Nitric oxide synthase (NOS)

Nitric oxide synthase (NOS)

Nitric oxide (NO), a unique messenger molecule regulates numerous physiological processes, including neurotransmission, smooth muscle contractility, platelet reactivity, and the cytotoxic activity of immune cells. Since the discovery of nitric oxide (NO) as the endotheliumderived relaxation factor, new roles for NO in biology continue to emerge. NO is synthesized by three distinct isoforms ofnitric oxide synthase (NOS) namely inducible NOS (iNOS), neuronal NOS (nNOS) and endothelial NOS (eNOS).

Nitric oxide synthases (NOSs) are a family of enzymes that catalyze the production of NO from L-arginine to L-citrulline. NOS enzymes exhibit a bidomain structure homologous to cytochrome P450 reductase. Nitric oxide is synthesized in cells from L-arginine catalyzed by three isoforms of nitric oxide synthase (NOS): inducible NOS (iNOS), endothelial NOS (eNOS), and neuronal NOS (nNOS). Three isoforms share similar structures and catalytic modes, but the mechanisms that control their activity are quite diverse. Expression of iNOS form is induced by inflammatory stimuli, while eNOS and nNOS are constitutively expressed. NO production in cells varies with the availability of L-arginine, and the cofactors: tetrahydrobiopterin, NADPH, heme, FAD, FMN. Protein-protein interactions such as dimerization and association with caveolins calmodulin (CaM), etc. also play a role in the regulation. CaM binding is required for maximum activity of the NOSs. The nNOS and eNOS require Ca2+ for CaM binding whereas iNOS is Ca2+ -independent. Post-translational modification that differs substantially among the various NOS types also plays role in their regulation of activity. NO is readily diffusible and is thus utilized close to its site of synthesis. So, subcellular distribution of the NOSs also regulates their activity.

Male infertility is temporarily or permanently caused by infection and inflammation of the male reproductive tract suggesting that testis function is compromised during illness or infection. The infection and inflammation caused in testis are related to infiltration of activated T- lymphocytes, increase in number of non-resident macrophages and mast cells following a bacterial or viral invasion. This immune response elevation in the testis is responsible for decline in sperm count causing infertility. The large amounts of nitric oxide (NO) is produced by activated inducible nitric oxide synthase (iNOS), which is involved in chronic immune response, after binding to calmodulin at all physiologically relevant concentration as a defense mechanism. In a similar manner, many studies have shown that NO and iNOS are known to up-regulate the damage in testis causing the infertility. The clinical significance of seminal oxidative stress is suggested by several independent studies indicating a link between peroxidative damage to human spermatozoa and the incidence infertility.

The role of iNOS

Inducible nitric oxide synthase is one of three known isoforms of nitric oxide synthases (NOSs). The iNOS is regulated in calcium independent manner and produces relatively larger amounts of NO than the other two isoforms, neuronal NOS (nNOS) and endothelial NOS (eNOS). The induction iNOS is triggered by cytokine and/or lipopolysaccharides (LPS), where it is inducible in a wide range of cells and tissues. It is also known as Type II, NOS-II and NOS-2. The iNOS is a soluble enzyme that is active in its dimeric form.

The NO, synthesized by iNOS, is a potent biological mediator which when expressed in high amounts causes DNA damage and cell death. Macrophages are important for early immune responses to invading microorganisms, and the production of NO is central to this function. NO is generated by iNOS following exposure to certain cytokines, such as interferon-g (IFN-g). Figure 2.2 depicts this pathway for expression of iNOS gene in macrophages.

There were significantly higher concentrations of nitric oxide in the seminal plasma of infertile patients than in healthy men. High concentrations of NO were significantly correlated with greater sperm DNA damage, and low concentrations of NO were significantly correlated with better sperm motility. Exogenous NO has an inhibitory effect on Tca8113 cells, and induced apoptosis via p53 dependent pathway.

NO regulation can occur at the transcriptional, posttranscriptional, translational, and posttranslational level. There have been a number of studies of the regulation of iNOS in various cell types, often yielding conflicting results.

Reference:

Prabhakara, K. (2013). Identification of inducible nitric oxide synthase binding proteins in human testis: Mammalian co-immunoprecipitation study. University of Houston-Clear Lake.

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