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Nitric oxide synthase
The nitric oxide synthases (NOS) are a group of enzymes (EC 126.96.36.199) responsible for the synthesis of nitric oxide from the terminal nitrogen atom of L-arginine in the presence of O2 and the cofactors nicotinamide adenine dinucleotide phosphate (NADPH), flavin adenine dinucleotide (FAD), tetrahydrobiopterin (BH4) and calmodulin. L-citrulline is a byproduct, which is the arginine without its terminal nitrogen.
The different forms of NO synthase have been classified as
- Neuronal NOS (nNOS or NOS1) which produces NO in neuronal tissue in both the central and peripheral nervous system. Neuronal NOS also performs a role in cell communication.
- Inducible NOS (iNOS or NOS2) which can be found in the immune system but is also found in the cardiovascular system. It uses the oxidative stress of NO (a free radical) to be used by macrophages in immune defence against pathogens.
- Endothelial NOS (eNOS or NOS3) generates NO in blood vessels and is involved with regulating vascular function. A constitutive Ca2+ dependent NOS provides a basal release of NO.
All three isoforms (each of which is presumed to function as a homodimer during activation) share a carboxyl-terminal reductase domain homologous to the cytochrome P450 reductases. They also share an amino-terminal oxygenase domain containing a heme prosthetic group, which are linked in the middle of the protein by a calmodulin-binding domain. Binding of calmodullin appears to act as a "molecular switch" to enable electron flow from flavin prosthetic groups in the reductase domain to heme. This facilitates the conversion of O2 and L-arginine to NO and L-citrulline. The reductase domain of each NOS isoform also contains an H4B prosthetic group, which is required for the efficient generation of NO. Unlike other enzymes where H4B is used as a source of reducting equivalents and is recycled by dihyrobiopterin reductase H4B, H4B appears to be necessary to maintain a stable conformation for electron transport possible by promoting homodimerization.
The originally identified nitric oxide synthase was the NOS isoform identified in neuronal tissue known as nNOS or NOS1 followed by the endothelial NOS called eNOS or NOS3. They were originally classified as "constituitvely expressed" and "Ca2+ sensitive" but it is now known that they are present in may different cell types and that expression is regulated under specific physiological conditions.
In NOS1 (neuronal) and NOS3 (endothelial), physiological concentrations of Ca2+ in cells regulate the binding of calmodullin to the "latch domains" thereby initiating electron transfer from the flavins to the heme moieties. In contrast, calmodullin remains tightly bound to the inducible and Ca2+ insensitive isoform termed iNOS or NOS2 even at a low intracellular Ca2+ activity, acting essentially as a subunit of this isoform.
It is interesting that NO may itself regulate NOS expression and activity and has been shown to play an important negative feedback regulatory role on endothelial NO synthase, and therefore vascular endothelial cell function. Both NOS1 and NOS2 have been shown to form ferrous-nitrosyl complexes in their heme prosthetic groups that may act partially to self inactivate these enzymes under certain conditions. The rate-limiting step for the production of nitric oxide may well be the availability of L-arginine in some cell types. This is may particularly be important after the induction of NOS2.
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