Biochemistry · Enzyme
Nitric oxide synthase (NOS) !
Nitric oxide synthase turns arginine into citrulline and nitric oxide, a gas that relaxes blood vessels, carries nerve signals and helps kill microbes.
Updated 2026-11-01
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Key facts
- Reaction: L-arginine + O₂ + NADPH → L-citrulline + NO, in two steps through N-hydroxy-L-arginine.
- Cofactors: NADPH, FAD, FMN, haem, tetrahydrobiopterin (BH4) and calmodulin; it works as a dimer.
- Three isoforms: eNOS/NOS3 (endothelium, Ca²⁺-calmodulin dependent), nNOS/NOS1 (neurons, Ca²⁺ dependent) and iNOS/NOS2 (macrophages, induced by cytokines and endotoxin, Ca²⁺-independent and high output).
- NO activates soluble guanylyl cyclase → cGMP → protein kinase G → smooth muscle relaxation (vasodilation).
- Citrulline can be recycled to arginine through argininosuccinate synthetase and lyase (citrulline–NO cycle).
- Also called
- eNOS (NOS3), nNOS (NOS1), iNOS (NOS2)
- EC number
- 1.14.13.39
- Genes
- NOS3
- Structure (PDB)
- 3NOS
Structure
- 3NOS: human eNOS oxygenase domain dimer with haem, BH4 and N-hydroxy-L-arginine (the reaction intermediate) in the active site.
- The reductase domain (FAD, FMN) passes electrons from NADPH to the haem of the other subunit of the dimer.
Regulation
- eNOS: activated by Ca²⁺-calmodulin, shear stress of blood flow and phosphorylation by Akt; inhibited by caveolin-1.
- iNOS: induced at the gene level by LPS, interferon-γ, TNF-α and IL-1; glucocorticoids suppress it.
- Without enough BH4 or arginine the enzyme 'uncouples' and makes superoxide instead of NO.
Inhibitors and toxins
- Asymmetric dimethylarginine (ADMA, endogenous)
- L-NMMA and L-NAME (experimental)
Clinical notes
- In septic shock, iNOS makes large amounts of NO, causing vasodilation and hypotension resistant to vasopressors.
- Endothelial dysfunction (less eNOS-derived NO) is an early step of atherosclerosis and hypertension; ADMA rises in kidney failure.
- Nitrates (nitroglycerin) release NO and treat angina; PDE5 inhibitors (sildenafil) prolong cGMP in erectile dysfunction; both together can cause severe hypotension.
Pathways
Related conditions
Related
- Nitric oxide (NO)
- Tetrahydrobiopterin (BH4)
- NADPH
- Molecules derived from amino acids
- Urea cycle
- Argininosuccinate lyase (ASL)
- Arginase 1
- Reactive oxygen species and antioxidants
Test yourself
Think of the answer, then tap the question to see it.
What are the products of nitric oxide synthase?
Nitric oxide and L-citrulline, from L-arginine, O₂ and NADPH.
Which NOS isoform does not depend on a rise in calcium, and where is it found?
Inducible NOS (iNOS, NOS2), in macrophages and other cells after cytokine or endotoxin stimulation.
How does NO relax vascular smooth muscle?
It activates soluble guanylyl cyclase; cGMP activates protein kinase G, which lowers cytosolic Ca²⁺.
What happens when NOS lacks tetrahydrobiopterin?
It becomes uncoupled and produces superoxide instead of NO, adding oxidative stress.
Why must nitrates and sildenafil not be combined?
Nitrates raise cGMP formation and sildenafil blocks its breakdown, causing excessive vasodilation and dangerous hypotension.
Educational information, not medical advice. For any symptom, see a health professional.
Sources: 3NOS: Human endothelial nitric oxide synthase with arginine substrate (RCSB Protein Data Bank, 2026); NOS3: Nitric oxide synthase 3, endothelial (human) (UniProt, 2026); PDB-101: Molecule of the Month: Nitric Oxide Synthase (RCSB Protein Data Bank (PDB-101), 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).
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Representative model, for educational purposes only.