Maurotoxin (abbreviated MTX) is a

peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...

toxin A toxin is a naturally occurring poison produced by metabolic activities of living cells or organisms. They occur especially as proteins, often conjugated. The term was first used by organic chemist Ludwig Brieger (1849–1919), derived ...

from the venom of the Tunisian chactoid

scorpion Scorpions are predatory arachnids of the Order (biology), order Scorpiones. They have eight legs and are easily recognized by a pair of Chela (organ), grasping pincers and a narrow, segmented tail, often carried in a characteristic forward cur ...

'' Scorpio maurus palmatus'', from which it was first isolated and from which the chemical gets its name. It acts by blocking several types of

voltage-gated potassium channel Voltage-gated potassium channels (VGKCs) are potassium channel, transmembrane channels specific for potassium and Voltage-gated ion channel, sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a ...

Chemistry

Maurotoxin is a peptide of 34

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

s (sequence VSCTGSKDCYAPCRKQTGCPNAKCINKSCKCYGC) cross-linked by four disulfide bridges (Cys3-Cys24, Cys9-Cys29, Cys13-Cys19, Cys31-Cys34), with an atypical pattern of organization compared with other scorpion toxins; this unusual pairing of

cysteine Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...

residues may be mediated by the presence of adjacent

proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the p ...

s. The peptide contains an

alpha helix An alpha helix (or α-helix) is a sequence of amino acids in a protein that are twisted into a coil (a helix). The alpha helix is the most common structural arrangement in the Protein secondary structure, secondary structure of proteins. It is al ...

linked by two disulfide bridges to a two-stranded antiparallel

beta sheet The beta sheet (β-sheet, also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a gene ...

Target

Scorpion toxins constitute the largest group of

potassium Potassium is a chemical element; it has Symbol (chemistry), symbol K (from Neo-Latin ) and atomic number19. It is a silvery white metal that is soft enough to easily cut with a knife. Potassium metal reacts rapidly with atmospheric oxygen to ...

(K⁺) channel blockers and are useful pharmacological probes to investigate ion channels and their functions. Maurotoxin (MTX) blocks various K⁺ -channels: * Apamin-sensitive small conductance Ca²⁺ - activated K⁺ channels (SK) * Intermediate conductance Ca²⁺ - activated K⁺ channels (IK) * Several types of

s (Kv1.1, Kv1.2, Kv1.3 and shaker B) The structural and pharmacological features of MTX suggest that MTX belongs to a new class of natural K⁺ channel blockers structurally intermediate between the Na⁺ (60–70 residues and four disulfide bridges) and K⁺ channel scorpion toxin families (less than 40 residues and three disulfide bridges). The intermediate conductance Ca²⁺-activated K⁺ (IK) channel is present in peripheral tissues, including secretory epithelia and

blood cell A blood cell (also called a hematopoietic cell, hemocyte, or hematocyte) is a cell produced through hematopoiesis and found mainly in the blood. Major types of blood cells include red blood cells (erythrocytes), white blood cells (leukocytes), ...

s. An important physiological role of the IK channel is to help maintain large electrical gradients for the sustained transport of ions such as Ca²⁺ that controls

T lymphocyte T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell ...

(T cell) proliferation. Thus IK blockers could be potential

immunosuppressant Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent the activity of the immune system. Classification Immunosuppressive drugs can be classified ...

s for the treatment of autoimmune disorders (such as rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis).

Mode of action

MTX occludes the pore region of various potassium channels (Kv1.2, IKCa1, Kv1.3) by establishing strong interactions between its

lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. Lysine contains an α-amino group (which is in the protonated form when the lysine is dissolved in water at physiological pH), an α-carboxylic acid group ( ...

-23 residue and the

glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid. Glycine is one of the proteinogenic amino acids. It is encoded by all the codons starting with GG (G ...

tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is ...

aspartate Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. The L-isomer of aspartic acid is one of the 22 proteinogenic amino acids, i.e., the building blocks of protein ...

(GYGD) motif of the channel. MTX thus blocks the channels by binding in the external vestibule of the pore to block the ion conduction pathway. Although Kv1.1, Kv1.2, and Kv1.3 have a very similar pore structure, they display different pharmacological sensitivity to MTX.

References

# Carlier, E., ''et al.'', Effect of maurotoxin, a four disulfide-bridged toxin from the chactoid scorpion Scorpio maurus, on Shaker K+ channels. J Pept Res, 2000. 55(6): p. 419–27. # Castle, N.A., ''et al.'', Maurotoxin: a potent inhibitor of intermediate conductance Ca2+-activated potassium channels. Mol Pharmacol, 2003. 63(2): p. 409–18. # Fu, W., ''et al.'', Brownian dynamics simulations of the recognition of the scorpion toxin maurotoxin with the voltage-gated potassium ion channels. Biophys J, 2002. 83(5): p. 2370–85. # Jensen, B.S., ''et al.'', The Ca2+-activated K+ channel of intermediate conductance:a possible target for immune suppression. Expert Opin Ther Targets, 2002. 6(6): p. 623–36. # Kharrat, R., ''et al.'', Chemical synthesis and characterization of maurotoxin, a short scorpion toxin with four disulfide bridges that acts on K+ channels. Eur J Biochem, 1996. 242(3): p. 491–8. # M'Barek, S., ''et al.'', A maurotoxin with constrained standard disulfide bridging: innovative strategy of chemical synthesis, pharmacology, and docking on K+ channels. J Biol Chem, 2003. 278(33): p. 31095–104. # Rochat, H., ''et al.'', Maurotoxin, a four disulfide bridges scorpion toxin acting on K+ channels. Toxicon, 1998. 36(11): p. 1609–11. # Visan, V., ''et al.'', Mapping of maurotoxin binding sites on hKv1.2, hKv1.3, and hIKCa1 channels. Mol Pharmacol, 2004. 66(5): p. 1103–12. {{Potassium channel blockers Neurotoxins Ion channel toxins Scorpion toxins