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#toxins

10 public questions tagged with this topic.

Immunological Applications

Which toxin is commonly used in immunotoxins?

Selecting optimal toxin component for immunoconjugate involves potency, intracellular stability, lack of mammalian cell surface receptors to avoid nonspecific uptake, and ability to produce recombinant fusion maintaining disulfide integrity. Diphtheria toxin secreted by toxigenic Corynebacterium diphtheriae, 58 kDa single polypeptide proteolytically cleaved into 21 kDa catalytic A fragment and 37 kDa binding-translocation B fragment linked by single disulfide Cys186-Cys201. Catalytic activity transfers ADP-ribose to elongation factor 2 with turnover number approximately 1000 per minute. Native receptor heparin binding EGF-like precursor widely expressed, so receptor-binding domain residues 1-389 deleted to generate DT388 retaining translocation domain helices capable of endosomal membrane insertion at acidic pH after furin cleavage. Similarly Pseudomonas exotoxin A 66 kDa secreted by Pseudomonas aeruginosa, ADP-ribosylates EF2 after binding CD91 receptor, truncated to PE38 removing domain Ia binding region retaining domain II translocation and domain III catalytic with C-terminal REDLK endoplasmic reticulum retrieval motif. Plant toxins like ricin A chain or gelonin inactivate ribosomes via depurination but require chemical conjugation via heterobifunctional crosslinkers SPDP forming disulfide bridge.

Ref: Weldon & Pastan FEBS J 2011 PE38 DT388 catalytic domain; Collier EF2 ADP-ribosylation translation arrest mechanism.

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Immunological Applications

Immunotoxins are composed of:

Immunotoxins constructed to overcome lack of selectivity of conventional chemotherapy achieve tumor specific delivery of ultrapotent protein toxins that cannot enter mammalian cells unaided. Design consists of targeting moiety typically single-chain variable fragment scFv or disulfide stabilized Fab derived from murine or humanized antibody recognizing tumor antigen CD22 on hairy cell leukemia, CD25 on adult T cell leukemia, mesothelin on mesothelioma, linked via flexible glycine-serine peptide or reducible disulfide bond formed between engineered cysteines to effector toxin devoid of native receptor binding domain to prevent off target internalization. Toxin moiety from Pseudomonas aeruginosa exotoxin A truncated to 38 kDa PE38 containing ADP-ribosylation domain plus translocation domain or diphtheria toxin DT388 lacking receptor domain 1-389, or plant toxin ricin A chain 32 kDa. This mechanistic insight supports diagnostic and therapeutic applications while reinforcing core immunological and cell biology principles taught in advanced curricula. This mechanistic detail underpins practical applications in diagnostics, vaccine design, and biopharmaceutical manufacturing.

Ref: Pastan et al Nature Rev Cancer 2006 6:559 immunotoxins PE38; Kreitman Clin Cancer Res 2009 fusion toxin de-immunized.

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Immunological Applications

Which toxin is commonly used in immunotoxins?

Diphtheria toxin produced Corynebacterium diphtheriae lysogenized temperate corynephage beta carrying tox gene regulated iron-dependent repressor DtxR provides ideal warhead immunotoxin because catalytic mechanism well characterized potency extreme one molecule sufficient kill cell enzymatic turnover inactivating millions ribosomes extensive clinical experience vaccine toxoid. AB architecture A domain catalytic 21 kDa active site Glu148 critical nucleophile performing NAD-dependent ADP-ribosylation EF2 B domain receptor-binding translocation B composed receptor-binding subdomain C-terminal 482-535 binding HBEGF ubiquitously expressed mediating endocytosis plus translocation domain hydrophobic helices forming pore acidic endosomal membrane pH 5.5 facilitating cytosolic entry. Wild-type B domain causes nonspecific toxicity liver peripheral nerves limiting therapeutic window. Immunotoxin construction receptor-binding subdomain deleted generating DT388 variant 1-388 retaining translocation helices TH8 TH9 catalytic preserving ability translocate abrogating native tropism reducing off-target 1000-fold. Fusion anti-CD22 scFv flexible linker produces BL22 CAT-3888 moxetumomab pasudotox improved affinity 14-fold mutagenesis heavy chain CDR3. Upon endocytosis furin cleaves arginine-rich loop disulfide reduction releasing A chain cytosol. Clinical immunotoxins denileukin diftitox Ontak IL-2 DT389 CD25 cutaneous T-cell lymphoma Tagraxofusp IL3 DT blastic plasmacytoid dendritic neoplasm illustrate successful retargeting achieving FDA approvals objective response 70 percent.

Ref: Pastan Diphtheria Toxin Immunotoxin Clinical Development 2009; FDA Ontak Tagraxofusp DT Fusion Mechanism Label; Collier Diphtheria Toxin Structure Function Catalysis Enzymology.

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Immunological Applications

Immunotoxins kill target cells mainly by:

Protein toxins employed immunotoxin design kill primarily through catalytic inactivation protein synthesis machinery requiring only few molecules cytosol triggering irreversible apoptosis. Diphtheria toxin fragment A 21 kDa ADP-ribosyltransferase modifies diphthamide residue unique post-translationally modified histidine 699 eukaryotic elongation factor 2 synthesized seven enzymes DPH1-7 adding 3-amino-3-carboxypropyl trimethylation diphthine amidation transferring ADP-ribose oxidized NAD imidazole inhibiting translocation peptidyl tRNA A site P site elongation cycle 80S ribosome mediated GTP hydrolysis. Pseudomonas exotoxin A domain III similarly ADP-ribosylates same residue furin cleavage toxin endosome separating catalytic domain. Ricin A chain N-glycosidase hydrolyzes N-glycosidic bond depurinating adenine 4324 sarcin-ricin loop GAGA tetraloop 28S rRNA preventing binding elongation factors eEF1 aminoacyl tRNA eEF2 interfering factor-dependent GTPase. Arrest translation rapidly depletes short-lived antiapoptotic proteins MCL-1 half-life 2h XIAP continuous turnover releasing Bak Bax oligomerization forming pores outer mitochondrial membrane cytochrome c release activating apoptosome caspase-9 caspase-3 cascade executing death concentrations 10^-11 M explaining extraordinary potency exceeding conventional small-molecule chemotherapeutics lacking enzymatic amplification catalytic turnover.

Ref: Collier 1967 Diphtheria Toxin ADP-ribosylation EF2 Discovery; Pastan PE38 Protein Synthesis Inhibition Mechanism; Lodish Protein Synthesis eEF2 Function Chapter 7.

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Membrane Transportation

The Na+/K+ ATPase inhibitor Palytoxin acts by:

Palytoxin ranks among most potent non-protein toxins known, isolated from zoanthid corals Palythoa species, with LD50 subnanomolar due to profound effects on ion homeostasis. Target is Na+/K+ ATPase, P-type pump normally undergoing strict alternating access never simultaneously open both sides. Structural and electrophysiological studies show palytoxin binds extracellular entrance near ouabain site but wedges gates open, stabilizing conformation where intracellular gate formed by M5-M8 and extracellular gate formed by M1-M4 both unlatched, generating continuous pore approximately 13 angstrom diameter spanning membrane. Electrophysiology reveals large non-selective conductance allowing sodium, potassium, lithium, even organic cations like choline and tetramethylammonium to flow passively down gradients, collapsing resting potential causing depolarization, secondary calcium overload via reverse sodium calcium exchange, ATP depletion. Pump cycling halted ATP hydrolysis blocked because enzyme arrested unable to complete E1-E2 transition, but functional outcome differs from simple inhibition by ouabain that blocks without creating channel. Thus palytoxin action defined as converting pump into non-specific ion channel.

Ref: Tosteson et al., Palytoxin Converts Na+/K+ ATPase into Non-Selective Ion Channel Mechanism.

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Applied Ecology

Biological magnification primarily affects:

Top consumers bear the highest biomagnified concentrations because they eat many prey that have already accumulated a persistent contaminant. Long life spans, lipid storage, and slow elimination can increase exposure further. Producers introduce the chemical into the food web, and herbivores and scavengers may also be harmed, but trophic integration generally gives apex consumers the greatest body burden when true biomagnification occurs. Climate, nutrients, disturbance, species traits, and food-web structure interact, so broad ecological generalisations describe tendencies rather than universal rules. Energy is lost as metabolic heat at every trophic transfer, while elements such as nitrogen and phosphorus are recycled through organisms and the physical environment. Mechanistic interpretation connects individual physiology and species interactions to population change, community composition, and ecosystem-level fluxes. Reliable inference requires the complete experimental design, definitions, units, and statistical evidence; missing labels cannot be reconstructed from an answer key alone. Net primary production equals gross primary production minus plant respiration and represents biomass or energy made available for growth and consumers.

Ref: Campbell Biology, Urry et al., 12th Ed., Unit 8 Ecology

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Applied Ecology

Which type of toxin persists and increases in concentration up trophic levels?

Persistent pollutants are resistant to chemical, photolytic, and biological degradation and are often removed slowly from organisms. If they are also bioavailable and stored in lipid or other tissues, uptake can exceed elimination and concentrations can rise through food chains. Essential nutrients are regulated physiologically, oxygen does not persist as a stored toxin, and readily biodegradable compounds are less likely to undergo strong biomagnification. Prevention requires reducing unnecessary plastic use, improving collection and recycling, controlling lost fishing gear, and limiting releases of fibres and tyre-wear particles. Because conventional polymers persist, fragmentation redistributes plastic into smaller pieces rather than removing its mass from the ecosystem. Trophic transfer can occur when predators consume contaminated prey, although evidence for consistent biomagnification of particle numbers remains system-dependent. Standardised sampling and contamination controls are essential because airborne fibres can enter samples during collection and laboratory processing. Particle size, shape, polymer type, weathering state, and associated chemicals all influence uptake and biological response, so microplastics are not a uniform toxicant.

Ref: Campbell Biology, Urry et al., 12th Ed., Unit 8 Ecology

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