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Ta3a

From Wikipedia, the free encyclopedia
Delta-myrmicitoxin-Ta3a
Ta3a structure prediction from AlphaFold
Identifiers
OrganismTetramorium africanum
Symbol?
UniProtP0DX61
Search for
StructuresSwiss-model
DomainsInterPro
Ta3a
Identifiers
3D model (JSmol)
  • InChI=1S/C159H248N36O38/c1-26-89(20)129(155(229)175-105(55-57-128(204)205)138(212)173-103(43-35-36-58-160)137(211)186-118(75-126(164)202)149(223)184-116(72-98-48-52-101(199)53-49-98)151(225)192-130(90(21)27-2)156(230)176-106(132(165)206)74-125(163)201)191-150(224)115(71-97-46-50-100(198)51-47-97)183-148(222)117(73-99-76-166-80-168-99)185-139(213)104(54-56-124(162)200)174-142(216)108(63-83(8)9)177-134(208)93(24)170-153(227)122-44-38-60-195(122)159(233)119(68-88(18)19)188-152(226)121(79-197)190-147(221)114(70-96-41-33-30-34-42-96)182-141(215)107(62-82(6)7)172-127(203)77-167-136(210)120(78-196)189-146(220)112(67-87(16)17)181-145(219)111(66-86(14)15)180-144(218)110(65-85(12)13)179-143(217)109(64-84(10)11)178-133(207)92(23)169-140(214)113(69-95-39-31-29-32-40-95)187-157(231)131(91(22)28-3)193-154(228)123-45-37-59-194(123)158(232)94(25)171-135(209)102(161)61-81(4)5/h29-34,39-42,46-53,76,80-94,102-123,129-131,196-199H,26-28,35-38,43-45,54-75,77-79,160-161H2,1-25H3,(H2,162,200)(H2,163,201)(H2,164,202)(H2,165,206)(H,166,168)(H,167,210)(H,169,214)(H,170,227)(H,171,209)(H,172,203)(H,173,212)(H,174,216)(H,175,229)(H,176,230)(H,177,208)(H,178,207)(H,179,217)(H,180,218)(H,181,219)(H,182,215)(H,183,222)(H,184,223)(H,185,213)(H,186,211)(H,187,231)(H,188,226)(H,189,220)(H,190,221)(H,191,224)(H,192,225)(H,193,228)(H,204,205)/t89-,90-,91-,92-,93-,94-,102-,103-,104-,105-,106-,107-,108-,109-,110-,111-,112-,113-,114-,115-,116-,117-,118-,119-,120-,121-,122-,123-,129-,130-,131-/m0/s1
    Key: IAQFHRWWIJXKQC-SWRHZYTASA-N
  • N[C@@]([H])(CC(C)C)C(=O)N[C@@]([H])(C)C(=O)N1[C@@]([H])(CCC1)C(=O)N[C@@]([H])([C@]([H])(CC)C)C(=O)N[C@@]([H])(Cc1ccccc1)C(=O)N[C@@]([H])(C)C(=O)N[C@@]([H])(CC(C)C)C(=O)N[C@@]([H])(CC(C)C)C(=O)N[C@@]([H])(CC(C)C)C(=O)N[C@@]([H])(CC(C)C)C(=O)N[C@@]([H])(CO)C(=O)NCC(=O)N[C@@]([H])(CC(C)C)C(=O)N[C@@]([H])(Cc1ccccc1)C(=O)N[C@@]([H])(CO)C(=O)N[C@@]([H])(CC(C)C)C(=O)N1[C@@]([H])(CCC1)C(=O)N[C@@]([H])(C)C(=O)N[C@@]([H])(CC(C)C)C(=O)N[C@@]([H])(CCC(=O)N)C(=O)N[C@@]([H])(CC1=CN=C-N1)C(=O)N[C@@]([H])(Cc1ccc(O)cc1)C(=O)N[C@@]([H])([C@]([H])(CC)C)C(=O)N[C@@]([H])(CCC(=O)O)C(=O)N[C@@]([H])(CCCCN)C(=O)N[C@@]([H])(CC(=O)N)C(=O)N[C@@]([H])(Cc1ccc(O)cc1)C(=O)N[C@@]([H])([C@]([H])(CC)C)C(=O)N[C@@]([H])(CC(=O)N)C(=O)N
Properties
C159H248N36O38
Molar mass 3271.947 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Ta3a (Delta-myrmicitoxin-Ta3a) is a vertebrate-selective neurotoxin found in the venom of the African ant species Tetramorium africanum. It is known to cause intense, long-lasting pain by targeting voltage-gated sodium channels in peripheral sensory neurons. Ta3a strongly reduces sodium channel inactivation, leading to heightened neuronal excitability.

Chemistry

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Ta3a belongs to the aculeatoxin family of peptides, found in the venom of Hymenoptera.[1] It is a 29-residue peptide, which is predicted to have an alpha-helical structure (amino acid sequence: LAPIFALLLLSGLFSLPALQHYIEKNYIN).[1] [2] Ta3a is similar to poneratoxin, a voltage-gated sodium channel toxin found in the ant species Paraponera clavata, as well as to other uncharacterised peptides from various other ant species.[1]

Target

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Ta3a targets voltage-gated sodium channels such as Nav1.6, Nav1.7 and Nav1.8, which are involved in peripheral pain signaling.[1][3] The half-maximal effective concentration (EC50) of Ta3a for the human Nav1.7 channel is 30 ± 9 nM.[1] Nav1.6 is similarly sensitive to Ta3a with an EC50 of 25 ± 2 nM, while Nav1.8 is less sensitive with an EC50 of 331 ± 58 nM.[1]

Mode of action

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Ant venom Nav toxins are distinct from other Nav modulators, but their effects more closely resemble those caused by small hydrophobic alkaloids. These peptides bind to the S2 voltage-sensing domain of Nav channels in their "activated" conformation, thereby maintaining channel activity. Ta3a exerts a significant regulatory effect on voltage-gated sodium channels, and its interaction with the Nav1.7 subtype was the one studied in more detail. Ta3a prolongs the duration that the channels remains active and increases the likelihood of the channels being open. Additionally, Ta3a shifts the activation of Nav1.7 to more negative (hyperpolarized) potentials, allowing Nav1.7 channels to remain active for extended periods even in the absence of strong depolarising stimuli. These prolonged, non-inactivating currents cause significant changes in the cell's membrane potential, due to the continuous sodium influx. Such prolonged sodium channel activation also permits sodium currents to persist at negative membrane potentials.

Toxicity

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The hallmark of Ta3a toxicity is acute pain, which is the most immediate and prominent symptom of Ta3a exposure.[2] This is due to the excessive activation of the Nav channels, which play a crucial role in pain transmission by enhancing the propagation of nerve signals, particularly pain-related signals.

Treatment

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Since Ta3a primarily exerts its effects by overactivating the Nav channels, sodium channel blockers represent a potential therapeutic approach. For instance, tetrodotoxin (TTX), a sodium channel blocker, has been shown to effectively inhibit the persistent currents induced by Ta3a in experimental settings.[2] However, no studies have yet been conducted on specific treatment methods for Ta3a poisoning.

References

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  1. ^ a b c d e f Robinson, Samuel D.; Deuis, Jennifer R.; Touchard, Axel; Keramidas, Angelo; Mueller, Alexander; Schroeder, Christina I.; Barassé, Valentine; Walker, Andrew A.; Brinkwirth, Nina; Jami, Sina; Bonnafé, Elsa; Treilhou, Michel; Undheim, Eivind A. B.; Schmidt, Justin O.; King, Glenn F.; Vetter, Irina (23 May 2023). "Ant venoms contain vertebrate-selective pain-causing sodium channel toxins". Nature Communications. 14 (1): 2977. Bibcode:2023NatCo..14.2977R. doi:10.1038/s41467-023-38839-1. PMC 10206162. PMID 37221205.
  2. ^ a b c Thapa, Ashvriya; Beh, Jia Hao; Robinson, Samuel D.; Deuis, Jennifer R.; Tran, Hue; Vetter, Irina; Keramidas, Angelo (October 2024). "A venom peptide-induced NaV channel modulation mechanism involving the interplay between fixed channel charges and ionic gradients". Journal of Biological Chemistry. 300 (10): 107757. Bibcode:2024JBiCh.300j7757T. doi:10.1016/j.jbc.2024.107757. PMC 11470524. PMID 39260690.
  3. ^ Bennett, David L.; Clark, Alex J.; Huang, Jianying; Waxman, Stephen G.; Dib-Hajj, Sulayman D. (1 April 2019). "The Role of Voltage-Gated Sodium Channels in Pain Signaling". Physiological Reviews. 99 (2): 1079–1151. doi:10.1152/physrev.00052.2017. PMID 30672368.