ARMD2_ARMGA
ID ARMD2_ARMGA Reviewed; 320 AA.
AC A0A2H3CZZ2;
DT 22-APR-2020, integrated into UniProtKB/Swiss-Prot.
DT 31-JAN-2018, sequence version 1.
DT 03-AUG-2022, entry version 14.
DE RecName: Full=Short-chain dehydrogenase/reductase ARMGADRAFT_1169971 {ECO:0000303|PubMed:21148562};
DE EC=1.1.1.- {ECO:0000269|PubMed:21148562};
DE AltName: Full=Melleolides biosynthesis cluster protein ARMGADRAFT_1169971;
GN ORFNames=ARMGADRAFT_1169971;
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 [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 [2]
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 [3]
RP FUNCTION.
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 [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: Short-chain dehydrogenase/reductase, 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 (Probable).
CC The first step in melleolides biosynthesis is performed by the
CC delta(6)-protoilludene synthase PRO1 which catalyzes the cyclization of
CC farnesyl diphosphate to protoilludene (PubMed:21148562). The orsellinic
CC acid synthase armB produces OA by condensing acetyl-CoA with 3 malonyl-
CC CoA units in a three-round chain elongation reaction folowed by a C2-C7
CC ring closure (By similarity). ArmB further catalyzes the trans-
CC esterification of OA to the various sesquiterpene alcohols resulting
CC from the hydroxylation of protoilludene (By similarity). The
CC melleolides cluster also includes 5 cytochrome P450 monooxygenases, 4
CC NAD(+)-dependent oxidoreductases, one flavin-dependent oxidoreductase,
CC and one O-methyltransferase (By similarity). The cytochrome P450
CC monooxygenases may be involved in protoilludene hydroxylation to
CC elaborate melleolides with multiple alcohol groups, such as melleolide
CC D, which carries alcohol functionalities at C-4, C-5, C-10, and C-13
CC (By similarity). The role of the NAD(+)-dependent enzymes remains
CC unknown (By similarity). Numerous melleolides, including arnamial, show
CC 5'-O-methylation of the aromatic moiety which may be catalyzed by the
CC methyltransferase encoded in the cluster (By similarity). The flavin-
CC dependent oxidoreductase might represent the dehydrogenase yielding the
CC aldehyde in position 1 of arnamial and other melleolides (By
CC similarity). Finally, several halogenase localized outside of the
CC cluster, are able to catalyze the transfer of a single chlorine atom to
CC the melleolide backbone, resulting in a 6'-chloromelleolide product (By
CC similarity). {ECO:0000250|UniProtKB:I3ZNU9,
CC ECO:0000269|PubMed:21148562, ECO:0000305}.
CC -!- PATHWAY: Secondary metabolite biosynthesis. {ECO:0000305}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Multi-pass membrane
CC protein {ECO:0000255}.
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:30963893}.
CC -!- SIMILARITY: Belongs to the short-chain dehydrogenases/reductases (SDR)
CC family. {ECO:0000305}.
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DR EMBL; KZ293696; PBK84762.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A2H3CZZ2; -.
DR SMR; A0A2H3CZZ2; -.
DR EnsemblFungi; PBK84762; PBK84762; ARMGADRAFT_1169971.
DR OMA; SFDRANI; -.
DR OrthoDB; 921996at2759; -.
DR Proteomes; UP000217790; Unassembled WGS sequence.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR002347; SDR_fam.
DR Pfam; PF00106; adh_short; 1.
DR PRINTS; PR00081; GDHRDH.
DR SUPFAM; SSF51735; SSF51735; 1.
PE 1: Evidence at protein level;
KW Glycoprotein; Membrane; NAD; NADP; Oxidoreductase; Reference proteome;
KW Transmembrane; Transmembrane helix.
FT CHAIN 1..320
FT /note="Short-chain dehydrogenase/reductase
FT ARMGADRAFT_1169971"
FT /id="PRO_0000449404"
FT TRANSMEM 19..39
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 235..255
FT /note="Helical"
FT /evidence="ECO:0000255"
FT ACT_SITE 192
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10001"
FT BINDING 22..30
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q92506"
FT BINDING 49..50
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q92506"
FT BINDING 81..83
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q92506"
FT BINDING 192..196
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q92506"
FT BINDING 227..229
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q92506"
FT CARBOHYD 157
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 320 AA; 35501 MW; 1BBF276F2C9FF724 CRC64;
MGSSSRVGDE NSLLDLTEKV AVVTGANSGI GLYILFHVAR AGAKVYLGAR TEAKFNSAIT
RLKTEGLDTS KVVWLPFDLS DPRKAKESAK WLLERENRLD ILINNAAKIL GPYAQTSDGL
SDSMVINHMS PYLFTKTLLP LLESTARQPG SDVRIVNVSS VAHRWVPNPR YDSLEAFNNN
FADTWKPKTN LYGYTKLANV LWTKELQRSF DRANIPILAM TVHPGNVMSE GNVKLFTSLM
FGTIINWVFS LFFISPFDGG YTPAFAAASR VIAEDRRKYA GAYIVPFGVI EEASEDARRE
DLAKDLLATT DAVLKQYDYA
