AAMAT_AMAPH
ID AAMAT_AMAPH Reviewed; 23 AA.
AC P85421; A0A023UBX2;
DT 02-SEP-2008, integrated into UniProtKB/Swiss-Prot.
DT 28-MAR-2018, sequence version 2.
DT 25-MAY-2022, entry version 31.
DE RecName: Full=Alpha-amanitin proprotein {ECO:0000303|PubMed:24613547};
DE Contains:
DE RecName: Full=Alpha-amanitin {ECO:0000303|PubMed:24613547};
DE AltName: Full=Amatoxin {ECO:0000303|PubMed:7642577};
DE AltName: Full=Gamma-amanitin {ECO:0000303|PubMed:11805306};
DE Flags: Precursor; Fragment;
OS Amanita phalloides (Death cap).
OC Eukaryota; Fungi; Dikarya; Basidiomycota; Agaricomycotina; Agaricomycetes;
OC Agaricomycetidae; Agaricales; Amanitaceae; Amanita.
OX NCBI_TaxID=67723;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND FUNCTION.
RX PubMed=24613547; DOI=10.1016/j.toxicon.2014.02.020;
RA Li P., Deng W., Li T.;
RT "The molecular diversity of toxin gene families in lethal Amanita
RT mushrooms.";
RL Toxicon 83:59-68(2014).
RN [2] {ECO:0000305}
RP PROTEIN SEQUENCE OF 1-8, FUNCTION, AND 3D-STRUCTURE.
RX PubMed=4865716; DOI=10.1126/science.159.3818.946;
RA Wieland T.;
RT "Poisonous principles of mushrooms of the genus Amanita. Four-carbon amines
RT acting on the central nervous system and cell-destroying cyclic peptides
RT are produced.";
RL Science 159:946-952(1968).
RN [3] {ECO:0000305}
RP PROTEIN SEQUENCE OF 1-8, FUNCTION, AND TOXIC DOSE.
RX PubMed=363352; DOI=10.3109/10409237809149870;
RA Wieland T., Faulstich H.;
RT "Amatoxins, phallotoxins, phallolysin, and antamanide: the biologically
RT active components of poisonous Amanita mushrooms.";
RL CRC Crit. Rev. Biochem. 5:185-260(1978).
RN [4] {ECO:0000305}
RP FUNCTION.
RX PubMed=7642577; DOI=10.1074/jbc.270.32.19114;
RA Chafin D.R., Guo H., Price D.H.;
RT "Action of alpha-amanitin during pyrophosphorolysis and elongation by RNA
RT polymerase II.";
RL J. Biol. Chem. 270:19114-19119(1995).
RN [5] {ECO:0000305}
RP FUNCTION.
RX PubMed=8702941; DOI=10.1074/jbc.271.35.21549;
RA Rudd M.D., Luse D.S.;
RT "Amanitin greatly reduces the rate of transcription by RNA polymerase II
RT ternary complexes but fails to inhibit some transcript cleavage modes.";
RL J. Biol. Chem. 271:21549-21558(1996).
RN [6]
RP REVIEW ON TOXICITY.
RX PubMed=12475187; DOI=10.1081/clt-120014646;
RA Enjalbert F., Rapior S., Nouguier-Soule J., Guillon S., Amouroux N.,
RA Cabot C.;
RT "Treatment of amatoxin poisoning: 20-year retrospective analysis.";
RL J. Toxicol. Clin. Toxicol. 40:715-757(2002).
RN [7]
RP STRUCTURE VERIFICATION BY CHEMICAL SYNTHESIS.
RX PubMed=29561592; DOI=10.1021/jacs.7b12698;
RA Matinkhoo K., Pryyma A., Todorovic M., Patrick B.O., Perrin D.M.;
RT "Synthesis of the Death-Cap Mushroom Toxin alpha-Amanitin.";
RL J. Am. Chem. Soc. 140:6513-6517(2018).
RN [8] {ECO:0000305}
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) IN COMPLEX WITH RNA POL II CORE
RP COMPLEX, AND HYDROXYLATION AT ILE-1 AND PRO-8.
RX PubMed=11805306; DOI=10.1073/pnas.251664698;
RA Bushnell D.A., Cramer P., Kornberg R.D.;
RT "Structural basis of transcription: alpha-amanitin-RNA polymerase II
RT cocrystal at 2.8 A resolution.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:1218-1222(2002).
RN [9] {ECO:0000305}
RP X-RAY CRYSTALLOGRAPHY (3.4 ANGSTROMS) IN COMPLEX WITH RNA POL II ELONGATION
RP COMPLEX.
RX PubMed=18552824; DOI=10.1038/nsmb.1458;
RA Brueckner F., Cramer P.;
RT "Structural basis of transcription inhibition by alpha-amanitin and
RT implications for RNA polymerase II translocation.";
RL Nat. Struct. Mol. Biol. 15:811-818(2008).
CC -!- FUNCTION: Major toxin belonging to the bicyclic octapeptides amatoxins
CC that acts by binding non-competitively to RNA polymerase II and greatly
CC slowing the elongation of transcripts from target promoters
CC (PubMed:4865716, PubMed:363352, PubMed:7642577, PubMed:8702941).
CC {ECO:0000269|PubMed:363352, ECO:0000269|PubMed:4865716,
CC ECO:0000269|PubMed:7642577, ECO:0000269|PubMed:8702941,
CC ECO:0000305|PubMed:24613547}.
CC -!- PTM: Processed by the macrocyclase-peptidase enzyme POPB to yield a
CC toxic cyclic decapeptide (PubMed:24613547). POPB first removes 10
CC residues from the N-terminus (By similarity). Conformational trapping
CC of the remaining peptide forces the enzyme to release this intermediate
CC rather than proceed to macrocyclization (By similarity). The enzyme
CC rebinds the remaining peptide in a different conformation and catalyzes
CC macrocyclization of the N-terminal 8 residues (By similarity).
CC {ECO:0000250|UniProtKB:A0A067SLB9, ECO:0000305|PubMed:24613547}.
CC -!- TOXIC DOSE: LD(50) is 0.35 mg/kg by intraperitoneal injection into mice
CC (PubMed:363352). LD(50) is 4 mg/kg by intravenous injection into rats,
CC and 0.1 mg/kg by intravenous injection into dogs (PubMed:363352).
CC LD(50) is 2 ug/kg by intracerebroventricular injection into mice, and
CC 10 ug/kg by intracerebroventricular injection into rats
CC (PubMed:363352). {ECO:0000269|PubMed:363352}.
CC -!- MISCELLANEOUS: The typical symptoms of amatoxin poisoning are gastro-
CC intestinal distress beginning 6-12 h after ingestion, a remission phase
CC lasting 12-24 h, and progressive loss of liver function culminating in
CC death within 3-5 days (PubMed:12475187). One of the few effective
CC treatments is liver transplantation (PubMed:12475187).
CC {ECO:0000303|PubMed:12475187}.
CC -!- SIMILARITY: Belongs to the MSDIN fungal toxin family. {ECO:0000305}.
CC -!- CAUTION: This peptide is cyclic. The peptide order is assigned by
CC homology with the gene sequence for alpha-amanitin from Amanita
CC bisporigera. {ECO:0000305}.
CC -!- CAUTION: In peptide sequencing work prior to 1968, the residue shown in
CC the first position was reported as a beta-methylleucine derivative that
CC could arise by either beta-methylation of leucine or gamma-methylation
CC of isoleucine. The correct structure has been determined to be derived
CC from isoleucine without methylation. {ECO:0000305}.
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DR EMBL; KC778577; AGO98233.1; -; Genomic_DNA.
DR EMBL; KF546288; AHX98312.1; -; Genomic_DNA.
DR EMBL; KF546289; AHX98313.1; -; Genomic_DNA.
DR PDB; 1K83; X-ray; 2.80 A; M=1-8.
DR PDB; 2VUM; X-ray; 3.40 A; M=1-8.
DR PDB; 3CQZ; X-ray; 2.80 A; M=1-8.
DR PDB; 6EXV; EM; 3.60 A; M=1-8.
DR PDBsum; 1K83; -.
DR PDBsum; 2VUM; -.
DR PDBsum; 3CQZ; -.
DR PDBsum; 6EXV; -.
DR AlphaFoldDB; P85421; -.
DR SMR; P85421; -.
DR DIP; DIP-46365N; -.
DR IntAct; P85421; 12.
DR EvolutionaryTrace; P85421; -.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
PE 1: Evidence at protein level;
KW 3D-structure; Direct protein sequencing; Hydroxylation; Thioether bond;
KW Toxin.
FT PEPTIDE 1..8
FT /note="Alpha-amanitin"
FT /evidence="ECO:0000269|PubMed:7642577,
FT ECO:0000269|PubMed:8702941"
FT /id="PRO_0000349137"
FT PROPEP 9..23
FT /evidence="ECO:0000250|UniProtKB:A8W7M4"
FT /id="PRO_0000443719"
FT MOD_RES 1
FT /note="(3R,4R)-4,5-dihydroxyisoleucine; in form alpha-
FT amanitin"
FT /evidence="ECO:0000269|PubMed:11805306"
FT MOD_RES 1
FT /note="(3R,4S)-4-hydroxyisoleucine; in form gamma-amanitin"
FT /evidence="ECO:0000269|PubMed:11805306"
FT MOD_RES 8
FT /note="4-hydroxyproline"
FT /evidence="ECO:0000269|PubMed:11805306,
FT ECO:0000269|PubMed:363352, ECO:0000269|PubMed:4865716"
FT CROSSLNK 1..8
FT /note="Cyclopeptide (Ile-Pro)"
FT /evidence="ECO:0000269|PubMed:18552824,
FT ECO:0000269|PubMed:363352, ECO:0000269|PubMed:4865716"
FT CROSSLNK 2..6
FT /note="2'-cysteinyl-6'-hydroxytryptophan sulfoxide (Trp-
FT Cys)"
FT /evidence="ECO:0000305"
FT NON_TER 1
FT /evidence="ECO:0000305"
FT TURN 4..6
FT /evidence="ECO:0007829|PDB:3CQZ"
SQ SEQUENCE 23 AA; 2345 MW; 3634A114ED3CB96B CRC64;
IWGIGCNPCV GDEVAALLTR GEA
