Practice question

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.