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10 Iron Uptake in Mycobacteria

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Abstract:

This chapter highlights both the well established and the yet poorly understood aspects of siderophoremediated iron acquisition in pathogenic and nonpathogenic mycobacteria, with a particular emphasis in the siderophore system of . The siderophore system is believed to play a crucial role in the procurement of a suitable iron supply to support bacterial multiplication in vivo and to be a key factor in the ability of this human pathogen to produce successful infections. The mycobacteria examined for iron-acquisition systems appear to rely on siderophores with high affinity for the ferric ion as the primary mechanism for iron acquisition. Transcription of genes of the exochelin (EXC) and mycobactin/carboxymycobactin (MBT/CMBT) systems is derepressed when the bacterium experiences iron limitations, thus leading to siderophore biosynthesis and siderophore-mediated iron uptake. Several Mycobacterium species produce two structurally related families of high-affinity Fe-binding siderophores, the MBTs and the CMBTs. Mutational analysis has conclusively linked the gene cluster to production of both MBTs and CMBTs. Mutational analysis has conclusively linked the gene cluster to production of both MBTs and CMBTs. Several Mycobacterium species that are normally found as environmental saprophytes release EXCs, the nonribosomally synthesized pentapeptidebased or hexapeptide-based siderophores, into the extracellular environment. More recently, analogues of salicyl-AMS have also been demonstrated to block MBT/CMBT biosynthesis and multiplication in iron-limiting conditions.

Citation: Quadri L. 2008. 10 Iron Uptake in Mycobacteria, p 167-183. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch10
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Image of Figure 1.
Figure 1.

(A) Representative structures of mycobactins and carboxymycobactins from (left) and exochelin MS from (right). The primary difference between mycobactins and carboxymycobactins is in the substituent at R. Alternative alkyl substituents at R, R, and R are found in the siderophores of other species. (B) chromosomal loci containing the genes of the mycobactin/carboxymycobactin system (upper scheme) and chromosomal locus containing the genes of the exochelin MS system (bottom scheme). The gene map represents three distinct chromosomal loci (, , and from left to right) that are shown in their relative orientation and separated from each other by a wavy line. The functions of most of the genes depicted have been predicted but not experimentally confirmed. Genes encoding proteins involved in siderophore biosynthesis, ferrisiderophore uptake or receptor functions, and siderophore secretion are shown in black, vertical-line hatched, and diagonal-line hatched arrows, respectively. Genes of unknown functions are shown in white. IdeR binding sequences (confirmed or predicted) are marked with the symbol ⊕. Gene (84 bp), encoding tRNA-Leu and located between and , is not depicted. See text for information on individual genes.

Citation: Quadri L. 2008. 10 Iron Uptake in Mycobacteria, p 167-183. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch10
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Image of Figure 2.
Figure 2.

(A) Mycobactin/carboxymycobactinmediated iron acquisition by intraphagosomal . The scheme shows alternatives for (ferri-) MBT/(ferri-)CMBT trafficking and delivery of iron to the bacterial cytoplasm. Under iron-limiting conditions, IdeR repression is decreased, and MBTs and CMBTs are synthesized by the siderophore biosynthesis machinery (SBM) and exported outside the cell by a yet unknown mechanism (a). Lipophilic MBTs have been shown to localize to the bacterial surface, perhaps at the membrane, where they can acquire Fe from ferri-CMBTs (b). MBTs at the cell surface have been suggested to function as ionophores to facilitate Fe transport across the membrane and/or act as transient stores of Fe (c). MBTs can also diffuse throughout the intracellular milieu of the macrophage and acquire Fe from cytoplasmic iron sources to form ferri-MBTs (d). Ferri-MBTs can diffuse in the intracellular milieu and accumulate in lipid droplets in contact with phagosomes (e). MBTs can sequester Fe from transferrin in the macrophage (f). CMBTs can acquire Fe from transferrin in vitro and are likely to do so in vivo as well (g). Porins may facilitate inward trafficking of ferri-CMBTs through the waxy cell envelope (h). Porins may also facilitate inward trafficking of ferri-MBTs. The IrtAB system has been proposed to transport ferri-CMBTs to the bacterial cytoplasm (i), but it is possible that the system transports ferri-MBTs as well. In the cytoplasm, an iron reductase (R) would release the iron from the chelates as Fe (j). It is also possible that a membrane reductase coupled with an iron transport system (FeT) removes Fe from ferrisiderophores at the extracellular side of the membrane and transports the Fe to the cytoplasm (k). Regardless of how Fe is delivered to the cytoplasm, it will be directed to synthesis of iron-containing compounds or temporarily stored (l). (B) Exochelin MS-mediated iron acquisition in . The MBT/CMBT system of , which is comparable to that of , is not shown. Under iron-limiting conditions, IdeR repression is decreased, and EXCs are synthesized and mobilized outside the cell, possibly through a mechanism involving ExiT (a). Secreted EXCs chelate Fe from environmental sources (b). Ferri-EXCs have been suggested to be bound at the cell envelope by the putative ferrisiderophore receptor FxuD, and possibly by a 29-kDa cell envelope protein not shown (c). Ferri-EXCs are likely to be transported to the cytoplasm by the FxuABC system (d), where an iron reductase would release the iron as Fe (e). Released Fe is directed to synthesis of iron-containing compounds or temporarily stored (f). (.)

Citation: Quadri L. 2008. 10 Iron Uptake in Mycobacteria, p 167-183. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch10
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Image of Figure 3.
Figure 3.

(A) Salicylic acid (Sal) adenylation catalyzed by the adenylation domain (A) of MbtA and MbtAdependent transesterification of the salicyl moiety onto the prosthetic group of the aroyl carrier protein domain (ArCP) of the multifunctional peptide synthetase MbtB. (B) Salicyl-AMP and its nonhydrolyzable mimic salicyl-AMS. The difference between these two molecules is highlighted.

Citation: Quadri L. 2008. 10 Iron Uptake in Mycobacteria, p 167-183. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch10
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