A4A1_LOXIN
ID A4A1_LOXIN Reviewed; 299 AA.
AC P0DM60; R9UDZ9;
DT 16-OCT-2013, integrated into UniProtKB/Swiss-Prot.
DT 16-OCT-2013, sequence version 1.
DT 03-AUG-2022, entry version 21.
DE RecName: Full=Dermonecrotic toxin LiSicTox-alphaIVA1;
DE EC=4.6.1.- {ECO:0000250|UniProtKB:Q4ZFU2};
DE AltName: Full=Dermonecrotic toxin 7;
DE Short=DT7;
DE AltName: Full=LiRecDT7 {ECO:0000303|PubMed:23733617};
DE AltName: Full=Phospholipase D;
DE Short=PLD;
DE AltName: Full=Sphingomyelin phosphodiesterase D 7;
DE Short=SMD 7;
DE Short=SMase D 7;
DE Short=Sphingomyelinase D 7;
DE Flags: Precursor;
OS Loxosceles intermedia (Brown spider).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida; Araneae;
OC Araneomorphae; Haplogynae; Scytodoidea; Sicariidae; Loxosceles.
OX NCBI_TaxID=58218;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, 3D-STRUCTURE MODELING, AND CATALYTIC
RP ACTIVITY.
RC TISSUE=Venom gland;
RX PubMed=23733617; DOI=10.1002/jcb.24594;
RA Vuitika L., Gremski L.H., Belisario-Ferrari M.R., Chaves-Moreira D.,
RA Ferrer V.P., Senff-Ribeiro A., Chaim O.M., Veiga S.S.;
RT "Brown spider phospholipase-D containing a conservative mutation (D233E) in
RT the catalytic site: identification and functional characterization.";
RL J. Cell. Biochem. 114:2479-2492(2013).
CC -!- FUNCTION: Dermonecrotic toxins cleave the phosphodiester linkage
CC between the phosphate and headgroup of certain phospholipids
CC (sphingolipid and lysolipid substrates), forming an alcohol (often
CC choline) and a cyclic phosphate (By similarity). This toxin acts on
CC sphingomyelin (SM) with high activity (PubMed:23733617). It may also
CC act on ceramide phosphoethanolamine (CPE), lysophosphatidylcholine
CC (LPC) and lysophosphatidylethanolamine (LPE), but not on
CC lysophosphatidylserine (LPS), and lysophosphatidylglycerol (LPG) (By
CC similarity). It acts by transphosphatidylation, releasing exclusively
CC cyclic phosphate products as second products (By similarity). Has
CC hemolytic activity in human erythrocytes in a dose-dependent manner
CC (PubMed:23733617). In vivo, this toxin induces dermonecrosis, edema,
CC hemorrhage, massive inflammatory response, as well as vascular
CC permeability (PubMed:23733617). In addition, thrombus formation has
CC also been detected in dermal blood vessels (PubMed:23733617). It also
CC induces platelet aggregation (By similarity). It is noteworthy that a
CC Glu-248 replaces the Asp present in paralogs, without decrease in
CC catalytic and hemolytic activities (PubMed:23733617).
CC {ECO:0000250|UniProtKB:A0A0D4WTV1, ECO:0000250|UniProtKB:P0CE80,
CC ECO:0000269|PubMed:23733617}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an N-(acyl)-sphingosylphosphocholine = an N-(acyl)-sphingosyl-
CC 1,3-cyclic phosphate + choline; Xref=Rhea:RHEA:60652,
CC ChEBI:CHEBI:15354, ChEBI:CHEBI:64583, ChEBI:CHEBI:143892;
CC Evidence={ECO:0000305|PubMed:23733617};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an N-(acyl)-sphingosylphosphoethanolamine = an N-(acyl)-
CC sphingosyl-1,3-cyclic phosphate + ethanolamine; Xref=Rhea:RHEA:60648,
CC ChEBI:CHEBI:57603, ChEBI:CHEBI:143891, ChEBI:CHEBI:143892;
CC Evidence={ECO:0000250|UniProtKB:A0A0D4WTV1};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1-acyl-sn-glycero-3-phosphocholine = a 1-acyl-sn-glycero-
CC 2,3-cyclic phosphate + choline; Xref=Rhea:RHEA:60700,
CC ChEBI:CHEBI:15354, ChEBI:CHEBI:58168, ChEBI:CHEBI:143947;
CC Evidence={ECO:0000250|UniProtKB:A0A0D4WTV1};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1-acyl-sn-glycero-3-phosphoethanolamine = a 1-acyl-sn-
CC glycero-2,3-cyclic phosphate + ethanolamine; Xref=Rhea:RHEA:60704,
CC ChEBI:CHEBI:57603, ChEBI:CHEBI:64381, ChEBI:CHEBI:143947;
CC Evidence={ECO:0000250|UniProtKB:A0A0D4WTV1};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:Q8I914};
CC Note=Binds 1 Mg(2+) ion per subunit. {ECO:0000250|UniProtKB:Q8I914};
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000305|PubMed:23733617}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000305|PubMed:23733617}.
CC -!- SIMILARITY: Belongs to the arthropod phospholipase D family. Class II
CC subfamily. Class IIa sub-subfamily. {ECO:0000305}.
CC -!- CAUTION: The most common activity assay for dermonecrotic toxins
CC detects enzymatic activity by monitoring choline release from
CC substrate. Liberation of choline from sphingomyelin (SM) or
CC lysophosphatidylcholine (LPC) is commonly assumed to result from
CC substrate hydrolysis, giving either ceramide-1-phosphate (C1P) or
CC lysophosphatidic acid (LPA), respectively, as a second product.
CC However, two studies from Lajoie and colleagues (2013 and 2015) report
CC the observation of exclusive formation of cyclic phosphate products as
CC second products, resulting from intramolecular transphosphatidylation.
CC Cyclic phosphates have vastly different biological properties from
CC their monoester counterparts, and they may be relevant to the pathology
CC of brown spider envenomation. {ECO:0000250|UniProtKB:A0A0D4WTV1,
CC ECO:0000250|UniProtKB:A0A0D4WV12, ECO:0000250|UniProtKB:Q4ZFU2}.
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DR EMBL; KC237286; AGN52903.1; -; mRNA.
DR AlphaFoldDB; P0DM60; -.
DR SMR; P0DM60; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0016829; F:lyase activity; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0008081; F:phosphoric diester hydrolase activity; IEA:InterPro.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR GO; GO:0044179; P:hemolysis in another organism; IEA:UniProtKB-KW.
DR GO; GO:0016042; P:lipid catabolic process; IEA:UniProtKB-KW.
DR Gene3D; 3.20.20.190; -; 1.
DR InterPro; IPR017946; PLC-like_Pdiesterase_TIM-brl.
DR SUPFAM; SSF51695; SSF51695; 1.
PE 1: Evidence at protein level;
KW Cytolysis; Dermonecrotic toxin; Disulfide bond; Hemolysis;
KW Hemorrhagic toxin; Hemostasis impairing toxin; Lipid degradation;
KW Lipid metabolism; Lyase; Magnesium; Metal-binding; Secreted; Signal; Toxin;
KW Zymogen.
FT SIGNAL 1..18
FT /evidence="ECO:0000255"
FT CHAIN 19..299
FT /note="Dermonecrotic toxin LiSicTox-alphaIVA1"
FT /id="PRO_0000423635"
FT ACT_SITE 30
FT /evidence="ECO:0000250|UniProtKB:Q8I914"
FT ACT_SITE 66
FT /note="Nucleophile"
FT /evidence="ECO:0000250|UniProtKB:Q8I914"
FT BINDING 50
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:Q8I914"
FT BINDING 52
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:Q8I914"
FT BINDING 110
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:Q8I914"
FT DISULFID 70..76
FT /evidence="ECO:0000250|UniProtKB:P0CE80"
FT DISULFID 72..217
FT /evidence="ECO:0000250|UniProtKB:P0CE80"
SQ SEQUENCE 299 AA; 34104 MW; 78D7AB5F037F1FDE CRC64;
MLFPTALIFG CWALVIEGAD NRRPIWNMGH MVNEVYQIDE FVDLGANSIE TDITFDDDAM
AEYSYHGVPC DCRRWCHKWE YVNVFLDGLR RATTPGDSKY RPELTLVVFD LKTGDLSSST
AYKGGKLFAQ KLLDRYWNGG NNGGRAYIII SIPDIDHYAF ITGFREALKN ANHEELLDKV
GYDFSGNDDL SSTRTALNKA GVKDREHVWQ SDGITNCILR GLDRVREAVR NRDSSNGYIN
KVYYWTIEKY VSVRDALDAG VDGIMTNEPD VIVNVLNEGN YRGRFRLANY DDNPWVTFK
