Chapter 19 : Metallobiology of Tuberculosis

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Iron is absolutely required for the life of most organisms, including mycobacteria. Iron is incorporated into proteins, either as a mono- or binuclear species or as part of heme groups or iron-sulfur clusters. Iron undergoes reversible changes in its oxidation state, oscillating between the oxidized ferric (Fe) and the reduced ferrous (Fe) forms. In addition, depending on the local ligand environment, iron-containing compounds exhibit a wide range of oxidation-reduction potentials. These unique properties make this metal a very versatile prosthetic component as a biocatalyst and electro-carrier in essential cellular pathways including respiration, the trichloroacetic acid (TCA) cycle, oxygen transport, gene regulation, defense against oxidative stress, and DNA biosynthesis ( ).

Citation: Rodriguez G, Neyrolles O. 2014. Metallobiology of Tuberculosis, p 377-387. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0012-2013
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Figure 1

Carboxymycobactin and mycobactin share a common core structure but differ in the length of the alkyl substitution that determines their polarity and hence solubility. The groups involved in binding of Fe(III) are indicated in bold.

Citation: Rodriguez G, Neyrolles O. 2014. Metallobiology of Tuberculosis, p 377-387. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0012-2013
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Figure 2

When experiencing iron limitation, produces carboxymycobactin (cMB) and mycobactin (MB). MB remains cell associated, although the precise location is not clear. cMB is secreted by a process dependent on the membrane proteins MmpL4 and MmpL5 and requiring the MmpS4 and MmpS5 membrane-associated proteins that function together with their cognate MmpL proteins. Proteins that mediate export of cMB across the outer membrane remain to be discovered. Once secreted, cMB chelates Fe and possibly requires an outer membrane and periplasmic protein to reach the IrtAB importer in the inner membrane. In the cytosol, the FAD binding domain of IrtA may reduce ferric iron to ferrous iron and dissociate the iron-siderophore complex. Released ferrous iron can be utilized and stored in ferritins. Excess iron binds to the regulator IdeR and activates its DNA binding activity. Binding of IdeR to the promoters of siderophore synthesis, secretion, and transport represses the expression of those genes, turning off iron uptake. Meanwhile, IdeR-Fe binding to the promoters of ferritins (ferritin and bacterioferritin) turns on iron storage, thereby preventing iron-mediated toxicity and maintaining iron homeostasis.

Citation: Rodriguez G, Neyrolles O. 2014. Metallobiology of Tuberculosis, p 377-387. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0012-2013
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Table 1

P-ATPases in

Citation: Rodriguez G, Neyrolles O. 2014. Metallobiology of Tuberculosis, p 377-387. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0012-2013

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