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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

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 r

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

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

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 d

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 univers

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 rele

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

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