Mechanisms of iron regulation in mycobacteria: role in physiology and virulence

Abstract

SummaryThe role of iron in mycobacteria as in other bacteria goes beyond the need for this essential cofactor. Limitation of this metal triggers an extensive response aimed at increasing iron acquisition while coping with iron deficiency. In contrast, iron-rich environments prompt these prokaryotes to induce synthesis of iron storage molecules and to increase mechanisms of protection against iron-mediated oxidative damage. The response to changes in iron availability is strictly regulated in order to maintain sufficient but not excessive and potentially toxic levels of iron in the cell. This response is also linked to other important processes such as protection against oxidative stress and virulence. In bacteria, iron metabolism is regulated by controlling transcription of genes involved in iron uptake, transport and storage. In mycobacteria, this role is fulfilled by the iron-dependent regulator IdeR. IdeR is an essential protein in Mycobacterium tuberculosis , the causative agent of human tuberculosis. It functions as a repressor of iron acquisition genes, but is also an activator of iron storage genes and a positive regulator of oxidative stress responses.

A genetic locus required for iron acquisition in Mycobacterium tuberculosis

“…The enzymatic activity of FadD protein was analyzed by radio-TLC and HPLC, as described (18). Formation of acyl adenylate was confirmed by using ESI-MS.…”

“…Acylation of mycobacterial Rv1344 holo-ACP was carried out by using FadD33͞FadD28 protein, both of which make acyl adenylates (18). The reaction mixture contained 50 mM Tris (pH 6.8), 10 mM MgCl 2, 1 mM Tris-(2-carboxyethyl)phosphine (TCEP), 100 M [ 14 C]lauroyl-CoA, and 5-10 m ACP.…”

“…This report of the biochemical reconstitution reveals unique molecular components of siderophore biosynthetic machinery that are crucial for iron sequestration during bacterial pathogenesis. required for iron acquisition and storage that are regulated by IdeR repressor (18). Because mbt biosynthetic cluster is regulated by IdeR repressor, we carefully analyzed other genes that could impart amphiphilicity to mycobactins and whose expression is modulated by the levels of iron in the growth medium.…”

Structure elucidation and biosynthesis of fuscachelins, peptide siderophores from the moderate thermophile Thermobifida fusca

“…This structurally diverse group of small molecules contains metalchelating motifs that commonly include hydroxamates, catechols, ␣-hydroxyacids, and heterocycles to bind iron with high affinity. Iron uptake is frequently a limiting factor for growth, including in human hosts, making siderophores virulence factors in a variety of human pathogens and a target for antimicrobial therapy (4)(5)(6).…”

Correction: Genome Watch: Enemies within

“…The expression of genes involved in iron uptake and storage are controlled at the level of transcription and the factors that regulate these genes are usually essential. One such transcription factor in mycobacteria is the iron-dependent regulator IdeR, a homologue of the diphtheria-toxin repressor (DtxR) in Corynebacterium diphtheriae [25][26][27] . In its Fe 2+ -bound state, IdeR represses genes that encode iron acquisition molecules and activates the expression of iron storage proteins and oxidative stress responses.…”