Arginine Metabolism: Boundaries of Our Knowledge
It is during the arginine synthesis pathway
NO is an anti-bacterial effector and can inhibit bacterial DNA synthesis by inhibiting bacterial Ribonucleotide Reductase1/2 and causing DSBs (Double-Stranded Breaks) in bacterial DNA. It can also increase the susceptibility of bacteria to oxidative DNA damage by blocking respiration. NO combines with O2- to form ONOO- (peroxynitrite anion) and oxidize bacterial lipids to produce nitrotyrosine, but the biological significance of these modifications is still unclear. Some bacteria contain low concentrations of GSH (Glutathione), and are susceptible to NO. The bacterial protein SoxRS (Superoxide Regulon) serves as a sensor for NO, and can activate transcription of a set of bacterial genes whose products defend the pathogen from oxidant damage by bacterial SOD (Superoxide Dismutase). OxyR (Peroxide Regulon), a transcription factor involved in stimulation of peroxide detoxification genes, is directly modified by H2O2 (Hydrogen Peroxide) or NO via S-nitrosylation and assists in protecting the bacterium from the NO donor S-nitrosocysteine. It also directs the transcription of bacterial genes such as AHP (Alkyl Hydroperoxide Reductase), which confers resistance, to peroxynitrite, and Catalase, which deactivates H2O2 (Ref.4 & 9). The bacterial protein FUR (Ferric Uptake Regulatory protein) also serves as an NO sensor. NO inactivates FUR by interacting with its iron cofactor, permitting expression of genes protective against oxidative stress. One bacterial gene regulated by FUR encodes a flavohemoglobin that can detoxify NO, protecting pathogens from NO. Thus multiple signaling pathways defend bacteria against NO. NO is also an anti-viral effector of the innate immune system. It can inhibit replication of Herpes viruses, Picornaviruses, Flaviviruses and Corona viruses by targeting viral proteases. Many RNA viruses depend on viral proteases to cleave large viral polyproteins into smaller viral polypeptides. In Toxoplasma gondii infection, the induction of iNOS serves as a nonspecific immune response that prevents parasite invasion.
Arginine synthesis pathway arge | …
Although NOS2 activity is independent of calcium concentrations, a variety of extracellular stimuli can activate distinct signaling pathways that converge to initiate expression of iNOS. Cell wall components of bacteria and fungi trigger the innate immune signaling cascade, leading to expression of iNOS. LPS (Lipopolysaccharide), a component of the wall of Gram-negative bacteria, binds to LBP (LPS-Binding Protein), which delivers LPS to CD14, a high-affinity LPS receptor. TLR4 (Toll-Like Receptor-4) in conjunction with the small extracellular protein MD2 interacts with the CD14-LPS complex, and then activates an intracellular signaling cascade via adaptors that include IRAK (Interleukin-1 Receptor-Associated Kinase) and MyD88 (Myeloid Differentiation Primary Response Gene-88). These adaptors in turn activate downstream molecules including TRAF6 (TNF Receptor-Associated Factor-6), TAB1 (TAK1-Binding Protein-1) and p38. LPS activation of TLR4 leads to phosphorylation of IKK (Inhibitor of KappaB Kinase), which phosphorylates the I-kappaB and releases the transcription factor NF-kappaB (Nuclear Factor-KappaB). NF-kappaB translocates from the cytoplasm to the nucleus, where it interacts with kappaB elements in the NOS2 5' flanking region, triggering NOS2 transcription (Ref.2, 3 & 8). Cytokines released from infected host cells also activate NO production, including TNF-Alpha (Tumor Necrosis Factor-Alpha) and IL-1Beta (Interleukin-1Beta). IFN-Gamma (Interferon-Gamma) interacts with the IFNR1 (Interferon Receptor-1) and IFNR2 complex, which activates kinases of the JAK (Janus Kinase) family and STAT (Signal Transducers and Activators of Transcription) pathways leading to synthesis of the transcription factor IRF1 (Interferon Response Factor-1) and stimulation of NOS2 mRNA transcription. IFN-Gamma also provides a synergistic boost to LPS induction of NOS2 transcription because IRF1 interacts with NF-kappaB, altering the conformation of the NOS2 promoter. Nuclear proteins that interact with members of the NF-kappaB family include the nonhistone chromosomal proteins, HMGI/Y (High Mobility Group Family). They enhance the binding of transcription factors, such as NF-kappaB and AP-1 (Activating Protein-1), to their binding sites by DNA-protein and protein-protein interactions (Ref.3 & 5). Other transcription factors, including STAT1Alpha and HIF1 (Hypoxia Inducible Factor-1) also regulate NOS2 expression.