NOS2 - Nitric oxide synthase 2 | Elisa - Clia - Antibody - Protein

Background:

Nitric Oxide Synthase 2 (NOS2), also known as inducible nitric oxide synthase (iNOS), is an enzyme that catalyzes the production of nitric oxide (NO) from the amino acid L-arginine. NOS2 is a homodimeric enzyme with each subunit containing multiple functional domains, including an oxygenase domain, a reductase domain, and a calmodulin-binding domain. Unlike other isoforms of nitric oxide synthase (NOS), such as NOS1 (neuronal NOS) and NOS3 (endothelial NOS), NOS2 is primarily regulated at the level of gene expression rather than by calcium/calmodulin-dependent activation.NOS2 catalyzes the conversion of L-arginine to L-citrulline and nitric oxide (NO) in the presence of molecular oxygen and cofactors such as nicotinamide adenine dinucleotide phosphate (NADPH) and tetrahydrobiopterin (BH4). NO is a signaling molecule with diverse physiological functions, including regulation of vascular tone, neurotransmission, immune response, and host defense against pathogens. Unlike constitutively expressed NOS isoforms (NOS1 and NOS3), NOS2 expression is inducible by various inflammatory stimuli, such as cytokines (e.g., interleukin-1β, tumor necrosis factor-alpha) and bacterial lipopolysaccharide (LPS). Induction of NOS2 leads to a rapid and sustained increase in NO production, which contributes to the host's defense against pathogens and the regulation of inflammatory responses. NO generated by NOS2 plays a critical role in the immune response to infection and inflammation. It acts as a potent antimicrobial agent by inhibiting the growth and replication of bacteria, viruses, and parasites. Additionally, NO modulates the function of immune cells, such as macrophages, neutrophils, and T cells, by regulating their activation, cytokine production, and cytotoxicity.

Protein Structure:

• Monomeric Units: NOS2 is initially synthesized as a monomer but functions as a homodimer.
• Cofactors: The enzyme requires several cofactors for its activity, including tetrahydrobiopterin (BH4), flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), heme, and NADPH.
• Domains: NOS2 consists of an oxygenase domain (binding heme and BH4) and a reductase domain (binding FAD, FMN, and NADPH).

Classification and Subtypes:

• Isoforms: There are three primary NOS isoforms: NOS1 (nNOS), NOS2 (iNOS), and NOS3 (eNOS). NOS2 is classified as the inducible form due to its regulation by inflammatory stimuli.
• Splice Variants: Alternative splicing of the NOS2 gene can generate different transcript variants, though their functional significance is less well understood.

Function and Biological Significance:

• NO Production: NOS2 produces large amounts of NO upon induction. NO is a versatile signaling molecule involved in various physiological processes.
• Immune Response: NO produced by NOS2 plays a critical role in the host defense by exerting antimicrobial and antiviral effects. It helps in the destruction of pathogens and infected cells.
• Inflammation: NOS2 is often upregulated in response to pro-inflammatory cytokines like IFN-γ, TNF-α, and IL-1β, as well as microbial products like lipopolysaccharide (LPS).
• Pathophysiological Roles: NO produced by NOS2 can have dual roles. While it is essential for pathogen killing and immune regulation, excessive NO production can lead to tissue damage and contribute to inflammatory diseases.

Interactions:

• Cytokines: NOS2 is induced by a variety of cytokines, including IFN-γ, TNF-α, and IL-1β, which activate transcription factors like NF-κB and STAT-1.
• Cellular Partners: NOS2 interacts with various cellular proteins and cofactors necessary for its enzymatic activity. For example, heat shock proteins can stabilize NOS2 and enhance its function.

Clinical Issues:

• Inflammatory Diseases: Overexpression of NOS2 is associated with various inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, and asthma, where excessive NO production contributes to tissue injury and inflammation.
• Cancer: NOS2 has a complex role in cancer. While NO can have anti-tumorigenic effects by inducing apoptosis in cancer cells, chronic inflammation and sustained NOS2 expression can promote tumorigenesis.
• Septic Shock: High levels of NO production during septic shock can lead to vasodilation and hypotension, complicating the clinical management of sepsis.
• Therapeutic Target: NOS2 inhibitors are being explored as potential therapeutics for conditions where excessive NO production is detrimental, such as in inflammatory diseases and certain cancers.

Summary:

Nitric oxide synthase 2 (NOS2 or iNOS) is an inducible enzyme that plays a vital role in the immune response by producing nitric oxide (NO) in response to inflammatory stimuli. While crucial for pathogen defense and immune regulation, dysregulated NOS2 activity is implicated in various inflammatory and autoimmune diseases, cancer, and septic shock. Understanding the regulation, function, and pathological roles of NOS2 is essential for developing targeted therapies for conditions associated with excessive NO production.