Makatoxin-3

Makatoxin-3 (a.k.a. MkTx-3, MKTX III or Makatx III) is an α-like scorpion neurotoxin found in the venom of Olivierus martensii. Makatoxin-3 both enhances the activation and slows down the inactivation of voltage-gated NaV1.7 channels, resulting in hyperexcitability of the neurons involved in pain perception.[1][2]

Chemical structure of Makatoxin-3

Source

Makatoxin-3 is a neurotoxin that can be found in the venom of the scorpion Olivierus martensii, also known as Buthus martensii Karsch (BmK) or the Chinese Scorpion.[3] This scorpion is also commonly known as the Chinese scorpion, as it is widely found in China, as well as Korea and Mongolia.[3] Makatoxins account for approximately 4% of the total BmK venom protein. After high temperature processing of the venom, Makatoxins make up 0.8% of the total protein.[1]

Chemistry

Makatoxin-3 is made up of 85 amino acid residues, 19 of which make up the signal peptide at the N-terminal, and four disulfide bonds.[4][5] It has a high sequence homology (90% identity) with two other toxins from the same Makatoxin protein family, Makatoxin-1 and Makatoxin-2.[2][4][5]

Properties
Protein Length Molecular Mass (Da)
85[2][5] 9,434[6]

The full amino acid sequence of Makatoxin-3 is the following (with the mature peptide underlined):

MNYLI VISFA LLLMT GVESG RDAYI AKKEN CTYFC ALNPY CNDLC TKNGA KSGYC QWAGR YGNAC WCIDL PDKVP IRIPG PCIGR[5]

For comparison, the amino acid sequence of Mktx-2 is (again with the mature peptide underlined):

MNYLI VISFA LLLMT SVESG RDAYI ADSEN CTYFC GSNPY CNDLC TENGA KSGYC QWAGR YGNAC WCIDL PDKVP IRIPG PCRGR[5]

Two key residues of Makatoxin-3 have been identified: K9 and R58. Their substitutions K9D and R58A in mutated Makatoxin-3 reduce the efficacy of the toxin to cause pain in mice.[2]

Makatoxin-3 is thermostable, as processing it by high temperature (60 °C) does not affect the bioactivity of Makatoxin-3 despite the protein concentration going down by 50%.[1] Makatoxin-3 is also stable in artificial gastric juice, but not in artificial intestinal juice, so Makatoxin-3 may be protected from enzymatic digestion.[1]

Target and Mode of Action

Makatoxin-3 is an α-toxin that binds to the S3-S4 loops of the voltage sensor domain IV (VSD4) of NaV1.7 in dorsal root ganglion (DRG) neurons.[1][2][4][5] It is a NaV1.7 agonist.[1] Makatoxin-3 has little to no effect on NaV1.1, NaV1.3, NaV1.6, NaV1.8, and NaV1.9 channels.[2]

Makatoxin-3 shows dose-dependent effects on both the activation and the inactivation of NaV1.7.[1][2] The toxin slows the inactivation kinetics of NaV1.7 currents. The average persistent currents are larger at both low (250 nmol/kg) and high (750 nmol/kg) concentrations due to the incomplete NaV1.7 channel inactivation at depolarized potentials (-45 mV and higher). At high concentration (750 nmol/kg), the curve of the peak current shifts to the left of the hyperpolarization direction, reaching the peak earlier than in the absence of the toxin; the action potential is also prolonged by shifting the steady-state fast inactivation current to hyperpolarization potentials by -9.3 mV.[1][2] Furthermore, at high concentration (750 nmol/kg), Makatoxin-3 causes NaV1.7 to open at hyperpolarized potential by shifting its voltage-dependent activation curve by -8.6 mV.[1][2]

Toxicity

Makatoxin-3 evokes pain and allodynia.[2] After injecting 25 nmol/kg, 50 nmol/kg, and 150 nmol/kg of Makatoxin-3 respectively, mice exhibit flinching behavior due to the pain-inducing effect for approximately 30 minutes before diminishing in a dose-dependent manner (the higher the dose, the higher the number of flinches).[1]

Therapeutic use

Interestingly, notwithstanding the pain response induced by the toxin, Makatoxin-3 also shows an analgesic effect in a dose-dependent manner (50 nmol/kg, 150 nmol/kg, and 450 nmol/kg). 450 nmol/kg elicits an 80% reduction of paw-flinch pain behavior in mice when they are intraperitoneally injected with another pain-inducing substance 30 minutes after the Makatoxin-3 injection.[1] However, if the scorpion body is processed by high temperature, it requires an even higher concentration of Makatoxin-3 to elicit the analgesic effect due to the loss of these peptides.[1] A mutant variant of the neurotoxin, Makatoxin-3-R58A, still produces the analgesic effect, but largely loses its pain-inducing effect.[1][2]

Unlike morphine, which is a strong opioid receptor analgesic with the addictive side effect, the analgesic activity induced by Makatoxin-3 cannot be reversed by naloxone (μ-opioid receptor antagonist). This means that Makatoxin-3 has an analgesic effect that is not dependent on the endogenous opioid system.[1] Therefore, Makatoxin-3 is being studied as a new potential painkiller.[1]

References
  1. Chen, Yonggen; Xu, Erjin; Sang, Ming; Wang, Zhiheng; Zhang, Yuxin; Ye, Juan; Zhou, Qian; Zhao, Chenglei; Hu, Chunping; Lu, Wuguang; Cao, Peng (2022-04-24). "Makatoxin-3, a thermostable Nav1.7 agonist from Buthus martensii Karsch (BmK) scorpion elicits non-narcotic analgesia in inflammatory pain models". Journal of Ethnopharmacology. 288: 114998. doi:10.1016/j.jep.2022.114998. ISSN 0378-8741. PMID 35063590.
  2. Lu, Wuguang; Cheng, Xiaoyang; Chen, Jiao; Wang, Mingyuan; Chen, Yonggen; Liu, Jinman; Sang, Ming; Zhao, Ningwei; Yan, Huaijiang; Cheng, Xiaolan; Zhou, Qian; Ye, Juan; Wang, Jin; Xu, Erjin; Tang, Zongxiang (2022-02-01). "A Buthus martensii Karsch scorpion sting targets Nav1.7 in mice and mimics a phenotype of human chronic pain". Pain. 163 (2): e202–e214. doi:10.1097/j.pain.0000000000002397. ISSN 1872-6623. PMID 34252912. S2CID 235808684.
  3. "Olivierus martensii", Wikipedia, 2022-03-22, retrieved 2022-10-26
  4. Goudet, Cyril; Chi, Cheng-Wu; Tytgat, Jan (2002-09-01). "An overview of toxins and genes from the venom of the Asian scorpion Buthus martensi Karsch". Toxicon. 40 (9): 1239–1258. doi:10.1016/S0041-0101(02)00142-3. ISSN 0041-0101. PMID 12220709.
  5. Zeng, Xian-Chun; Li, Wen-Xin; Zhu, Shun-Yi; Peng, Fang; Zhu, Zhi-Hui; Liu, Hui; Mao, Xin (2001-02-01). "Molecular cloning and sequence analysis of cDNAs encoding a β-toxin-like peptide and two MkTx I homologues from scorpion Buthus martensii Karsch". Toxicon. 39 (2): 225–232. doi:10.1016/S0041-0101(00)00119-7. ISSN 0041-0101. PMID 10978740.
  6. "UniProt". www.uniprot.org. Retrieved 2022-10-28.

Chemistry details:

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