large, covering hundreds of tree root systems over approximately 75
CC hectares of the forest floor (PubMed:30963893). Based on observed
CC growth rates of the fungus, the minimum age of this large individual
CC can be estimated as 2500 years (PubMed:30963893).
CC {ECO:0000269|PubMed:30963893, ECO:0000269|PubMed:31746694,
CC ECO:0000305|PubMed:29614282}.
CC -!- SIMILARITY: Belongs to the terpene synthase family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=Beneath us - Issue 225 of
CC May 2020;
CC URL="https://web.expasy.org/spotlight/back_issues/225/";
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DR EMBL; KC852198; AGR34199.1; -; mRNA.
DR EMBL; KZ293696; PBK84744.1; -; Genomic_DNA.
DR AlphaFoldDB; P0DL13; -.
DR SMR; P0DL13; -.
DR EnsemblFungi; PBK84744; PBK84744; ARMGADRAFT_1000221.
DR KEGG; ag:AGR34199; -.
DR OMA; ESRFMEN; -.
DR OrthoDB; 1143139at2759; -.
DR BioCyc; MetaCyc:MON-20282; -.
DR SABIO-RK; P0DL13; -.
DR Proteomes; UP000217790; Unassembled WGS sequence.
DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB.
DR GO; GO:0010333; F:terpene synthase activity; IDA:UniProtKB.
DR GO; GO:0016114; P:terpenoid biosynthetic process; IDA:UniProtKB.
DR Gene3D; 1.10.600.10; -; 1.
DR InterPro; IPR008949; Isoprenoid_synthase_dom_sf.
DR InterPro; IPR034686; Terpene_cyclase-like_2.
DR SFLD; SFLDG01020; Terpene_Cyclase_Like_2; 1.
DR SUPFAM; SSF48576; SSF48576; 1.
PE 1: Evidence at protein level;
KW Lyase; Magnesium; Metal-binding; Reference proteome; Virulence.
FT CHAIN 1..345
FT /note="Delta(6)-protoilludene synthase"
FT /id="PRO_0000422215"
FT MOTIF 84..88
FT /note="DDXXD motif"
FT /evidence="ECO:0000305"
FT BINDING 84
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q9UR08"
FT BINDING 84
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q9UR08"
FT BINDING 176
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q9UR08"
FT BINDING 220
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="3"
FT /evidence="ECO:0000250|UniProtKB:Q9UR08"
FT BINDING 224
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="3"
FT /evidence="ECO:0000250|UniProtKB:Q9UR08"
FT BINDING 228
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="3"
FT /evidence="ECO:0000250|UniProtKB:Q9UR08"
FT BINDING 325..326
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q9UR08"
FT VARIANT 90
FT /note="A -> S (in strain: FU02472)"
FT VARIANT 210
FT /note="N -> K (in strain: FU02472)"
FT VARIANT 343
FT /note="S -> F (in strain: FU02472)"
SQ SEQUENCE 345 AA; 39793 MW; 4C707A66F7BE6A5A CRC64;
MSQRIFLPDT LANWQWPRHL NPHYAEVKKA SAAWAKSFRA FQTKAQEAFD RCDFNLLASF
AYPLADEARL RSGCDLMNLF FVIDEYSDVA TEEEVRAQKD IVMDAIRNTE KPRPAGEWIG
GEVSRQFWDL AKKTASTQAQ KRFIDTFDEY LESVVQQAAD RNNSHVRGIE SYLEVRRNTI
GAKPSFALLE FDMQLPDEVI NHPVIKELEN SCIDMLCLGN DVVSYNLEQA RDDDGHNIVT
IAMNELRTDV AGAMIWVDEY HKQLESRFME NFKKVPRWGG PIDLQVARYC DGLGNWVRAN
DQWSFESERY FGKKGPEIIQ RRWITLMPKM VSEELGPQIV DGSHL
