DtxR

DtxR, short for diphtheria toxin repressor, is a metal-dependent transcriptional regulator found in Corynebacterium diphtheriae and related Corynebacterium species. It functions as a global regulator of iron homeostasis and virulence gene expression, including repression of the diphtheria toxin (tox) gene when iron is abundant. The DtxR protein is encoded by the chromosomal dtxR gene and acts by binding specific DNA sequences known as DtxR boxes in the promoters of target genes.

Mechanism and regulation: DtxR activity depends on binding divalent metal ions, most notably Fe2+. In iron-replete conditions, metal-bound DtxR adopts a conformation that allows high-affinity DNA binding. When bound to DtxR boxes, it represses transcription of numerous genes involved in iron uptake and metabolism, as well as the tox gene carried by the beta prophage. Under iron-limited conditions, DtxR loses its effective DNA-binding ability, leading to derepression of its regulon. This iron-responsive regulation coordinates toxin production and iron acquisition with the bacterium’s environmental iron availability, contributing to the pathogen’s adaptation and virulence.

Structure and family: DtxR belongs to the DtxR family of metal-dependent transcriptional regulators. It typically forms a dimer and comprises an N-terminal DNA-binding helix-turn-helix domain and a C-terminal regulatory domain that coordinates metal ions. The metal-induced conformational change enables or enhances DNA binding to regulate gene expression.

Regulatory scope and significance: In addition to the tox operon, DtxR controls a broad set of genes involved in iron uptake, storage, and homeostasis. Through this regulation, DtxR links metal sensing to virulence, influencing toxin production and the bacterium’s ability to thrive in iron-limited environments such as the human host. DtxR homologs are widespread in Gram-positive bacteria and are studied for insights into metalloregulation and potential antimicrobial targets.