Almost all about citrulline in mammals

Abstract

Citrulline (Cit, C6H13N3O3), which is a ubiquitous amino acid in mammals, is strongly related to arginine. Citrulline metabolism in mammals is divided into two fields: free citrulline and citrullinated proteins. Free citrulline metabolism involves three key enzymes: NO synthase (NOS) and ornithine carbamoyltransferase (OCT) which produce citrulline, and argininosuccinate synthetase (ASS) that converts it into argininosuccinate. The tissue distribution of these enzymes distinguishes three "orthogonal" metabolic pathways for citrulline. Firstly, in the liver, citrulline is locally synthesized by OCT and metabolized by ASS for urea production. Secondly, in most of the tissues producing NO, citrulline is recycled into arginine via ASS to increase arginine availability for NO production. Thirdly, citrulline is synthesized in the gut from glutamine (with OCT), released into the blood and converted back into arginine in the kidneys (by ASS); in this pathway, circulating citrulline is in fact a masked form of arginine to avoid liver captation. Each of these pathways has related pathologies and, even more interestingly, citrulline could potentially be used to monitor or treat some of these pathologies. Citrulline has long been administered in the treatment of inherited urea cycle disorders, and recent studies suggest that citrulline may be used to control the production of NO. Recently, citrulline was demonstrated as a potentially useful marker of short bowel function in a wide range of pathologies. One of the most promising research directions deals with the administration of citrulline as a more efficient alternative to arginine, especially against underlying splanchnic sequestration of amino acids. Protein citrullination results from post-translational modification of arginine; that occurs mainly in keratinization-related proteins and myelins, and insufficiencies in this citrullination occur in some auto-immune diseases such as rheumatoid arthritis, psoriasis or multiple sclerosis.

l-Citrulline supplementation improves O2 uptake kinetics and high-intensity exercise performance in humans

“…As such, the majority of an oral Cit load passes into the systemic circulation, as reflected by a significant increase in plasma [Cit] after Cit ingestion in the current study and numerous previous reports (8,16,42,51,53). Thereafter, the bulk of plasma Cit is converted to Arg, mostly in the kidneys (15,24,59,65,70), but also in several other tissues (15,23,70). This is compatible with the significant increase in plasma [Arg] in this study and several previous studies (32,47,53,62) following Cit supplementation.…”

“…Consequently, the majority of an oral Cit bolus passes into the systemic circulation (43). Cit is then extracted by the kidneys to be converted, in sequence, to argininosuccinate and Arg by the enzymes arginoinosuccinate synthase and arginoinosuccinate lyase, respectively (15,24,59,65,70). Synthesis of Arg from Cit is prevalent in other tissues (15,23,70), and this process is facilitated since Cit does not compete with ADMA for cell transport (50, 69).…”

“…Cit is then extracted by the kidneys to be converted, in sequence, to argininosuccinate and Arg by the enzymes arginoinosuccinate synthase and arginoinosuccinate lyase, respectively (15,24,59,65,70). Synthesis of Arg from Cit is prevalent in other tissues (15,23,70), and this process is facilitated since Cit does not compete with ADMA for cell transport (50,69). Importantly, it has been shown that oral Cit supplementation more effectively increases the circulating (32,47,53,62) and tissue (63) [Arg] than an equivalent dose of Arg and that Cit supplementation can increase NOS activation (63) and NO biomarkers (46,53).…”

Two weeks of watermelon juice supplementation improves nitric oxide bioavailability but not endurance exercise performance in humans

“…[29] (+2 fold) and Collins et al [30] (+10% with the lower dose; +25% with the higher dose) compared to the respective placebo/control conditions. Following oral ingestion, circulating L-citrulline is taken up by a number of tissues and subsequently converted, via the stepwise activity of the enzymes, arginoinosuccinate synthase and arginoinosuccinate lyase, to Larginine [17,49,50]. Therefore, the findings of this study suggest that chronic watermelon juice supplementation can increase the circulating L-arginine pool and, by extension, substrate for nitric oxide synthase.…”

The effects on plasma L-arginine levels of combined oral L-citrulline and L-arginine supplementation in healthy males

“…11) L-Citrulline is present in the body and is a potent endogenous precursor of L-arginine as part of the recycling system within the L-citrulline-NO cycle. 12,13) NO synthase catalyzes a complex enzymatic reaction that leads to NO formation from L-arginine and oxygen, generating L-citrulline as a by-product. Interestingly, a clinical trial has shown that oral intake of L-citrulline dose dependently and more effectively increases plasma L-arginine levels than L-arginine supplementation alone in healthy human volunteers.…”