Nitric oxide synthase

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nitric oxide synthase 1 (neuronal)
Identifiers
Symbol(s)	NOS1 NOS
Entrez	4842
OMIM	163731
RefSeq	NM_000620
UniProt	P29475
Other data
EC number	1.14.13.39
Locus	Chr. 12 q14-qter

nitric oxide synthase 1 (neuronal) adaptor protein
Identifiers
Symbol(s)	NOS1AP
Entrez	9722
OMIM	605551
RefSeq	NM_014697
UniProt	O75052
Other data
Locus	Chr. 1 q23.3

nitric oxide synthase 2A (inducible, hepatocytes)
Identifiers
Symbol(s)	NOS2A NOS2
Entrez	4843
OMIM	163730
RefSeq	NM_000625
UniProt	P35228
Other data
EC number	1.14.13.39
Locus	Chr. 17 q11.2-q12

nitric oxide synthase 2B
Identifiers
Symbol(s)	NOS2B
Entrez	4844
OMIM	600719
RefSeq	[1]
UniProt	P81272
Other data
Locus	Chr. 17 p13.1-q25

nitric oxide synthase 2C
Identifiers
Symbol(s)	NOS2C
Entrez	4845
OMIM	600720
RefSeq	[2]
UniProt	Q14961
Other data
Locus	Chr. 17 p13.1-q25

nitric oxide synthase 3 (endothelial cell)
Identifiers
Symbol(s)	NOS3
Entrez	4846
OMIM	163729
RefSeq	NM_000603
UniProt	P29474
Other data
EC number	1.14.13.39
Locus	Chr. 7 q35-q36

The nitric oxide synthases (NOS) are a group of enzymes (EC 1.14.13.39) responsible for the synthesis of nitric oxide (NO) 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), flavin mononucleotide (FMN), heme, tetrahydrobiopterin (BH₄).

[edit] Classification

NOS was first identified by Furchgott (1980) who experimented on the aortas of Rabbits. Since then, 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 and is associated with plasma membranes.
• 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 or Constitutive / cNOS) generates NO in blood vessels and is involved with regulating vascular function. A constitutive Ca²⁺ dependent NOS provides a basal release of NO. eNos is associated with plasma membranes surrounding cells and the membranes of Golgi bodies within cells.

[edit] Structure

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 is linked in the middle of the protein to a calmodulin-binding domain. Binding of calmodulin 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 oxygenase domain of each NOS isoform also contains an BH₄ prosthetic group, which is required for the efficient generation of NO. Unlike other enzymes where BH₄ is used as a source of reducing equivalents and is recycled by dihydrobiopterin reductase (EC 1.5.1.33), BH₄ activates heme-bound O₂ by donating a single electron, which is then recaptured to enable nitric oxide release.

The first nitric oxide synthase to be identified was found in neuronal tissue (NOS1 or nNOS); the endothelial NOS (eNOS or NOS3) was the third to be identified. They were originally classified as "constituitvely expressed" and "Ca²⁺ sensitive" but it is now known that they are present in many different cell types and that expression is regulated under specific physiological conditions.

In NOS1 and NOS3, 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, calmodulin remains tightly bound to the inducible and Ca²⁺-insensitive isoform (iNOS or NOS2) even at a low intracellular Ca²⁺ activity, acting essentially as a subunit of this isoform.

Nitric oxide may itself regulate NOS expression and activity. Specifically, NO has been shown to play an important negative feedback regulatory role on NOS3, 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 may be particularly important after the induction of NOS2.

[edit] Function

In the NOS reaction the guanidino nitrogen of Arg undergoes a five-electron oxidation via an NOHLA (N-ω-hydroxy-L-arginine) intermediate to yield NO.

A very commonly used supplement by body-builders, the NO produced from L-Arginine gives an intense "muscular pump", a vasodilator.