Corynebacterium diphtheriae: Diphtheria toxin, the tox operon, and its regulation by Fe2⁺ activation of apo-DtxR

Over the past 4 decades, perhaps no other infectious disease has been as successfully studied as diphtheria (1, 2). Indeed, the study of diphtheria toxin established the structure-function paradigm for the study of other toxins in the bacterial protein toxin field. Moreover, when coupled with the molecular genetic study of the iron-activated regulatory element, DtxR, that controls the expression of diphtheria toxin, we now have a detailed understanding of the entire tox genetic system, from the regulation of expression to the molecular mechanism of diphtheria toxin action. In this article, we review the development of our current understanding of diphtheria toxin, from its structure-function relationships to its mechanism of entry into the eukaryotic cell cytosol, the molecular mechanism of transition metal ion activation of DtxR and its regulation of tox expression, and finally, the protein engineering of diphtheria toxin for the development of highly potent and selective cell-surface receptor-targeted fusion protein toxins for the treatment of human diseases.