Nitric oxide synthase 2 (inducible)

Nitric oxide synthase 2 (inducible) (NOS2), also known as inducible NOS (iNOS), is an enzyme that in humans is encoded by the NOS2 gene. It is one of the three key isoforms of nitric oxide synthase (NOS), which are responsible for the production of nitric oxide (NO) from L-arginine. NO is a crucial cellular signaling molecule involved in many physiological and pathological processes. Unlike the other NOS isoforms, which are constitutively active, iNOS is induced in response to inflammatory stimuli, making it a central player in the immune response, as well as in various inflammatory diseases and conditions.

Function

iNOS synthesizes nitric oxide in response to a series of cues such as cytokines, bacterial lipopolysaccharides, or other inflammatory stimuli. This production of NO is part of the macrophage's mechanism to defend against pathogens. Nitric oxide acts as a free radical and is an important mediator of immunity and inflammation. It is also involved in various biological functions including vasodilation, neurotransmission, and apoptosis.

Structure

The NOS2 gene is located on chromosome 17 in humans and has a complex regulation, being inducible by a variety of stimuli. The enzyme itself is a homodimer, each monomer consisting of an oxygenase domain and a reductase domain. The binding of calmodulin, flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), and tetrahydrobiopterin (BH4) are essential for its activity.

Regulation

The expression of iNOS is tightly regulated at both transcriptional and post-transcriptional levels. Various cytokines and microbial products can induce the expression of iNOS, primarily through the activation of nuclear factor kappa B (NF-κB) and other transcription factors. The regulation of iNOS expression is crucial for controlling its activity, as excessive or prolonged NO production can lead to tissue damage and contribute to the pathogenesis of inflammatory diseases.

Clinical Significance

iNOS plays a significant role in the pathophysiology of various diseases, including asthma, arthritis, sepsis, and cancer. Its induced expression and the subsequent overproduction of NO can lead to inflammatory damage, contributing to the severity of these conditions. Consequently, iNOS and its signaling pathways have been targets for therapeutic intervention in these diseases.

Pharmacology

Inhibitors of iNOS have been explored as therapeutic agents in conditions where excessive NO production is detrimental. These inhibitors aim to selectively inhibit iNOS activity, thereby reducing NO levels and mitigating inflammation and damage. However, the development of selective iNOS inhibitors has been challenging due to the similarities between the NOS isoforms.

See Also

• Nitric oxide synthase
• Nitric oxide
• Inflammation
• Immune system