TX36A_PHONI
ID TX36A_PHONI Reviewed; 82 AA.
AC P29425; Q95UF2;
DT 01-APR-1993, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2002, sequence version 2.
DT 25-MAY-2022, entry version 69.
DE RecName: Full=Delta-ctenitoxin-Pn2a {ECO:0000305};
DE Short=Delta-CNTX-Pn2a {ECO:0000305};
DE AltName: Full=Delta-CNTX-Pn1c {ECO:0000303|PubMed:29342943};
DE AltName: Full=Neurotoxin Tx2-6 {ECO:0000303|PubMed:12123835, ECO:0000303|PubMed:1397265, ECO:0000303|PubMed:16278100};
DE Short=PnTx2-6 {ECO:0000303|PubMed:16278100};
DE Flags: Precursor;
OS Phoneutria nigriventer (Brazilian armed spider) (Ctenus nigriventer).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida; Araneae;
OC Araneomorphae; Entelegynae; Lycosoidea; Ctenidae; Phoneutria.
OX NCBI_TaxID=6918;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Venom gland;
RX PubMed=12123835; DOI=10.1016/s0014-5793(02)02988-5;
RA Matavel A., Cruz J.S., Penaforte C.L., Araujo D.A.M., Kalapothakis E.,
RA Prado V.F., Diniz C.R., Cordeiro M.N., Beirao P.S.L.;
RT "Electrophysiological characterization and molecular identification of the
RT Phoneutria nigriventer peptide toxin PnTx2-6.";
RL FEBS Lett. 523:219-223(2002).
RN [2]
RP PROTEIN SEQUENCE OF 35-82, FUNCTION, SUBCELLULAR LOCATION, BIOASSAY, AND
RP MASS SPECTROMETRY.
RC TISSUE=Venom;
RX PubMed=1397265; DOI=10.1016/0014-5793(92)81318-g;
RA Cordeiro M.N., Diniz C.R., Valentim A.D.C., von Eickstedt V.R.D.,
RA Gilroy J., Richardson M.;
RT "The purification and amino acid sequences of four Tx2 neurotoxins from the
RT venom of the Brazilian 'armed' spider Phoneutria nigriventer (Keys).";
RL FEBS Lett. 310:153-156(1992).
RN [3]
RP PROTEIN SEQUENCE OF 35-82, SUBCELLULAR LOCATION, MASS SPECTROMETRY, AND
RP BIOASSAY.
RC TISSUE=Venom;
RX PubMed=16278100; DOI=10.1016/j.cbpc.2005.09.010;
RA Richardson M., Pimenta A.M., Bemquerer M.P., Santoro M.M., Beirao P.S.,
RA Lima M.E., Figueiredo S.G., Bloch C. Jr., Vasconcelos E.A., Campos F.A.,
RA Gomes P.C., Cordeiro M.N.;
RT "Comparison of the partial proteomes of the venoms of Brazilian spiders of
RT the genus Phoneutria.";
RL Comp. Biochem. Physiol. 142:173-187(2006).
RN [4]
RP PROTEIN SEQUENCE OF 35-82, FUNCTION, SUBCELLULAR LOCATION, AND MASS
RP SPECTROMETRY.
RC TISSUE=Venom;
RX PubMed=19231838; DOI=10.1021/bi802158p;
RA Matavel A., Fleury C., Oliveira L.C., Molina F., de Lima M.E., Cruz J.S.,
RA Cordeiro M.N., Richardson M., Ramos C.H., Beirao P.S.;
RT "Structure and activity analysis of two spider toxins that alter sodium
RT channel inactivation kinetics.";
RL Biochemistry 48:3078-3088(2009).
RN [5]
RP FUNCTION.
RX PubMed=18397797; DOI=10.1016/j.toxicon.2008.02.010;
RA Nunes K.P., Costa-Goncalves A., Lanza L.F., Cortes S.F., Cordeiro M.N.,
RA Richardson M., Pimenta A.M., Webb R.C., Leite R., De Lima M.E.;
RT "Tx2-6 toxin of the Phoneutria nigriventer spider potentiates rat erectile
RT function.";
RL Toxicon 51:1197-1206(2008).
RN [6]
RP FUNCTION.
RX PubMed=20722794; DOI=10.1111/j.1743-6109.2010.01978.x;
RA Nunes K.P., Cordeiro M.N., Richardson M., Borges M.N., Diniz S.O.,
RA Cardoso V.N., Tostes R., De Lima M.E., Webb R.C., Leite R.;
RT "Nitric oxide-induced vasorelaxation in response to PnTx2-6 toxin from
RT Phoneutria nigriventer spider in rat cavernosal tissue.";
RL J. Sex. Med. 7:3879-3888(2010).
RN [7]
RP FUNCTION.
RX PubMed=22925420; DOI=10.1111/j.1743-6109.2012.02878.x;
RA Nunes K.P., Toque H.A., Borges M.H., Richardson M., Webb R.C.,
RA de Lima M.E.;
RT "Erectile function is improved in aged rats by PnTx2-6, a toxin from
RT Phoneutria nigriventer spider venom.";
RL J. Sex. Med. 9:2574-2581(2012).
RN [8]
RP FUNCTION.
RX PubMed=21975567; DOI=10.1038/ijir.2011.47;
RA Nunes K.P., Wynne B.M., Cordeiro M.N., Borges M.H., Richardson M.,
RA Leite R., DeLima M.E., Webb R.C.;
RT "Increased cavernosal relaxation by Phoneutria nigriventer toxin, PnTx2-6,
RT via activation at NO/cGMP signaling.";
RL Int. J. Impot. Res. 24:69-76(2012).
RN [9]
RP REVIEW (ERECTILE DYSFUNCTION).
RX PubMed=23583324; DOI=10.1016/j.toxicon.2013.03.017;
RA Nunes K.P., Torres F.S., Borges M.H., Matavel A., Pimenta A.M.,
RA De Lima M.E.;
RT "New insights on arthropod toxins that potentiate erectile function.";
RL Toxicon 69:152-159(2013).
RN [10]
RP FUNCTION AS ERECTILE POTENTIATOR, PHARMACEUTICAL (ERECTILE DYSFUNCTION),
RP AND MUTAGENESIS OF 1-MET--CYS-63; 64-ILE--GLY-68 AND CYS-80.
RX PubMed=26119670; DOI=10.1016/j.juro.2015.06.081;
RA Silva C.N., Nunes K.P., Torres F.S., Cassoli J.S., Santos D.M.,
RA Almeida F.M., Matavel A., Cruz J.S., Santos-Miranda A., Nunes A.D.,
RA Castro C.H., Machado de Avila R.A., Chavez-Olortegui C., Lauar S.S.,
RA Felicori L., Resende J.M., Camargos E.R., Borges M.H., Cordeiro M.N.,
RA Peigneur S., Tytgat J., de Lima M.E.;
RT "PnPP-19, a synthetic and nontoxic peptide designed from a Phoneutria
RT nigriventer toxin, potentiates erectile function via NO/cGMP.";
RL J. Urol. 194:1481-1490(2015).
RN [11]
RP PHARMACEUTICAL (PAIN), AND MUTAGENESIS OF 1-MET--CYS-63; 64-ILE--GLY-68 AND
RP CYS-80.
RX PubMed=28031732; DOI=10.1186/s40409-016-0091-6;
RA da Fonseca Pacheco D., Freitas A.C., Pimenta A.M., Duarte I.D.,
RA de Lima M.E.;
RT "A spider derived peptide, PnPP-19, induces central antinociception
RT mediated by opioid and cannabinoid systems.";
RL J. Venom. Anim. Toxins Incl. Trop. Dis. 22:34-34(2016).
RN [12]
RP PHARMACEUTICAL (PAIN), AND MUTAGENESIS OF 1-MET--CYS-63; 64-ILE--GLY-68 AND
RP CYS-80.
RX PubMed=28087360; DOI=10.1016/j.niox.2017.01.004;
RA Freitas A.C., Silva G.C., Pacheco D.F., Pimenta A.M., Lemos V.S.,
RA Duarte I.D., de Lima M.E.;
RT "The synthetic peptide PnPP-19 induces peripheral antinociception via
RT activation of NO/cGMP/K(ATP) pathway: role of eNOS and nNOS.";
RL Nitric Oxide 64:31-38(2017).
RN [13]
RP PHARMACEUTICAL (PAIN), AND MUTAGENESIS OF 1-MET--CYS-63; 64-ILE--GLY-68 AND
RP CYS-80.
RX PubMed=29342943; DOI=10.3390/toxins10010043;
RA Freitas A.C.N., Peigneur S., Macedo F.H.P., Menezes-Filho J.E., Millns P.,
RA Medeiros L.F., Arruda M.A., Cruz J., Holliday N.D., Tytgat J., Hathway G.,
RA de Lima M.E.;
RT "The peptide PnPP-19, a spider toxin derivative, activates mu-opioid
RT receptors and modulates calcium channels.";
RL Toxins 10:1-12(2018).
CC -!- FUNCTION: Toxin that is known to potentiate erectile function
CC (PubMed:18397797). It binds voltage-dependently to sodium channels
CC (Nav), inhibits the inactivation of the activated channels and
CC decreases the peak inward current (PubMed:19231838, PubMed:26119670).
CC The toxin delays inactivation of Nav1.2/SCN2A, Nav1.3/SCN3A,
CC Nav1.4/SCN4A and Nav1.8/SCN10A, slows the inactivation process and
CC decreases the sodium peak amplitude of Nav1.5/SCN5A and Nav1.6/SCN8A
CC (PubMed:26119670). In vivo, it enhances erectile function by inducing
CC the release of nictric oxide (NO): it slows the sodium current, leading
CC to depolarization, which leads to an increase in calcium influx
CC (probably via activation of N-type calcium channels) which in turn
CC activates neuronal NO synthase (nNOS/NOS1), inducing nitric oxide (NO)
CC production (PubMed:20722794, PubMed:21975567). In a final step, NO
CC activates soluble guanylate cyclase (GUCY1A1/GUCY1B1) which in turn
CC increases cGMP formation, resulting in penile erection
CC (PubMed:23583324). It is noteworthy that the toxin does not provoke
CC erection by inhibiting phosphodiesterase type 5 (PDE5A), an enzyme that
CC hydrolysis cGMP (PubMed:23583324). In vivo, it also causes scratching,
CC lacrimation, hypersalivation, sweating and agitation followed by
CC spastic paralysis of the anterior and posterior extremities and death
CC at dose levels of 0.79 mg/mouse (PubMed:1397265, PubMed:16278100). It
CC is insecticidal to the larval and adult forms of the house fly
CC (PubMed:1397265). The toxin also improves cavernosal relaxation in
CC different models where erectile dysfonction is observed, such as
CC deoxycorticosterone-acetate (DOCA)-salt hypertensive rats, mice models
CC for type-1 diabetes, as well as elderly rats (PubMed:18397797,
CC PubMed:21975567, PubMed:22925420). {ECO:0000269|PubMed:1397265,
CC ECO:0000269|PubMed:16278100, ECO:0000269|PubMed:18397797,
CC ECO:0000269|PubMed:19231838, ECO:0000269|PubMed:20722794,
CC ECO:0000269|PubMed:21975567, ECO:0000269|PubMed:22925420,
CC ECO:0000269|PubMed:26119670, ECO:0000305|PubMed:23583324}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:1397265}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000305|PubMed:1397265}.
CC -!- DOMAIN: The presence of a 'disulfide through disulfide knot'
CC structurally defines this protein as a knottin. {ECO:0000305}.
CC -!- MASS SPECTROMETRY: Mass=5291.3; Method=Plasma desorption;
CC Evidence={ECO:0000269|PubMed:1397265};
CC -!- MASS SPECTROMETRY: Mass=5289.0; Method=Unknown;
CC Evidence={ECO:0000269|PubMed:16278100};
CC -!- MASS SPECTROMETRY: Mass=5289.31; Mass_error=0.03; Method=Electrospray;
CC Evidence={ECO:0000269|PubMed:19231838};
CC -!- PHARMACEUTICAL: PnPP-19, a 19 AA-peptide that is N-terminally
CC acetylated and C-terminally amidated, has been suggested to be a
CC promising drug candidate for the treatment of erectile dysfunction
CC (PubMed:26119670). The peptide potentiates erection through an increase
CC in nitric oxide (NO)/cGMP production (PubMed:26119670). It has no
CC apparent toxicity (when tested on brain, heart, lung, liver and kidney)
CC and low immunogenicity in mice (PubMed:26119670). It acts by a
CC different mechanism than the native toxin, since it does not affect
CC sodium channels, has no effect on the rat heart, and is independent of
CC extracellular calcium influx through N-type calcium channels
CC (PubMed:26119670). In addition, it has a long half-life since its
CC potentiating effect is observed 15 minutes after injection and lasts
CC about one hour (PubMed:26119670). {ECO:0000269|PubMed:26119670}.
CC -!- PHARMACEUTICAL: PnPP-19, a 19 AA-peptide that is N-terminally
CC acetylated and C-terminally amidated, has been suggested to be a
CC promising drug candidate for the treatment of pain (PubMed:29342943).
CC The peptide induces both peripheral and central antinociception
CC (PubMed:28031732, PubMed:28087360). This antinociceptive effect
CC involves the activation of opioid and cannabinoid receptors along with
CC the activation of the NO/cGMP/KATP pathway (PubMed:28031732,
CC PubMed:28087360, PubMed:29342943). {ECO:0000269|PubMed:28031732,
CC ECO:0000269|PubMed:28087360, ECO:0000269|PubMed:29342943}.
CC -!- SIMILARITY: Belongs to the neurotoxin 03 (Tx2) family. 06 subfamily.
CC {ECO:0000305}.
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DR EMBL; AY054746; AAL14349.1; -; mRNA.
DR PIR; S29216; S29216.
DR AlphaFoldDB; P29425; -.
DR ArachnoServer; AS000243; delta-ctenitoxin-Pn2a.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0017080; F:sodium channel regulator activity; IEA:UniProtKB-KW.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR InterPro; IPR035285; CNTX.
DR Pfam; PF17492; D_CNTX; 1.
PE 1: Evidence at protein level;
KW Direct protein sequencing; Disulfide bond; Ion channel impairing toxin;
KW Knottin; Neurotoxin; Pharmaceutical; Secreted; Signal; Toxin;
KW Voltage-gated sodium channel impairing toxin.
FT SIGNAL 1..17
FT /evidence="ECO:0000255"
FT PROPEP 18..34
FT /evidence="ECO:0000269|PubMed:1397265,
FT ECO:0000269|PubMed:16278100, ECO:0000269|PubMed:19231838"
FT /id="PRO_0000035498"
FT CHAIN 35..82
FT /note="Delta-ctenitoxin-Pn2a"
FT /evidence="ECO:0000269|PubMed:1397265"
FT /id="PRO_0000035499"
FT DISULFID 37..51
FT /evidence="ECO:0000305"
FT DISULFID 44..57
FT /evidence="ECO:0000305"
FT DISULFID 48..80
FT /evidence="ECO:0000305"
FT DISULFID 50..65
FT /evidence="ECO:0000305"
FT DISULFID 59..63
FT /evidence="ECO:0000305"
FT MUTAGEN 1..63
FT /note="Missing: In PnPP-19 (acetylated and amidated); loss
FT of activity on sodium channels."
FT /evidence="ECO:0000269|PubMed:26119670"
FT MUTAGEN 64..68
FT /note="ICRQG->GERRQ: In PnPP-19 (acetylated and amidated);
FT loss of activity on sodium channels."
FT /evidence="ECO:0000269|PubMed:26119670"
FT MUTAGEN 80
FT /note="C->S: In PnPP-19 (acetylated and amidated); loss of
FT activity on sodium channels."
FT /evidence="ECO:0000269|PubMed:26119670"
SQ SEQUENCE 82 AA; 9031 MW; F4CEA5E7B8D53E59 CRC64;
MKVAILFLSI LVLAVASESI EESRDDFAVE ELGRATCAGQ DQPCKETCDC CGERGECVCG
GPCICRQGYF WIAWYKLANC KK
