Nitric oxide synthase (NOS) is a family of enzymes that produce nitric oxide (NO), a simple gaseous molecule with profound effects throughout the body. NO is a powerful signaling molecule involved in many biological processes.
What is Nitric Oxide Synthase?
Nitric oxide synthase enzymes catalyze the production of nitric oxide (NO) from the amino acid L-arginine. This process involves a five-electron oxidation of a specific nitrogen atom within L-arginine. The reaction also requires molecular oxygen and reduced nicotinamide-adenine-dinucleotide phosphate (NADPH) as co-substrates.
The synthesis of NO occurs in two steps. First, NOS hydroxylates L-arginine to Nω-hydroxy-L-arginine, which remains bound to the enzyme. In the second step, the enzyme oxidizes Nω-hydroxy-L-arginine to yield L-citrulline and nitric oxide. This reaction also requires cofactors such as flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), and (6R-)5,6,7,8-tetrahydrobiopterin (BH4).
Different Forms of Nitric Oxide Synthase
There are three main forms, or isoforms, of nitric oxide synthase, each found in different parts of the body and serving distinct purposes: neuronal NOS (nNOS or NOS1), inducible NOS (iNOS or NOS2), and endothelial NOS (eNOS or NOS3). All three isoforms are homodimers and contain heme.
Neuronal NOS (nNOS) is primarily found in central and peripheral neurons. Its activity is regulated by calcium and calmodulin, and it plays a role in synaptic plasticity within the central nervous system.
Endothelial NOS (eNOS) is mostly expressed in endothelial cells, which line blood vessels. Like nNOS, eNOS activity is also dependent on calcium and calmodulin, and it helps regulate blood vessel dilation.
Inducible NOS (iNOS) can be expressed in many cell types, often in response to immune activators like lipopolysaccharide or cytokines. Unlike the other two forms, iNOS generates large amounts of NO and, once synthesized, is constitutively active due to tight binding with calmodulin.
Essential Roles in Body Systems
The nitric oxide produced by NOS enzymes plays diverse and important roles in maintaining normal physiological functions across various body systems. In the cardiovascular system, NO is a powerful vasodilator, meaning it relaxes blood vessels. This action helps regulate blood pressure and ensures proper blood flow throughout the body. Nitric oxide also helps prevent platelets from clumping together and adhering to blood vessel walls, contributing to vascular health.
In the nervous system, NO acts as a neurotransmitter, influencing processes such as memory and learning. It is involved in synaptic plasticity in the central nervous system and contributes to smooth muscle relaxation in peripheral nerves.
Within the immune system, NO generated by iNOS plays a role in defense against pathogens, exhibiting cytostatic effects on parasitic target cells. This contributes to the body’s non-specific host defense mechanisms against bacterial, viral, and fungal infections.
Nitric Oxide Synthase in Health and Disease
Dysregulation of nitric oxide synthase activity or NO production can contribute to a range of health conditions. In the cardiovascular system, reduced NO bioavailability, often due to eNOS dysfunction, is linked to conditions like hypertension and atherosclerosis. For instance, many cardiovascular risk factors can lead to oxidative stress, which can impair eNOS function and reduce NO production.
Overactivity of iNOS can contribute to chronic inflammatory conditions and septic shock, as large amounts of NO are produced, leading to harmful effects.
Imbalances in nNOS and iNOS activity have also been implicated in neurodegenerative disorders, such as stroke and Alzheimer’s disease. For example, while normal levels of NO can be neuroprotective, overproduction by nNOS can become neurotoxic following neuronal damage. Additionally, altered NOS function has been associated with conditions like diabetes and certain cancers.