A21_LOXIN
ID A21_LOXIN Reviewed; 305 AA.
AC Q1W695;
DT 06-MAR-2007, integrated into UniProtKB/Swiss-Prot.
DT 02-MAY-2006, sequence version 1.
DT 03-AUG-2022, entry version 57.
DE RecName: Full=Dermonecrotic toxin LiSicTox-alphaII1;
DE EC=4.6.1.- {ECO:0000250|UniProtKB:Q4ZFU2};
DE AltName: Full=Dermonecrotic toxin 4;
DE Short=DT4 {ECO:0000303|PubMed:21590705};
DE AltName: Full=LiRecDT4 {ECO:0000303|PubMed:17296256, ECO:0000303|PubMed:21590705};
DE AltName: Full=Phospholipase D;
DE AltName: Full=Sphingomyelin phosphodiesterase D 4;
DE Short=SMD 4;
DE Short=SMase D 4;
DE Short=Sphingomyelinase D 4;
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, BIOASSAY, AND CATALYTIC ACTIVITY.
RC TISSUE=Venom gland;
RX PubMed=17296256; DOI=10.1016/j.biochi.2006.12.002;
RA da Silveira R.B., Pigozzo R.B., Chaim O.M., Appel M.H., Silva D.T.,
RA Dreyfuss J.L., Toma L., Dietrich C.P., Nader H.B., Veiga S.S., Gremski W.;
RT "Two novel dermonecrotic toxins LiRecDT4 and LiRecDT5 from Brown spider
RT (Loxosceles intermedia) venom: from cloning to functional
RT characterization.";
RL Biochimie 89:289-300(2007).
RN [2]
RP FUNCTION.
RX PubMed=21590705; DOI=10.1002/jcb.23177;
RA Chaves-Moreira D., Souza F.N., Fogaca R.T., Mangili O.C., Gremski W.,
RA Senff-Ribeiro A., Chaim O.M., Veiga S.S.;
RT "The relationship between calcium and the metabolism of plasma membrane
RT phospholipids in hemolysis induced by brown spider venom phospholipase-D
RT toxin.";
RL J. Cell. Biochem. 112:2529-2540(2011).
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) wih high activity (PubMed:17296256). It may also act
CC on ceramide phosphoethanolamine (CPE), lysophosphatidylcholine (LPC)
CC 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). Shows
CC high hemolytic activity (PubMed:17296256, PubMed:21590705). Causes
CC dermonecrosis, induces inflammatory response, platelet aggregation and
CC increases vessel permeability (PubMed:17296256). Shows no lethality
CC when injected at higher dose into mice (PubMed:17296256). May cause
CC complement-dependent hemolysis as well as in a complement-independent
CC manner (By similarity). The hemolysis provoked in a complement-
CC independent manner may be composed of several steps (By similarity).
CC The toxin may bind to erythrocyte membranes, may hydrolyze membrane
CC phospholipids (SM and LPC) thus generating metabolism products that may
CC cause hemolysis, probably by provoking an increase of calcium inside
CC cells (By similarity). The calcium influx may be due to the opening of
CC L-type calcium channels, since L-type calcium channel blockers inhibit
CC calcium influx (By similarity). {ECO:0000250|UniProtKB:A0A0D4WTV1,
CC ECO:0000250|UniProtKB:P0CE80, ECO:0000269|PubMed:17296256,
CC ECO:0000269|PubMed:21590705}.
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:17296256};
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:17296256}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000305|PubMed:17296256}.
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; DQ431848; ABD91846.1; -; mRNA.
DR AlphaFoldDB; Q1W695; -.
DR SMR; Q1W695; -.
DR ArachnoServer; AS000144; Sphingomyelinase D (LiSicTox-alphaII1).
DR GO; GO:0005576; C:extracellular region; NAS:UniProtKB.
DR GO; GO:0016829; F:lyase activity; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004620; F:phospholipase activity; IDA:UniProtKB.
DR GO; GO:0008081; F:phosphoric diester hydrolase activity; IEA:InterPro.
DR GO; GO:0090729; F:toxin activity; IDA:UniProtKB.
DR GO; GO:0044398; P:envenomation resulting in induction of edema in another organism; IDA:UniProtKB.
DR GO; GO:0044478; P:envenomation resulting in positive regulation of platelet aggregation in another organism; IDA:UniProtKB.
DR GO; GO:0044179; P:hemolysis in another organism; IEA:UniProtKB-KW.
DR GO; GO:0016042; P:lipid catabolic process; IEA:UniProtKB-KW.
DR GO; GO:0006644; P:phospholipid metabolic process; IDA:UniProtKB.
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 Lipid degradation; Lipid metabolism; Lyase; Magnesium; Metal-binding;
KW Secreted; Signal; Toxin; Zymogen.
FT SIGNAL 1..18
FT /evidence="ECO:0000255"
FT PROPEP 19..26
FT /evidence="ECO:0000250"
FT /id="PRO_0000279567"
FT CHAIN 27..305
FT /note="Dermonecrotic toxin LiSicTox-alphaII1"
FT /id="PRO_0000279568"
FT ACT_SITE 38
FT /evidence="ECO:0000250|UniProtKB:Q8I914"
FT ACT_SITE 74
FT /note="Nucleophile"
FT /evidence="ECO:0000250|UniProtKB:Q8I914"
FT BINDING 58
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:Q8I914"
FT BINDING 60
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:Q8I914"
FT BINDING 118
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:Q8I914"
FT DISULFID 78..84
FT /evidence="ECO:0000250|UniProtKB:P0CE80"
FT DISULFID 80..223
FT /evidence="ECO:0000250|UniProtKB:P0CE80"
SQ SEQUENCE 305 AA; 34869 MW; 36591D40D877908E CRC64;
MLLHIALILG CWSVFSEGAE TDVAERADGR RPIWNMGHMV NGIWQIDQFV DLGVNSIEFD
INFDKNGKPV YTYHGVPCDC FRSCLNWEYF GEFLTALRHR TTPGDKLYKE KLILFVFDMK
TNSLYDNQAY QAGVNMATDI FKYYWNNGQN GGRAYFILSI PNLNHYDLIK GFRETITKKG
HPELMEKVGY DFSANDNIPD VEKAYGKVGV TDHVWQSDGI TNCIARGLSR VKEAVKERDS
GGVINKVYIW TIDKFSSTRD ALDAGVDGIM TNYPYVLNDV LKEGAYKNKF RMATYEDNPW
VTFKA
