# Genomic and Metabolic Characteristics of the Pathogenicity in Pseudomonas aeruginosa
## 4 Metabolic Pathways Associated with Pathogenicity
### Virulence Factors
#### 4.1.1 Secretion Systems
This involves a high degree of complexity; therefore, this system has thirty-six genes, encoded in five operons, that are organized  
Figure 2: The secretion systems in _P. aeruginosa_. Five secretion pathways are present in _P. aeruginosa_: The T3 SS and T6 SS transport proteins from the bacterial cytoplasm to the cytosol of the target cell. On the other hand, the T1 SS, T2 SS and T5 SS transport proteins from the bacterial cytoplasm to the extracellular medium. and clustered together in the _P. aeruginosa_ chromosome. These genes are implicated in the biogenesis and regulation of the type III secretory-translocation machinery [53]. One of the important components of T3 SS in _P. aeruginosa_ is the production of at least four effector proteins: ExoS, ExoT, ExoU, and ExoY, that cause cytotoxicity at different levels [66]. The ExoT and ExoS are homologous bifunctional effectors and are both ADP-ribosyltransferases (ADPRT) and GTPase-activating protein (GAP) activity. These effector proteins seem to target host signaling pathways, specifically through ADP-ribosylation of Ras, affecting the function of the host cell [67; 68; 69]. ExoU is an effector with lipase activity that has broad substrate specificity, causing tissue destruction. ExoY is an adenylate cyclase that increases cAMP levels intracellularly and induces rounding of cells by disrupting the actin in their cytoskeleton [70]. In _P. aeruginosa_, type III secretion is regulated at two levels: transcription of T3 SS genes and initiation of secretion. Both are switched on upon contact with host cells, leading to the production of a large amount of secreted type III components [71; 72]. Transcription of T3 SS genes is induced under limiting calcium conditions or shortly after contact of these bacteria with their host cells [53]. Transcription of T3 SS genes is controlled by the ExsA master regulator, which is a member of the AraC family of transcriptional activators [73]. ExsA binds to a nucleotide sequence upstream of the RNA polymerase binding site of T3 SS promoters [74]. ExsA autoregulates its expression by binding to the promoter region of _exsCEBA_ (coding region of the T3 SS regulatory complex) [75]. Downstream of this regulatory complex operon is the anti-activator _exs_D gene which inhibits exsA-dependent transcription [72]. The exsC, an anti-anti-activator, binds directly to exsD in under low calcium conditions, which promotes the inactivation of ExsA, thus allowing interaction with the promoter region [76]. There is also a secreted anti-anti-anti-activator, ExsE, that binds to ExsC preventing it from inhibiting ExsD [77]. In general, when ExsE is secreted, it remains intracellularly, which favors the formation of ExsE-ExsC and ExsA-ExsD complexes, thus avoiding ExsA-dependent transcription. On the other hand, in the absence of ExsE, no binding to ExsC takes place. Thus, ExsC sequesters ExsD, allowing ExsA to activate the transcription of T3 SS genes [76; 77]. Besides this pathway, the T3 SS regulon is under control by several upstream regulators, including cAMP biosynthesis [42], a global regulator, Vfr, and ResT/LadS/GacAS two-component regulatory systems [74; 78]. Another trigger for the expression of genes in the T3 SS system is a spermidine transporter, SupDEFGH, which allows _P. aeruginosa_ to have the ability to detect and sense the signaling molecules in the fluid of its host's tissues and, consequently, induces the expression of T3 SS genes [79]. When the spermidine transporter genes are deleted, host-cell-dependent induction of T3 SS genes is inhibited, and so are bacterial cytotoxicity and expression of _exsCEBA_ and effector genes induced by calcium depletion [74]. Spermidine is an organic polycation, belonging to the group known as polyamines, which play important roles in stress response, acid tolerance, and antimicrobial resistance [80; 81; 82]. Some studies show that polyamines can either induce resistance to various classes of antibiotics or increase susceptibility. For example, in _P.