Citrullin: the pathway in the body

Citrullin is part of the pathway “Arginine and nitric oxide”. This page shows the whole pathway; the station of Citrullin is highlighted.

Where this laboratory value sits: Citrulline — from the gut. Citrulline is an amino acid that is not built into proteins. Gut cells make it from glutamine and release it into the blood; the kidney captures it again. Source 1

In brief

Nitric oxide (NO) is a short-lived gas that NO synthases form from the amino acid arginine. In the vessel wall it triggers relaxation of the muscle cells via the messenger cGMP; ADMA inhibits its formation.

The pathway step by step

1. Citrulline → Argininosuccinate ASS · Aspartate, ATP In the kidney, argininosuccinate synthetase links citrulline with the amino acid aspartate. This step uses ATP. Source 1, 2
2. Argininosuccinate → Arginine ASL Argininosuccinate lyase splits off fumarate, leaving arginine. Arginine also comes from dietary protein and from the breakdown of the body's own proteins. Source 2, 1
3. Arginine → Ornithine Arginase · Manganese Arginase splits arginine into ornithine and urea. It carries manganese in its active centre. Within the cell, arginase and NO synthase share the same arginine. Source 2
4. Methylarginine → ADMA Protein breakdown When these proteins are broken down, the methylated arginine is released on its own: ADMA. It resembles arginine so closely that it fits into NO synthase and blocks it there. Source 4, 5
5. ADMA → Dimethylamine DDAH The enzyme DDAH splits ADMA into dimethylamine and citrulline. How much ADMA a cell contains therefore depends mainly on DDAH. Source 4, 5
6. Arginine → Nitric oxide NO synthase · BH4, NADPH NO synthase converts arginine to citrulline and releases NO. It needs oxygen, NADPH and the cofactor BH4; without enough BH4 it releases superoxide instead of NO. Source 3
7. Nitric oxide → cGMP Guanylate cyclase · Haem iron, GTP NO enters the muscle cell of the vessel wall and binds there to the haem iron of soluble guanylate cyclase. The enzyme then converts GTP to cGMP. Source 6, 3
8. cGMP → Vascular muscle Protein kinase G cGMP switches on protein kinase G. It lowers free calcium in the muscle cell, the cell relaxes, and the vessel widens. Source 6, 3

Cofactors in this pathway

• Arginine — Starting material from which NO synthase forms NO and citrulline Source 3In the ORY catalogue as a laboratory value: Arginin
• Tetrahydrobiopterin (BH4) — Cofactor of NO synthase Source 3
• Riboflavin (FAD, FMN) — As FAD and FMN, electron carriers within NO synthase Source 3
• Niacin (NADPH) — NADPH supplies NO synthase with electrons Source 3
• Iron — Haem iron in NO synthase and in guanylate cyclase, to which NO binds Source 3, 6In the ORY catalogue as a laboratory value: Eisen
• Calcium — Activates NO synthase via calmodulin Source 3In the ORY catalogue as a laboratory value: Calcium (intrazellulär)
• Manganese — Metal centre of arginase, which splits arginine into ornithine and urea Source 2
• Methionine (SAM) — As S-adenosylmethionine, provides PRMT with the methyl groups for ADMA Source 4In the ORY catalogue as a laboratory value: Methionin

What acts on this pathway

• Glyceryl trinitrate — Glyceryl trinitrate releases nitric oxide in the body, which switches on the same guanylate cyclase as the body's own NO. The prescribing information describes this mechanism. Source 7

Sources

1. Curis E, Nicolis I et al. Almost all about citrulline in mammals. Amino Acids 2005 · PubMed 16082501
2. Morris SM Jr. Enzymes of arginine metabolism. J Nutr 2004 · PubMed 15465778
3. Förstermann U, Sessa WC. Nitric oxide synthases: regulation and function. Eur Heart J 2012 · PubMed 21890489
4. Pope AJ, Karuppiah K et al. Role of the PRMT-DDAH-ADMA axis in the regulation of endothelial nitric oxide production. Pharmacol Res 2009 · PubMed 19682581
5. Teerlink T, Luo Z et al. Cellular ADMA: regulation and action. Pharmacol Res 2009 · PubMed 19682580
6. Derbyshire ER, Marletta MA. Structure and regulation of soluble guanylate cyclase. Annu Rev Biochem 2012 · PubMed 22404633
7. US prescribing information Nitroglycerin (DailyMed), section Clinical Pharmacology, Mechanism of Action · Prescribing information

Whole pathway: Arginine and nitric oxide

Related pathways

• Nitrosative stress — nitric oxide
• Spermidine — ornithine
• Calprotectin — Eisen, Calcium (intrazellulär)
• Carnitine — Eisen, Methionin
• Estradiol — Eisen, Methionin

As of 2026-09-16. Draft written by Claude to schema v2; sources checked in PubMed; expert review pending
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