Figure 10

MAP upregulates a novel iron pathway, irtAB , for iron assimilation in response to host nitric oxide synthase-2 expression. Interactome network analysis identified a network composed of 4 genes (MAP3734c-3736c and MAP3737). MAP3734c-3736c forms an iron regulation pathway and is the equivalent of irtAB in M. tuberculosis H37Rv. A) IrtA (MAP3735c and MAP3736c) binds and releases non-ferrated carboxymycobactin (cMyco) into the host cell. cMyco binds iron (Fe-cMyco) and is transported back into MAP via MAP2960c (not identified in interactome) and IrtB (MAP3734c). MAP3737, a PPE protein, may serve as a signal transduction molecule and sense NO buildup. Upregulation of this pathway is linked to NOS-2 expression by the host. Figure is based in part by Farhana et al.[106]. B) MAP3734c-3736c forms a homodimer and transport Fe-cMyco inside the MAP cell. Once Fe-cMyco is inside, the FAD-binding domain of IrtA (MAP3735c and MAP3736c) becomes activated and binds to flavin, which accepts electrons from NAD(P)H. This allows flavin reductase to function as an iron reductase. Reduction of Fe³⁺ to Fe²⁺ dissociates iron from carboxymycobatin so it can be utilized by MAP.