Maurotoxin (abbreviated MTX) is a

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A ...

toxin A toxin is a naturally occurring organic poison produced by metabolic activities of living cells or organisms. Toxins occur especially as a protein or conjugated protein. The term toxin was first used by organic chemist Ludwig Brieger (1849– ...

from the venom of the Tunisian chactoid

scorpion Scorpions are predatory arachnids of the order Scorpiones. They have eight legs, and are easily recognized by a pair of grasping pincers and a narrow, segmented tail, often carried in a characteristic forward curve over the back and always end ...

Scorpio maurus ''Scorpio maurus'' is a species of North African and Middle Eastern scorpion, also known as the large-clawed scorpion or Israeli gold scorpion and lesser known as Zerachia scorpion. This is a small/medium-sized scorpion from the family Scorpion ...

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 transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a crucial role in returning the depolarized ce ...

Chemistry

Maurotoxin is a peptide of 34

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

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 formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, sometime ...

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 prot ...

s. The peptide contains an

alpha helix The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues e ...

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 g ...

Target

Scorpion toxins constitute the largest group of

potassium Potassium is the chemical element with the symbol K (from Neo-Latin ''kalium'') and atomic number19. Potassium is a silvery-white metal that is soft enough to be cut with a knife with little force. Potassium metal reacts rapidly with atmosphe ...

(K⁺) channel blockers and are useful pharmacological probes to investigate ion channels and their functions. Maurotoxin (MTX) blocks various K⁺ -channels: *

Apamin Apamin is an 18 amino acid globular peptide neurotoxin found in apitoxin ( bee venom). Dry bee venom consists of 2–3% of apamin. Apamin selectively blocks SK channels, a type of Ca2+-activated K+ channel expressed in the central nervous syste ...

-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 Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...

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 A T cell is a type of lymphocyte. T cells are one of the important white blood cells 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 rec ...

(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 activity of the immune system. Classification Immunosuppressive drugs can be classified in ...

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. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...

-23 residue and the glycine-

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 non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...

- glycine-

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. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...

(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