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-MAY-2023, entry version 89.
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-
CC         glycero-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:0031640; P:killing of cells of another organism; IEA:UniProtKB-KW.
DR   GO; GO:0016042; P:lipid catabolic process; IEA:UniProtKB-KW.
DR   CDD; cd08576; GDPD_like_SMaseD_PLD; 1.
DR   Gene3D; 3.20.20.190; Phosphatidylinositol (PI) phosphodiesterase; 1.
DR   InterPro; IPR017946; PLC-like_Pdiesterase_TIM-brl.
DR   SUPFAM; SSF51695; PLC-like phosphodiesterases; 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
//