# L-Citrulline: A Non-Essential Amino Acid with Important Roles in Human Health
## 2 L-Citrulline Biochemistry
### L-Citrulline Metabolism
#### 2.2.1 Arginine Biosynthesis  
In mammals, Arg is classified as a semi-essential or conditionally essential amino acid, depending on the individual's health status and stage of development [19]. Arg is a derivative from endogenous de novo Arg synthesis, body protein breakdown or dietary intake (Figure 2). Arg synthesized from CIT represents 60% of the organism's de novo Arg synthesis, although only 5-15% is circulating Arg [20]. Enterocytes release CIT into the portal circulation and transport it to the kidneys, where about 83% CIT catabolizes to Arg in the cells of proximal tubules [21]. ASS converts CIT into arginosuccinate in the presence of aspartate and ATP and arginosuccinate converts into fumarate and Arg by arginosuccinate lyase (ASL). Arg is synthesized in the intestinal-renal axis, where small intestine epithelial cells participate, along with the kidney proximal tubule cells [1]. Although other cells types and tissues contain the enzymes ASS and ASL to convert CIT to arginosuccinate and finally to Arg [22], the most important synthesis is in the liver and kidney. Moreover, elevated plasma concentrations of CIT can be a marker of kidney dysfunction, since plasma  
Figure 2: Metabolism of citrulina. NO: Nitric oxide; NOS: Nitric oxide synthase; ADMA: Asymmetric dimethyl arginine; ASS: Argininosuccinate synthase; ASL: Argininosuccinate lyase.  
CIT is degraded in the kidney for the renal synthesis of Arg. Arg suffers intense hepatic catabolism, yet CIT is not metabolized by the liver, it seems that giving CIT supplements enables Arg to be administered whilst avoiding its hepatic uptake [3].  
Arginine Catabolism  
Arg metabolism is highly compartmentalized. Arginase is a binuclear manganese metalloenzyme which catalyzes Arg hydrolysis to L-ornithine and urea (Figure 2). Two different genetic isoforms of arginase differ in their tissue distribution, subcellular localization, and immunological reactivity. Arginase I is a cytosolic enzyme whose predominant expression lies in the liver, as part of the urea cycle, in which its function is the elimination of nitrogen generated in amino acid metabolism. However, to a much lesser extent, arginase I has been detected in extra-hepatic tissues such as endothelial cells as well as vascular smooth muscle cells [23]. On the other hand, arginase II is a mitochondrial enzyme that is widely distributed in extrahepatic cells and tissues (such as kidney, small intestine, brain, red blood cells and immune cells) [24]. Arginase II of the intestinal mucosa has a high activity, in fact the splanchnic area accounts for 40% of the dietary Arg extracted, thus explaining the low plasma concentrations of Arg. Therefore, the constitutive levels of arginase activity in endothelial cells limit the bioavailability of Arg as a substrate for the synthesis of endothelial nitric oxide (NO) by NOS and nitric oxide-dependent vasodilatory function [25]. Both enzymes, arginase and NOS, compete for the same substrate, and this competition depends on tissue type and the presence of stimuli [11].