Bioinformatics analyses allowed the identification of a number of point mutations in the investigated genomes (see Supplementary Table S4). are further divided into subgroups, as recently described in an excellent review by [6]. The genome of the laboratory strain H37Rv contains 99 and 69 genes, but these numbers are variable in different clinical strains [7,8]. Moreover, genes are often identified in pairs and are likely co-expressed; however, the individual genes are also present throughout the genome [9]. PE and PPE are not found outside of the genus genes; only two pairs of PE and PPE proteins have been identified in [8]. The PE and Diclofenac sodium PPE proteins have evolved in association with the duplication of gene cluster regions encoding type VII secretion systems [8]. The ESX system seems to have a significant role in the export of PE/PPE PRKCA proteins, where ESX-5 is responsible for exporting various proteins lacking Sec or Tat signal peptides [10,11]. The crystal structure of a PE-PPE heterodimer bound to ESX secretion-associated protein G (EspG) showed the interaction between EspG and the PPE domain [12]. It was proposed that EspG delivers PE-PPE to ESX machinery for secretion, and the secretion of most PE-PPE proteins in is mediated by EspG from the ESX-5 system [13]. ESX-5 is only present in slow-growing mycobacteria and is responsible for the secretion of multiple Diclofenac sodium substrates. As identified by proteomic analysis, all detectable PE and PPE proteins in the cell surface and cell envelope fractions are routed through ESX-5 [14]. The growth analysis of the mutant on defined carbon sources revealed that ESX-5 is involved in the uptake of fatty acids. Ates et al. [14] postulated that the ESX-5 system is responsible for the transport of cell envelope proteins that are required for nutrient uptake. Authors have speculated that these proteins might in this way compensate for the lack of MspA-like porins in slow-growing mycobacteria. Mitra et al. [15] identified PPE36 and PPE62, as well as Rv0265c as heme-binding cell surface receptors of essential for heme utilization. More recently, Tullius et al. [16] identified PPE37 as being essential for heme-iron acquisition in strains and media for their work. It was reported that some PPE proteins are secreted to the bacterial surface and interact with other proteins, as well as components of the host immune system [17,18]. PPE proteins affect Diclofenac sodium hostCpathogen interactions and immune evasion [19]. PPE-dependent immune escape during infection [20] the interactions of PPE with toll-like receptor 2 (TLR-2), cytokine release by activation of macrophages and dendritic cells, promoting apoptosis and necrosis of host cells, have also been reported [21,22,23,24,25]. PE/PPE proteins need to be surface-associated or released in a soluble form to interact directly with the host; therefore, they require transportation throughout the bacterial inner membrane with their cognate Type VII secretion systems, ESX-1, ESX-3 and ESX-5 [26,27,28,29]. The ESX-3 secretion system is involved in the transport of PPE-PPW proteins engaged in iron acquisition throughout mycobactin (PPE4/PE5) or heme (PPE36/PPE37) [15,16,30,31]. On the other hand, PPE-SVP and PPE-MPTR are secreted by ESX-5 [10,14,32]. PE8/PPE15 of the PPE-SVP family compose an operon together with EsxI-J and are necessary for the secretion of a specific subset of proteins that are important for bacterial virulence in and [33]. PPE38 is required for the secretion of all detected PE_PGRS and PPE-MPTR proteins [34]. PE/PPE proteins are important players in hostCpathogen interactions and affect the immunological response of the host organism. On the other hand, some members of the PE/PPE family are outer membrane nutrient transport proteins involved in iron acquisition. Numerous studies have established that relies on fatty acids and cholesterol in a nutritionally stringent environment of the macrophage phagolysosome during latency [35]. However, during its life-cycle in the necrotic tissue and caseum or the lymph and blood of a newly infected person, also encounters a transient abundance.