Mambalgins

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Mambalgin-1
Mambalgin.png
The structure of mambalgin-1, showing the three "finger" loops in red (loop I), blue (loop II), and green (loop III), with core disulfide bonds highlighted in yellow. [1]
Identifiers
Organism Dendroaspis polylepis polylepis
Symbol?
PDB 5DU1
UniProt P0DKR6
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Structures Swiss-model
Domains InterPro
Mambalgin-2
Identifiers
Organism Dendroaspis polylepis polylepis
Symbol?
PDB 2MFA
UniProt P0DKS3
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Structures Swiss-model
Domains InterPro
Mambalgin-3
Identifiers
Organism Dendroaspis angusticeps
Symbol?
UniProt C0HJB0
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Structures Swiss-model
Domains InterPro

Mambalgins are peptides found in the venom of the black mamba (Dendroaspis polylepis polylepis), an elapid snake. Mambalgins are members of the three-finger toxin (3FTx) protein family and have the characteristic three-finger protein fold. First reported by French researchers in 2012, mambalgins are unusual members of the 3FTx family in that they have the in vivo effect of causing analgesia without apparent toxicity. Their mechanism of action is potent inhibition of acid-sensing ion channels. [2] [3]

Contents

Structure

Mambalgins known to date consist of 57 amino acid residues and fold into a characteristic three-finger toxin (3FTx) structure. Two isoforms were originally described, called mambalgin-1 and mambalgin-2, which differ by a single amino acid residue. [2] A third variant which differs by a single residue at another site, has subsequently been reported from venom profiling of the Eastern green mamba (Dendroaspis augusticeps). [4] [5]

The X-ray structure of mambalgin-1 has been solved and consists of a three-finger protein fold with the typical three beta sheet-containing "finger" loops emanating from a central core stabilized by disulphide bonds; however, the structure differs from most 3FTx proteins in having an elongated second loop and shortened first and third loops. [1] Mambalgins have relatively low sequence similarity to other 3FTx proteins and are most closely related to the 3FTx subclass known as the non-conventional or "weak" toxins. [2] [4] [1]

Function

Mambalgins are potent inhibitors of acid-sensing ion channels (ASICs), which are multimeric membrane proteins that respond to low pH and whose activation is thought to be involved in perception of pain. Mambalgins have been shown to interact specifically with ASIC subtypes present in the central nervous system (homomeric ASIC1a and heteromeric ASIC1a/ASIC2a or ASIC1a/ASIC2b), as well as those found in sensory neurons (ASIC1b and ASIC1a/ASIC1b). They have no effect on other ASICs or on other types of ion channel proteins. [2] These interactions are likely mediated in part by mambalgins' positive electrostatic potential facilitating binding to negatively charged ASICs. [2] [6] Mambalgins are believed to trap ASICs in a closed conformation. [4] [6] [1]

In tests performed on laboratory mice, mambalgins have the in vivo effect of analgesia without the toxic effects seen with most 3FTx proteins, and in particular, without the clinical manifestations associated with inhibition of nicotinic acetylcholine receptors, the targets of most 3FTx proteins including mambalgins' closest relatives. Furthermore, the analgesic effects of mambalgins does not confer side effects such as respiratory depression and drug tolerance, both associated with opioid analgesics. [2]

Summary of the different pathways that mambalgins and PcTx1 follow (non-opioid and opioid pathways) Esquema mambalgina.jpg
Summary of the different pathways that mambalgins and PcTx1 follow (non-opioid and opioid pathways)

In addition to mambalgins, at least three other peptides from three different taxa have been identified as interacting with ASICs: PcTx1, from the South American tarantula Psalmopoeus cambridgei ; APETx2, from the sea anemone Anthopleura elegantissima ; and MitTx, a heterodimer from the snake Micrurus tener tener . PcTx1 and APETx2, like mambalgins, are ASIC inhibitors, albeit with different subtype specificities; MitTx is an activator associated with causing pain in vivo. The four proteins have no detectable sequence similarity. [2] [4] The natural function of ASIC-inhibiting analgesic peptides is unclear, as all are produced by predator animals yet have no known toxic effects on the corresponding prey. [4]

Applications

In laboratory experiments using laboratory mice, mambalgins appear to exert clinically significant analgesic effects without the side effects typically associated with opioid analgesics. Although this property has attracted interest as a basis for development of pharmaceutical drugs, [7] [8] mambalgins or their derivatives are not in clinical use. [9]

Related Research Articles

<span class="mw-page-title-main">Mamba</span> Genus of venomous snakes

Mambas are fast-moving, highly venomous snakes of the genus Dendroaspis in the family Elapidae. Four extant species are recognised currently; three of those four species are essentially arboreal and green in colour, whereas the black mamba, Dendroaspis polylepis, is largely terrestrial and generally brown or grey in colour. All are native to various regions in sub-Saharan Africa and all are feared throughout their ranges, especially the black mamba. In Africa there are many legends and stories about mambas.

<span class="mw-page-title-main">Snake venom</span> Highly modified saliva containing zootoxins

Snake venom is a highly toxic saliva containing zootoxins that facilitates in the immobilization and digestion of prey. This also provides defense against threats. Snake venom is injected by unique fangs during a bite, whereas some species are also able to spit venom.

<span class="mw-page-title-main">Black mamba</span> Species of venomous snake

The black mamba is a species of highly venomous snake belonging to the family Elapidae. It is native to parts of sub-Saharan Africa. First formally described by Albert Günther in 1864, it is the second-longest venomous snake after the king cobra; mature specimens generally exceed 2 m and commonly grow to 3 m (9.8 ft). Specimens of 4.3 to 4.5 m have been reported. Its skin colour varies from grey to dark brown. Juvenile black mambas tend to be paler than adults and darken with age. Despite the common name, the skin of a black mamba is not black, but rather describes the inside of its mouth, which it displays when feeling threatened.

<span class="mw-page-title-main">Dendrotoxin</span> Chemical compound

Dendrotoxins are a class of presynaptic neurotoxins produced by mamba snakes (Dendroaspis) that block particular subtypes of voltage-gated potassium channels in neurons, thereby enhancing the release of acetylcholine at neuromuscular junctions. Because of their high potency and selectivity for potassium channels, dendrotoxins have proven to be extremely useful as pharmacological tools for studying the structure and function of these ion channel proteins.

<span class="mw-page-title-main">Calciseptine</span> Neurotoxin

Calciseptine (CaS) is a natural neurotoxin isolated from the black mamba Dendroaspis p. polylepis venom. This toxin consists of 60 amino acids with four disulfide bonds. Calciseptine specifically blocks L-type calcium channels, but not other voltage-dependent Ca2+ channels such as N-type and T-type channels.

<span class="mw-page-title-main">Psalmotoxin</span>

Psalmotoxin (PcTx1) is a spider toxin from the venom of the Trinidad tarantula Psalmopoeus cambridgei. It selectively blocks Acid Sensing Ion Channel 1-a (ASIC1a), which is a proton-gated sodium channel.

<span class="mw-page-title-main">Phrixotoxin</span>

Phrixotoxins are peptide toxins derived from the venom of the Chilean copper tarantula Phrixotrichus auratus, also named Paraphysa scrofa. Phrixotoxin-1 and -2 block A-type voltage-gated potassium channels; phrixotoxin-3 blocks voltage-gated sodium channels. Similar toxins are found in other species, for instance the Chilean rose tarantula.

<span class="mw-page-title-main">Acid-sensing ion channel</span> Class of transport proteins

Acid-sensing ion channels (ASICs) are neuronal voltage-insensitive sodium channels activated by extracellular protons permeable to Na+. ASIC1 also shows low Ca2+ permeability. ASIC proteins are a subfamily of the ENaC/Deg superfamily of ion channels. These genes have splice variants that encode for several isoforms that are marked by a suffix. In mammals, acid-sensing ion channels (ASIC) are encoded by five genes that produce ASIC protein subunits: ASIC1, ASIC2, ASIC3, ASIC4, and ASIC5. Three of these protein subunits assemble to form the ASIC, which can combine into both homotrimeric and heterotrimeric channels typically found in both the central nervous system and peripheral nervous system. However, the most common ASICs are ASIC1a and ASIC1a/2a and ASIC3. ASIC2b is non-functional on its own but modulates channel activity when participating in heteromultimers and ASIC4 has no known function. On a broad scale, ASICs are potential drug targets due to their involvement in pathological states such as retinal damage, seizures, and ischemic brain injury.

α-Neurotoxin Group of neurotoxic peptides found in the venom of snakes

α-Neurotoxins are a group of neurotoxic peptides found in the venom of snakes in the families Elapidae and Hydrophiidae. They can cause paralysis, respiratory failure, and death. Members of the three-finger toxin protein family, they are antagonists of post-synaptic nicotinic acetylcholine receptors (nAChRs) in the neuromuscular synapse that bind competitively and irreversibly, preventing synaptic acetylcholine (ACh) from opening the ion channel. Over 100 α-neurotoxins have been identified and sequenced.

<span class="mw-page-title-main">Muscarinic toxin 1</span>

Muscarinic toxin 1 (MT1) belongs to the family of small peptides of 65 amino acid residues derived from the venom of African mamba snakes, with dual specificity for muscarinic receptor subtypes M1 and M4. Muscarinic toxins like the nicotinic toxins have the three-finger fold structure, characteristic of the large superfamily of toxins that act at cholinergic synapses.

Tamulotoxin is a venomous neurotoxin from the Indian Red Scorpion.

<span class="mw-page-title-main">Fasciculin</span> Class of toxins found in some snake venoms

Fasciculins are a class of toxic proteins found in certain snake venoms, notably some species of mamba. Investigations have revealed distinct forms in some green mamba venoms, in particular FAS1 and FAS2 Fasciculins are so called because they cause intense fasciculation in muscle fascicles of susceptible organisms, such as the preferred prey of the snakes. This effect helps to incapacitate the muscles, either killing the prey, or paralysing it so that the snake can swallow it.

HsTx1 is a toxin from the venom of the scorpion Heterometrus spinifer. HsTx1 is a very potent inhibitor of the rat Kv1.3 voltage-gated potassium channel.

<span class="mw-page-title-main">Three-finger toxin</span> Toxin protein

Three-finger toxins are a protein superfamily of small toxin proteins found in the venom of snakes. Three-finger toxins are in turn members of a larger superfamily of three-finger protein domains which includes non-toxic proteins that share a similar protein fold. The group is named for its common structure consisting of three beta strand loops connected to a central core containing four conserved disulfide bonds. The 3FP protein domain has no enzymatic activity and is typically between 60-74 amino acid residues long. Despite their conserved structure, three-finger toxin proteins have a wide range of pharmacological effects. Most members of the family are neurotoxins that act on cholinergic intercellular signaling; the alpha-neurotoxin family interacts with muscle nicotinic acetylcholine receptors (nAChRs), the kappa-bungarotoxin family with neuronal nAChRs, and muscarinic toxins with muscarinic acetylcholine receptors (mAChRs).

Dendroaspis natriuretic peptide (DNP) is a 38-residue peptide and a member of natriuretic peptide family. It is structurally similar to the atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) and possesses biologic properties similar to these natriuretic peptides.

μ-THTX-Cl6a, also known as Cl6a, is a 33-residue peptide toxin extracted from the venom of the spider Cyriopagopus longipes. The toxin acts as an inhibitor of the tetrodotoxin-sensitive (TTX-S) voltage-gated sodium channel (NaV1.7), thereby causing sustained reduction of NaV1.7 currents.

<span class="mw-page-title-main">GiTx1</span>

GiTx1 (β/κ-theraphotoxin-Gi1a) is a peptide toxin present in the venom of Grammostola iheringi. It reduces both inward and outward currents by blocking voltage-gated sodium and potassium channels, respectively.

Protoxin-I, also known as ProTx-I, or Beta/omega-theraphotoxin-Tp1a, is a 35-amino-acid peptide neurotoxin extracted from the venom of the tarantula Thrixopelma pruriens. Protoxin-I belongs to the inhibitory cystine knot (ICK) family of peptide toxins, which have been known to potently inhibit voltage-gated ion channels. Protoxin-I selectively blocks low voltage threshold T-type calcium channels, voltage gated sodium channels and the nociceptor cation channel TRPA1. Due to its unique ability to bind to TRPA1, Protoxin-I has been implicated as a valuable pharmacological reagent with potential applications in clinical contexts with regards to pain and inflammation

AsKC11 is a toxin found in the venom of the sea anemone, Anemonia sulcata. This toxin is part of the Kunitz peptide family and has been shown to be an activator of G protein-coupled inwardly-rectifying potassium (GIRK) channels 1/2, involved in the regulation of cellular excitability. 

Phlotoxin (phltx1) is a neurotoxin from the venom of the tarantula Phlogiellus that targets mostly voltage-sensitive sodium channels and mainly Nav1.7. The only non-sodium voltage-sensitive channel that is inhibited by Phlotoxin is the Kv3.4. Nav1.4 and Nav1.6 seem to be Phlotoxin-1 sensitive to some extent as well.

References

  1. 1 2 3 4 Mourier G, Salinas M, Kessler P, Stura EA, Leblanc M, Tepshi L, et al. (February 2016). "Mambalgin-1 Pain-relieving Peptide, Stepwise Solid-phase Synthesis, Crystal Structure, and Functional Domain for Acid-sensing Ion Channel 1a Inhibition". The Journal of Biological Chemistry. 291 (6): 2616–2629. doi: 10.1074/jbc.m115.702373 . PMC   4742732 . PMID   26680001.
  2. 1 2 3 4 5 6 7 Diochot S, Baron A, Salinas M, Douguet D, Scarzello S, Dabert-Gay AS, et al. (October 2012). "Black mamba venom peptides target acid-sensing ion channels to abolish pain" (PDF). Nature. 490 (7421): 552–555. Bibcode:2012Natur.490..552D. doi:10.1038/nature11494. PMID   23034652. S2CID   4337253.
  3. ↑ Oliveira AL, Viegas MF, da Silva SL, Soares AM, Ramos MJ, Fernandes PA (2022-06-10). "The chemistry of snake venom and its medicinal potential". Nature Reviews. Chemistry. 6 (7): 451–469. doi:10.1038/s41570-022-00393-7. PMC   9185726 . PMID   35702592.
  4. 1 2 3 4 5 Baron A, Diochot S, Salinas M, Deval E, Noël J, Lingueglia E (December 2013). "Venom toxins in the exploration of molecular, physiological and pathophysiological functions of acid-sensing ion channels" (PDF). Toxicon. Special Issue: Toxins: from Threats to Benefits. 75: 187–204. doi:10.1016/j.toxicon.2013.04.008. PMID   23624383.
  5. ↑ Lauridsen LP, Laustsen AH, Lomonte B, Gutiérrez JM (March 2016). "Toxicovenomics and antivenom profiling of the Eastern green mamba snake (Dendroaspis angusticeps)" (PDF). Journal of Proteomics. 136: 248–261. doi:10.1016/j.jprot.2016.02.003. PMID   26877184.
  6. 1 2 Salinas M, Besson T, Delettre Q, Diochot S, Boulakirba S, Douguet D, Lingueglia E (May 2014). "Binding site and inhibitory mechanism of the mambalgin-2 pain-relieving peptide on acid-sensing ion channel 1a". The Journal of Biological Chemistry. 289 (19): 13363–13373. doi: 10.1074/jbc.m114.561076 . PMC   4036345 . PMID   24695733.
  7. ↑ Yong E (2012-10-03). "Painkilling chemicals with no side effects found in black mamba venom - Not Exactly Rocket Science". Not Exactly Rocket Science. Retrieved 2017-07-05.
  8. ↑ Gallagher J (2012-10-03). "Black mamba venom is 'better painkiller' than morphine". BBC News. Retrieved 2017-07-05.
  9. ↑ Netirojjanakul C, Miranda LP (June 2017). "Progress and challenges in the optimization of toxin peptides for development as pain therapeutics". Current Opinion in Chemical Biology. Next Generation Therapeutics. 38: 70–79. doi:10.1016/j.cbpa.2017.03.004. PMID   28376346.
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