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[Biochemistry](https://durgical.com/en/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](https://www.enzyme-database.org/query.php?ec=1.14.13.39)

**Genes**
NOS3

**Structure (PDB)**
[3NOS](https://www.rcsb.org/structure/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

- [Urea cycle](https://durgical.com/en/biochemistry/pathways/urea-cycle/)

## Related conditions

- [Arterial hypertension](https://durgical.com/en/conditions/arterial-hypertension/)
- [Stable angina](https://durgical.com/en/conditions/stable-angina/)
- [Erectile dysfunction](https://durgical.com/en/conditions/erectile-dysfunction/)
- [Sepsis and septic shock](https://durgical.com/en/conditions/sepsis-and-septic-shock/)
- [Preeclampsia](https://durgical.com/en/conditions/preeclampsia/)

## Related

- [Nitric oxide (NO)](https://durgical.com/en/biochemistry/molecules/nitric-oxide/)
- [Tetrahydrobiopterin (BH4)](https://durgical.com/en/biochemistry/molecules/tetrahydrobiopterin/)
- [NADPH](https://durgical.com/en/biochemistry/molecules/nadph/)
- [Molecules derived from amino acids](https://durgical.com/en/biochemistry/topics/molecules-derived-from-amino-acids/)
- [Urea cycle](https://durgical.com/en/biochemistry/pathways/urea-cycle/)
- [Argininosuccinate lyase (ASL)](https://durgical.com/en/biochemistry/enzymes/argininosuccinate-lyase/)
- [Arginase 1](https://durgical.com/en/biochemistry/enzymes/arginase-1/)
- [Reactive oxygen species and antioxidants](https://durgical.com/en/biochemistry/topics/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.

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Educational information, not medical advice. For any symptom, see a health professional.

Sources: [3NOS: Human endothelial nitric oxide synthase with arginine substrate](https://www.rcsb.org/structure/3NOS) (RCSB Protein Data Bank, 2026); [NOS3: Nitric oxide synthase 3, endothelial (human)](https://www.uniprot.org/uniprotkb/P29474/entry) (UniProt, 2026); [PDB-101: Molecule of the Month: Nitric Oxide Synthase](https://pdb101.rcsb.org/motm/133) (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.

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Source: https://durgical.com/en/biochemistry/enzymes/nitric-oxide-synthase/
License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/biochemistry/enzymes/nitric-oxide-synthase/