B1H1_LOXIN
ID B1H1_LOXIN Reviewed; 304 AA.
AC Q2XQ09; B2KKW1; Q27Q55;
DT 28-NOV-2006, integrated into UniProtKB/Swiss-Prot.
DT 20-DEC-2005, sequence version 1.
DT 03-AUG-2022, entry version 57.
DE RecName: Full=Dermonecrotic toxin LiSicTox-betaIA1i;
DE EC=4.6.1.- {ECO:0000250|UniProtKB:Q4ZFU2};
DE AltName: Full=Dermonecrotic toxin 3;
DE Short=DT3 {ECO:0000303|PubMed:21590705};
DE AltName: Full=Dermonecrotic toxin-like I;
DE AltName: Full=LiRecDT3 {ECO:0000303|PubMed:17900646, ECO:0000303|PubMed:21590705};
DE AltName: Full=Loxtox i6;
DE AltName: Full=P3;
DE AltName: Full=Phospholipase D;
DE Short=PLD;
DE AltName: Full=Sphingomyelin phosphodiesterase D 3;
DE Short=SMD 3;
DE Short=Smase D 3;
DE Short=Sphingomyelinase D 3;
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, AND CATALYTIC ACTIVITY.
RC TISSUE=Venom gland;
RX PubMed=16581177; DOI=10.1016/j.biochi.2006.02.008;
RA da Silveira R.B., Pigozzo R.B., Chaim O.M., Appel M.H., Dreyfuss J.L.,
RA Toma L., Mangili O.C., Gremski W., Dietrich C.P., Nader H.B., Veiga S.S.;
RT "Molecular cloning and functional characterization of two isoforms of
RT dermonecrotic toxin from Loxosceles intermedia (Brown spider) venom
RT gland.";
RL Biochimie 88:1241-1253(2006).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Venom gland;
RX PubMed=17825864; DOI=10.1016/j.toxicon.2007.07.001;
RA Kalapothakis E., Chatzaki M., Goncalves-Dornelas H., de Castro C.S.,
RA Silvestre F.G., Laborne F.V., de Moura J.F., Veiga S.S.,
RA Chavez-Olortegui C., Granier C., Barbaro K.C.;
RT "The Loxtox protein family in Loxosceles intermedia (Mello-Leitao) venom.";
RL Toxicon 50:938-946(2007).
RN [3]
RP IMPORTANT SITES FOR ACTIVITY ON SPHINGOMYELIN.
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).
RN [4]
RP FUNCTION, AND BIOASSAY.
RX PubMed=17900646; DOI=10.1016/j.toxicon.2007.08.001;
RA Ribeiro R.O., Chaim O.M., da Silveira R.B., Gremski L.H., Sade Y.B.,
RA Paludo K.S., Senff-Ribeiro A., de Moura J., Chavez-Olortegui C.,
RA Gremski W., Nader H.B., Veiga S.S.;
RT "Biological and structural comparison of recombinant phospholipase D toxins
RT from Loxosceles intermedia (brown spider) venom.";
RL Toxicon 50:1162-1174(2007).
RN [5]
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) with low activity (PubMed:16581177). 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). Induces
CC inflammatory response but no or very weak hemolysis, dermonecrosis,
CC vascular permeability, edema, and cytotoxicity against renal epithelial
CC cells (PubMed:16581177, PubMed:17900646, PubMed:21590705). Causes
CC swelling and erythema (PubMed:16581177). In vivo, is not lethal to mice
CC when intraperitoneally injected (PubMed:17900646).
CC {ECO:0000250|UniProtKB:A0A0D4WTV1, ECO:0000269|PubMed:16581177,
CC ECO:0000269|PubMed:17900646, 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:16581177};
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:16581177}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000305|PubMed:16581177}.
CC -!- SIMILARITY: Belongs to the arthropod phospholipase D family. Class II
CC subfamily. Class IIb 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; DQ267927; ABB71184.1; -; mRNA.
DR EMBL; DQ388596; ABD48088.1; -; mRNA.
DR EMBL; EF535255; ABU43334.1; -; mRNA.
DR AlphaFoldDB; Q2XQ09; -.
DR SMR; Q2XQ09; -.
DR ArachnoServer; AS000143; Sphingomyelinase D (LiSicTox-betaIA1i).
DR BRENDA; 3.1.4.4; 8287.
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: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 Disulfide bond; Lipid degradation; Lipid metabolism; Lyase; Magnesium;
KW Metal-binding; Secreted; Signal; Zymogen.
FT SIGNAL 1..21
FT /evidence="ECO:0000255"
FT PROPEP 22..26
FT /evidence="ECO:0000250"
FT /id="PRO_0000262457"
FT CHAIN 27..304
FT /note="Dermonecrotic toxin LiSicTox-betaIA1i"
FT /id="PRO_0000262458"
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 SITE 122
FT /note="May prevent sphingomyelin recognition"
FT /evidence="ECO:0000305|PubMed:16480957"
FT SITE 161
FT /note="May prevent sphingomyelin recognition"
FT /evidence="ECO:0000305|PubMed:16480957"
FT DISULFID 78..84
FT /evidence="ECO:0000250|UniProtKB:P0CE80"
FT DISULFID 80..223
FT /evidence="ECO:0000250|UniProtKB:P0CE80"
FT CONFLICT 10
FT /note="I -> T (in Ref. 2; ABD48088/ABU43334)"
FT /evidence="ECO:0000305"
FT CONFLICT 29..31
FT /note="SRK -> KRR (in Ref. 2)"
FT /evidence="ECO:0000305"
FT CONFLICT 35..37
FT /note="DIA -> NMG (in Ref. 2)"
FT /evidence="ECO:0000305"
FT CONFLICT 42..52
FT /note="DLGLVDEYLGD -> AIEQIDEFVNL (in Ref. 2)"
FT /evidence="ECO:0000305"
FT CONFLICT 56..57
FT /note="GL -> NI (in Ref. 2)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 304 AA; 34314 MW; 6ABD94B3BA18815B CRC64;
MLLPAVISFI VYAVFLQEAN GHAAERADSR KPIWDIAHMV NDLGLVDEYL GDGANGLELD
VAFTADGTAD KMYHGVPCDC FRSCTRTEGF TKYMDYIRQL TTPGNSKFKS QLILLIMDLK
LNGIEPNVAY AAGKSVAEKL LSGYWQNGKS GARAYIVLSL ETITRPNFIS GFRDAIKASG
HEELFEKIGW DFSGNEDLGE IRRVYQKYGI EDHIWQGDGI TNCLPRGDYR LTEAMKKKND
PNYKYTLKVY TWSIDKESSI RNALRLGVDA VMTNYPARVK SILRESEFSG THRMATYDDN
PWQK
