A311_LOXLA
ID A311_LOXLA Reviewed; 311 AA.
AC Q8I914;
DT 16-JAN-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 86.
DE RecName: Full=Dermonecrotic toxin LlSicTox-alphaIII1i;
DE EC=4.6.1.- {ECO:0000250|UniProtKB:Q4ZFU2};
DE AltName: Full=LlH17;
DE AltName: Full=Phospholipase D;
DE Short=PLD;
DE AltName: Full=Sphingomyelin phosphodiesterase D 1;
DE Short=Lox-SMaseD {ECO:0000303|PubMed:14732720};
DE Short=SMD 1;
DE Short=SMase D 1 {ECO:0000303|PubMed:14732720};
DE Short=Sphingomyelinase D 1;
DE AltName: Full=Sphingomyelinase I;
DE Short=SMase I {ECO:0000303|PubMed:12419302};
DE Flags: Precursor;
OS Loxosceles laeta (South American recluse spider) (Scytodes laeta).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida; Araneae;
OC Araneomorphae; Haplogynae; Scytodoidea; Sicariidae; Loxosceles.
OX NCBI_TaxID=58217;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND CATALYTIC ACTIVITY.
RC TISSUE=Venom gland;
RX PubMed=12419302; DOI=10.1016/s0006-291x(02)02521-4;
RA Fernandes-Pedrosa M.F., Junqueira de Azevedo I.L.M.,
RA Goncalves-de-Andrade R.M., van den Berg C.W., Ramos C.R.R., Ho P.L.,
RA Tambourgi D.V.;
RT "Molecular cloning and expression of a functional dermonecrotic and
RT haemolytic factor from Loxosceles laeta venom.";
RL Biochem. Biophys. Res. Commun. 298:638-645(2002).
RN [2]
RP FUNCTION, CATALYTIC ACTIVITY, COFACTOR, BIOPHYSICOCHEMICAL PROPERTIES, AND
RP SUBSTRATE SPECIFICITY.
RX PubMed=14732720; DOI=10.1074/jbc.c300563200;
RA van Meeteren L.A., Frederiks F., Giepmans B.N., Pedrosa M.F.,
RA Billington S.J., Jost B.H., Tambourgi D.V., Moolenaar W.H.;
RT "Spider and bacterial sphingomyelinases D target cellular lysophosphatidic
RT acid receptors by hydrolyzing lysophosphatidylcholine.";
RL J. Biol. Chem. 279:10833-10836(2004).
RN [3]
RP X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) OF 27-311, DISULFIDE BONDS,
RP METAL-BINDING SITES, ACTIVE SITES, AND COFACTOR.
RX PubMed=15654080; DOI=10.1074/jbc.m412437200;
RA Murakami M.T., Fernandes-Pedrosa M.F., Tambourgi D.V., Arni R.K.;
RT "Structural basis for metal ion coordination and the catalytic mechanism of
RT sphingomyelinases D.";
RL J. Biol. Chem. 280:13658-13664(2005).
RN [4]
RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 27-311, DISULFIDE BONDS,
RP METAL-BINDING SITES, ACTIVE SITES, NOMENCLATURE, AND COFACTOR.
RX PubMed=16480957; DOI=10.1016/j.bbrc.2006.01.123;
RA Murakami M.T., Fernandes-Pedrosa M.F., de Andrade S.A., Gabdoulkhakov A.,
RA Betzel C., Tambourgi D.V., Arni R.K.;
RT "Structural insights into the catalytic mechanism of sphingomyelinases D
RT and evolutionary relationship to glycerophosphodiester
RT phosphodiesterases.";
RL Biochem. Biophys. Res. Commun. 342:323-329(2006).
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:12419302,
CC PubMed:14732720). It also act on acyl- and alkyl-
CC lysophosphatidylcholine (LPC), but not on sphingosylphosphorylcholine
CC (SPC) and phosphatidylcholine (PC) (PubMed:14732720). It may also act
CC on ceramide phosphoethanolamine (CPE), and lysophosphatidylethanolamine
CC (LPE), but not on lysophosphatidylserine (LPS), and
CC lysophosphatidylglycerol (LPG) (By similarity). It acts by
CC transphosphatidylation, releasing exclusively cyclic phosphate products
CC as second products (By similarity). Induces complement-dependent
CC hemolysis and dermonecrosis (PubMed:12419302). Also induces increased
CC vascular permeability, edema, inflammatory response, and platelet
CC aggregation (By similarity). {ECO:0000250|UniProtKB:A0A0D4WTV1,
CC ECO:0000250|UniProtKB:P0CE80, ECO:0000269|PubMed:12419302,
CC ECO:0000269|PubMed:14732720}.
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:12419302, ECO:0000305|PubMed:14732720};
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:0000305|PubMed:14732720};
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:0000269|PubMed:14732720, ECO:0000269|PubMed:15654080,
CC ECO:0000269|PubMed:16480957, ECO:0000312|PDB:1XX1,
CC ECO:0000312|PDB:2F9R};
CC Note=Binds 1 Mg(2+) ion per subunit. {ECO:0000269|PubMed:14732720,
CC ECO:0000269|PubMed:15654080, ECO:0000269|PubMed:16480957,
CC ECO:0000312|PDB:1XX1, ECO:0000312|PDB:2F9R};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=44.4 uM for 1-oleoyl-LPC {ECO:0000269|PubMed:14732720};
CC Vmax=212 nmol/min/mg enzyme toward 1-oleoyl-LPC
CC {ECO:0000269|PubMed:14732720};
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000305|PubMed:12419302}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000305|PubMed:12419302}.
CC -!- SIMILARITY: Belongs to the arthropod phospholipase D family. Class I
CC 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; AY093599; AAM21154.1; -; mRNA.
DR PDB; 1XX1; X-ray; 1.75 A; A/B/C/D=27-311.
DR PDB; 2F9R; X-ray; 1.85 A; A/B/C/D=27-311.
DR PDBsum; 1XX1; -.
DR PDBsum; 2F9R; -.
DR AlphaFoldDB; Q8I914; -.
DR SMR; Q8I914; -.
DR ArachnoServer; AS000132; Sphingomyelinase D (LlSicTox-alphaIII1i).
DR BRENDA; 3.1.4.41; 6922.
DR SABIO-RK; Q8I914; -.
DR EvolutionaryTrace; Q8I914; -.
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 3D-structure; Cytolysis; Dermonecrotic toxin; Disulfide bond; Hemolysis;
KW Lipid degradation; Lipid metabolism; Lyase; Magnesium; Metal-binding;
KW Secreted; Signal; Toxin; Zymogen.
FT SIGNAL 1..21
FT /evidence="ECO:0000255"
FT PROPEP 22..26
FT /evidence="ECO:0000305|PubMed:15654080"
FT /id="PRO_0000035583"
FT CHAIN 27..311
FT /note="Dermonecrotic toxin LlSicTox-alphaIII1i"
FT /id="PRO_0000035584"
FT ACT_SITE 38
FT /evidence="ECO:0000269|PubMed:15654080"
FT ACT_SITE 73
FT /note="Nucleophile"
FT /evidence="ECO:0000269|PubMed:15654080"
FT BINDING 58
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000269|PubMed:15654080,
FT ECO:0000269|PubMed:16480957, ECO:0000312|PDB:1XX1,
FT ECO:0000312|PDB:2F9R"
FT BINDING 60
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000269|PubMed:15654080,
FT ECO:0000269|PubMed:16480957, ECO:0000312|PDB:1XX1,
FT ECO:0000312|PDB:2F9R"
FT BINDING 117
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000269|PubMed:15654080,
FT ECO:0000269|PubMed:16480957, ECO:0000312|PDB:1XX1,
FT ECO:0000312|PDB:2F9R"
FT DISULFID 77..83
FT /evidence="ECO:0000269|PubMed:15654080,
FT ECO:0000269|PubMed:16480957"
FT STRAND 30..38
FT /evidence="ECO:0007829|PDB:1XX1"
FT HELIX 45..52
FT /evidence="ECO:0007829|PDB:1XX1"
FT STRAND 55..64
FT /evidence="ECO:0007829|PDB:1XX1"
FT STRAND 67..72
FT /evidence="ECO:0007829|PDB:1XX1"
FT STRAND 86..88
FT /evidence="ECO:0007829|PDB:1XX1"
FT HELIX 89..99
FT /evidence="ECO:0007829|PDB:1XX1"
FT STRAND 113..118
FT /evidence="ECO:0007829|PDB:1XX1"
FT HELIX 125..127
FT /evidence="ECO:0007829|PDB:1XX1"
FT HELIX 128..142
FT /evidence="ECO:0007829|PDB:1XX1"
FT HELIX 145..147
FT /evidence="ECO:0007829|PDB:1XX1"
FT STRAND 154..160
FT /evidence="ECO:0007829|PDB:1XX1"
FT HELIX 162..164
FT /evidence="ECO:0007829|PDB:1XX1"
FT HELIX 165..177
FT /evidence="ECO:0007829|PDB:1XX1"
FT HELIX 181..186
FT /evidence="ECO:0007829|PDB:1XX1"
FT STRAND 187..191
FT /evidence="ECO:0007829|PDB:1XX1"
FT STRAND 196..198
FT /evidence="ECO:0007829|PDB:1XX1"
FT HELIX 202..212
FT /evidence="ECO:0007829|PDB:1XX1"
FT STRAND 218..222
FT /evidence="ECO:0007829|PDB:1XX1"
FT HELIX 229..243
FT /evidence="ECO:0007829|PDB:1XX1"
FT STRAND 252..256
FT /evidence="ECO:0007829|PDB:1XX1"
FT HELIX 261..270
FT /evidence="ECO:0007829|PDB:1XX1"
FT STRAND 273..278
FT /evidence="ECO:0007829|PDB:1XX1"
FT HELIX 280..288
FT /evidence="ECO:0007829|PDB:1XX1"
FT TURN 290..295
FT /evidence="ECO:0007829|PDB:1XX1"
FT STRAND 296..298
FT /evidence="ECO:0007829|PDB:1XX1"
SQ SEQUENCE 311 AA; 34874 MW; 23024A2C4E7F4CC0 CRC64;
MYAHLALILG CWTVVLQGAE TDVGERADNR RPIWNLAHMV NAVAQIPDFL DLGANALEAD
VTFKGSVPTY TYHGTPCDFG RDCIRWEYFN VFLKTLREYT TPGNAKYRDG FILFVLDLKT
GSLSNDQVRP AGENVAKELL QNYWNNGNNG GRAYVVLSLP DIGHYEFVRG FKEVLKKEGH
EDLLEKVGYD FSGPYLPSLP TLDATHEAYK KAGVDGHIWL SDGLTNFSPL GDMARLKEAI
KSRDSANGFI NKIYYWSVDK VSTTKAALDV GVDGIMTNYP NVLIGVLKES GYNDKYRLAT
YDDNPWETFK N
