Origins of Recombinant Toxins: History
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Contributor:
Elena Efremenko
,
Aysel Aslanli
,
Ilya Lyagin

Toxins produced by various living organisms (bacteria, yeast, scorpions, snakes, spiders and other living organisms) are the main pathogenic factors causing severe diseases and poisoning of humans and animals. To date, recombinant forms of these toxins are widely used as antimicrobial agents, anticancer drugs, vaccines, etc. Various modifications, which in this case can be introduced into such recombinant proteins, can lead to a weakening of the toxic potency of the resulting toxins or, conversely, increase their toxicity. Thus, it is important to publicly discuss the situations and monitor the emergence of such developments.

  • protein
  • recombinant toxin
  • antivenom
  • vaccines
  • killer toxins
  • enzymatic antidots

1. Introduction

To date, recombinant toxins from various biological sources (bacteria, yeast, scorpions, snakes, spiders and other living organisms) are widely used as: (i) antimicrobial agents for medical purposes, as well as antimicrobial additives for the food and biotechnological industries, (ii) groundwork for the creation of drugs with anticancer activity and the treatment of neurodegenerative diseases and (iii) the basis to develop vaccines, etc. Multiple works have been performed to study the mechanisms of action of genetically modified toxins and their applications [1][2][3][4][5][6] (Figure 1).
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Figure 1. Various applications of recombinant toxins.
The protein/polypeptide nature of most of these natural toxins allows them to obtain their recombinant forms. The potential for developing these biomolecules in high enough quantities is the basis for further advancements in developing vaccines and drugs with reduced cost and their widespread use, on the one hand. On the other hand, the production of recombinant toxins avoids the need to work directly with the natural sources of these biomolecules (animals and microbial pathogens). Obtaining genetic constructs encoding the synthesis of recombinant toxins expands the possibilities of their synthesis in special modified forms. Like many recombinant proteins, recombinant toxins can be obtained in high yields using different expression systems, including extracellular secretion, and further isolated and finely purified using affine carriers [7][8].

2. Spectrum of Recombinant Toxins and Their Origins

Most of proteinaceous toxins well-studied to date are produced by various bacteria. However, toxins that are found in yeast, snake, scorpion and spider venoms and other living organisms are also actively studied by various scientific groups today. Recombinant toxins obtained from various origins and purposes of their obtaining are presented in Table 1 [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64].
Table 1. Recombinant toxins from various origins and the purposes of their obtaining.
Protein Origin Reference
Production
BoNT Bacteria Clostridium botulinum [9]
Killer toxins K1, K28, K1L Yeast Saccharomyces paradoxus [10][11][12]
Killer toxin Kpkt Yeast Tetrapisispora phaffii [13][14]
ppa1, Tppa2, Tce3, Cbi1 Scorpions of the genus Tityus and Centruroides [15]
β/δ agatoxin-1 Spider Agelena orientalis [16]
Purotoxin-1 Spiders of the genus Geolycosa sp. [17]
Azemiopsin, Three-Finger Toxins Viper Azemipos feae [18][19]
MdumPLA2 Coral snake Micrurus dumerilii [20]
APHC3, HCRG21 Sea anemone Heteractis crispa [21][22]
Toxicity assays
C3bot, C3botE174Q, C2IIa Bacteria Clostridium botulinum [23][24][25]
LeTx Bacteria Bacillus anthracis [26]
HlyII Bacteria Bacillus cereus [27][28]
Cry1Ia Bacteria Bacillus thuringiensis [29]
BFT Bacteria Bacterioides fragilis [30]
EGFP-SbB, translocation domain
(TD) of the diphtheria toxin		 Bacteria Corynebacterium diphtheriae [31][32]
In1B Bacteria Listeria monocytogenes [33]
LcrV Bacteria Yersinia pestis [34]
AtaT2 Bacteria Escherichia coli [35]
Killer toxin Kpkt Yeast Tetrapisispora phaffii [36]
MeICT, KTx Scorpion Mesobuthus eupeus [37][38][39]
Tbo-IT2 Spider Tibellus oblongus [40]
α-conotoxins, α-cobratoxin Marine snail and snake venom [41]
Three-Finger Toxins Viper Azemipos feae [42]
α-neurotoxins Cobra Naja melanoleuca [43]
Hct-S3 Sea anemone Heteractis crispa [44]
Immunology assays
BoNT Bacteria Clostridium botulinum [45]
Beta and epsilon toxins Bacteria Clostridium perfringens [46][47]
Cholera toxin subunit B (CTB) Bacteria Vibrio cholerae [48]
Ancrod, batroxobin, RVV-V Snakes Calloselasma rhodostoma, Bothrops atrox, Daboia russelii [49][50]
Modifications
BoNT/B-MY, C2IN-C3lim Bacteria Clostridium botulinum [51][52]
DT389-YP7, s-DAB-IL-2(V6A), DT2219 Bacteria Corynebacterium diphtheriae [53][54][55]
rPA83m + plant virus spherical particles (SPs) Bacteria Bacillus anthracis [56][57][58]
SElP + Zn Bacteria Staphylococcus aureus [59]
PE38 + AgNP Bacteria Pseudomonas aeruginosa [60]
CTB-KDEL Bacteria Vibrio cholerae [61]
GFP-L2-AgTx2 Scorpions Mesobuthus eupeus and Orthochirus scrobiculosus [62]
LgRec1ALP1 Spiders of the genus Loxosceles [63]
Ms 9a-1 fragments and homologues Sea anemone Metridium senile [64]

3. Diversity of Modern Purposes for Obtaining Recombinant Toxins

Finding ways of obtaining effective antibodies and the development of vaccines against recombinant toxins is one of the main goals today [65][66]. For maximal quality and efficiency of immunologic medications, initial toxins should be highly purified, be in sufficient quantities and stimulate selective immune response. Recombinant toxins’ production solves the first two issues, though vaccines can still have cross-specificity.

4. Prediction of Toxicity of Synthetic Recombinant Proteins

The majority of the publications of recent years emphasize the importance of using bioinformatics methods to identify new variants of toxins and clarify the mechanisms of their toxic effects. Molecular modeling facilitates the understanding of the interaction of toxins with their receptors and/or targets, especially when these compounds are bound to the membrane, and biochemical approaches to the study of these processes are complex [67]. Due to advances in synthetic biology, the cost and time required for the development and synthesis of individual recombinant products are steadily decreasing. Many research laboratories regularly create genetically modified proteins as a part of their research activities. However, manipulations of amino acid sequences in proteins can lead to the unintended production of protein toxins. Therefore, the ability to determine the toxicity of a protein before its synthesis reduces the risk of the potential danger of synthetic production of protein toxins. For this purpose, various methods based on machine learning are being developed to predict the toxicity of proteins in silico based on a number of initial data (Figure 2).
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Figure 2. Machine-learning methods based tools for protein toxicity prediction.

5. Potential Enzymatic Antidotes for Recombinant Toxins

Due to the wide variety of toxins known to date and differences in the mechanisms of their action, there is an urgent need to create antidotes that both have a specific effect and are active against a wide range of toxins. The main directions of antidote development today are either the creation of various inhibitors capable of blocking the sites of binding of toxins to targets or the production of proteins (usually antibodies) capable of acting as bioscavengers via binding directly to the toxins themselves, thereby limiting their interactions with targets [68]. However, the search and development of new antidotes based on other principals, namely using molecules capable of detoxifying toxins by their enzymatic transformation into less toxic or nontoxic molecules, may become a promising alternative to existing solutions. To date, several enzymes are known that can act as antitoxins against various bacterial toxic substances, as well as enzymes that exhibit hydrolytic activity against PrP (Table 3, [69][70][71][72][73][74][75][76][77]).
Table 3. Enzymes as antidotes for toxic and prion proteins.
Table 3. Enzymes as antidotes for toxic and prion proteins.
Protein Enzyme Mechanism of Action Reference
Guanylyltransferase TglT from Mycobacterium tuberculosis Serine protein
kinase TakA		 Specifically, phosphorylates the cognate toxin at residue S78, thereby neutralizing toxicity [69]
HepT toxin from Shewanella oneidensis Minimal
nucleotidyltransferase
(MNT)		 MNT acts as an adenylyltransferase and mediates the transfer of three AMPs to a tyrosine residue next to the RNase
domain of HepT		 [70]
Bacterial GhoT toxin Endoribonuclease GhoS is a sequence-specific endoribonuclease that cleaves mRNA encoding GhoT, preventing its translation [71]
Hha toxin from Escherichia coli An oxygen-dependent
antitoxin TomB		 Inactivation of the Hha by oxidation with molecular oxygen mediated by the TomB [72]
Mycobacterium tuberculosis toxin DarT DarG—DNA ADP-ribosyl glycohydrolase DarG could reverse the DNA ADP-ribosylation by DarT [73]
PrP Commercially available
subtilisin enzyme, Prionzyme		 Proteolytic inactivation/degradation [74]
PrP Subtilisin 309 and Subtilisin 309-v Proteolytic inactivation/degradation [75]
PrP Nattokinase (NK, also known as subtilisin NAT) produced by Bacillus subtilis natto NK is capable of decreasing amyloid structure of recombinant human PrP
fibrils		 [76]
PrP Keratinase KerA from
B. licheniformis PWD-1		 Proteolytic inactivation/degradation [77]

This entry is adapted from the peer-reviewed paper 10.3390/ijms24054630

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