Metallobiology of Tuberculosis

Abstract

Transition metals are essential constituents of all living organisms, playing crucial structural and catalytic parts in many enzymes and transcription factors. However, transition metals can also be toxic when present in excess. Their uptake and efflux rates must therefore be carefully controlled by biological systems. In this chapter, we summarize the current knowledge about uptake and efflux systems in Mycobacterium tuberculosis for mainly three of these metals, namely iron, zinc, and copper. We also propose questions for future research in the field of metallobiology of host-pathogen interactions in tuberculosis.

Figure 1

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

Figure 2

When experiencing iron limitation, M. tuberculosis 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 which function together with their cognate MmpL proteins. Protein(s) that mediate export of cMB across the outer membrane remain to be discovered. Once secreted, cMB chelates Fe⁺³ 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⁺² binding to the promoters of ferritins (ferritin and bacterioferritin) turns on iron storage thereby, preventing iron mediated toxicity and maintaining iron homeostasis.