The fractional conversion of proline to ornithine was 0. Given the low arginine content of human milk and implied high rate of arginine synthesis, the objective of this study was to document whether human infants are able to synthesize arginine and to clearly identify the dietary precursors.
To our knowledge, this is the first multistable isotope study quantifying the metabolism of arginine in enterally fed human preterm infants. We have demonstrated that arginine and its intermediary metabolites, ornithine and citrulline, are synthesized from proline.
Conversely, we have shown that there is no conversion in vivo of the carbon skeleton from dietary glutamate into arginine or its precursors as measured by this method. Clearly, in enterally fed human infants, proline is the major, if not the only, dietary precursor for arginine.
This observation has significant implications when considering arginine requirements. We know of no other potential dietary precursor for arginine; therefore, proline and arginine must be regarded as codependant, with arginine and proline requirements considered in reference to the sum of arginine and proline intake. The sum of the molar content of arginine 0. Then, it follows that arginine or proline intake is likely inadequate during periods of the NICU stay as this level of protein intake for preterm infants cannot be met with human milk until full feeds are established and fully fortified.
These observations suggest that the low arginine documented in preterm infants 7 relates to inadequate intake of proline and arginine.
Whether this is clinically important with either short- or long-term effects is unknown. The enteral turnover measurements of arginine and proline in our study are the first to be published for healthy growing preterm infants; therefore, it is necessary to discuss our results with reference to adult human studies and piglet studies as a model for the preterm infant.
However in the study by Castillo et al. The higher rate in premature neonates compared with adults can be explained by the higher rate of endogenous protein turnover in newborns, which may be as much as 4—6 times greater than that of adults 25 , 26 and the increased requirement for arginine to meet the metabolic demands of growth. There are no comparable data in either human infants or adults. The only available data in humans is i. This similarity suggests that the pattern of metabolism of the two amino acids, i.
The similarity in this ratio for arginine and proline suggests that the splanchnic metabolism of proline in humans may be much higher than previously believed and deserves further investigation to elucidate the proline requirements for the splanchnic organs and whether it is required for protein synthesis alone, amino acid precursor, or other metabolic roles. Of note, in our estimates of enteral turnover, for both arginine and proline, is the considerable variation among subjects, which is greater for arginine than proline reflecting the multiple metabolic roles for arginine, notably creatine and NO synthesis.
The source of this variation is likely multifactorial. It is well recognized that protein turnover rates in preterm infants are much higher than adults and show considerable variation among individuals.
For example, Denne et al. Protein synthesis is the largest component of arginine flux, and therefore, this likely explains the variation observed in our study. In addition, and by necessity, it was not possible to standardize feeds in this study beyond feed volume, and therefore, variation in nutrient intake will have contributed to the overall variation. The milk of choice is expressed breast milk to which fortifier is added when preterm infants reach full feeds. The amount of protein and arginine in breast milk also displays considerable variation.
Montagne et al. There are no human data with which to compare the fractional synthesis rates of ornithine and citrulline; however, these are similar to the synthesis rates reported for the piglet We did not measure any glutamate tracer in the urine glutamate pool. Recognizing that this was a possibility because of high dilution from dietary and endogenous glutamate, we dosed more on a per kg body weight basis than the other tracers.
Because glutamate has a relatively low solubility, we estimated that this was the maximum dose of glutamate that could be given enterally to the infants without risk of inducing feed intolerance. It is possible that absorption of free intraluminal glutamate may have been incomplete; however, this is an unlikely explanation as enrichment of the arginine and proline tracers was significant, and in piglets, it has been demonstrated that almost all enteral glutamate is absorbed and subsequently metabolized by the small intestine A further possible reason for the lack of enrichment of the glutamate pool is that of proton substitution.
This happens when a labeled deuterium atom is replaced by an unlabeled proton. This is an unlikely explanation in this case because the isomer used was [2,4,4,D 3 ] glutamate, and these deuterium atoms are unlikely to be spontaneously replaced because of their location on the molecule.
For example, studying deuterium exchange in arginine, Huang et al. By studying leucine metabolism using two tracers, one carbon the other deuterium labeled, Hoerr et al. Despite the lack of evidence that deuterium substitution may be occurring, the use of a carbon-labeled tracer would circumvent the issue and also allow measurement of oxidation.
Notwithstanding these issues, we conclude that as there was no measurable enrichment of glutamate, it is clear that enterally supplied glutamate is entirely metabolized by the splanchnic organs on first pass. This is in keeping with the findings of others that there is a substantial metabolism of glutamate and glutamine by the gut 30 , 34 , Therefore, although it is clear that P5C synthase is present in piglet enterocytes 18 and that arginine may be synthesized from glutamine in isolated enterocytes 18 , there is negligible, or undetectably low, synthesis of arginine from dietary glutamate in healthy growing preterm infants in vivo , despite the significant metabolism of glutamate by the splanchnic organs.
We hypothesize that in the neonatal enterocyte in vivo that the carbon chain of glutamate is used primarily as an energy source and is rapidly oxidized 36 with the nitrogen atom either excreted or used through transamination.
The main finding in our study is that the dietary precursor for arginine is proline, with no synthesis from glutamate. This is consistent with our work using the neonatal pig in which we have demonstrated, using a number of dietary approaches 14 , 15 , 37 , 38 , that arginine can only be synthesized from proline through citrulline and that there is no in vivo synthesis from enteral glutamate.
Crit Care Med 31 : — Article Google Scholar. Pediatr Res 53 : — Morris SM Jr Enzymes of arginine metabolism. J Nutr : S—S. Amino acids and other nitrogenous substances. Am J Clin Nutr 30 : — J Pediatr : 86— J Pediatr 81 : — J Nutr Biochem 15 : — J Pediatr : — Pediatr Res 38 : 17— Biol Neonate 67 : — J Nutr : — Am J Physiol : E—E L-arginine may interact with certain medications, including 22 :.
Additionally, L-arginine may interact with certain supplements and substances, including 22 :. Keep L-arginine supplements in a cool, dry area. Avoid exposing the supplement to heat or moisture. L-arginine supplementation during pregnancy is typically prescribed and monitored by a healthcare provider for a specific reason, such as preeclampsia or the risk of preeclampsia and intrauterine growth restriction IUGR 22 , This increased need may not be met through diet, especially in women living in low-resource settings without access to protein-rich foods Additionally, although the increased demand for arginine during pregnancy can be provided through diet, protein or individual amino acid supplements may be necessary under certain circumstances.
This may include women who follow restrictive diets or are experiencing severe nausea and vomiting during pregnancy , rendering them unable to meet demands through dietary intake. However, supplements during pregnancy should always be approved and monitored by a healthcare provider. If you are pregnant and interested in taking supplemental L-arginine, consult your healthcare provider for advice. L-arginine supplements have not been researched in breastfeeding women.
The safety of L-arginine has been demonstrated in many populations, including pregnant women and older adults. However, some people, including those with conditions that affect the liver or kidneys, should avoid L-arginine L-arginine supplements are sometimes used in children in the clinical setting and deemed safe when prescribed in appropriate doses. Yet, arginine supplementation in children should always be monitored by a healthcare provider.
This advice is extremely important to follow, as giving a child too high a dose of L-arginine may result in serious side effects and can even be fatal After consumption, your gut and liver rapidly metabolize L-arginine before it has the chance to reach systemic circulation.
For this reason, some argue that L-citrulline , a precursor to L-arginine, may be a better choice for increasing arginine levels. L-citrulline is an amino acid that may be used as an alternative to L-arginine when taken as a supplement.
L-citrulline is converted into L-arginine through a series of enzymatic reactions that take place primarily in your kidneys Research shows that L-citrulline supplements can raise body levels of L-arginine. In fact, some studies show that L-citrulline is more effective at increasing arginine levels than L-arginine supplements 29 , 30 , 31 , 32 , Research has likewise shown that L-citrulline supplements may offer benefits similar to those of L-arginine supplements.
For example, similarly to L-arginine, L-citrulline has been shown to help reduce blood pressure and improve erectile dysfunction in some studies 34 , Additionally, studies show that when L-citrulline used on its own or in combination with L-arginine, it may improve athletic performance and enhance muscle recovery in athletes 33 , 36 , 37 , Furthermore, some of these studies found that citrulline supplements may be more effective than L-arginine supplements at enhancing athletic performance 39 , Therefore, athletes may benefit more from L-citrulline or a combination of L-arginine and L-citrulline over L-arginine alone.
If you have erectile dysfunction, you may be interested in herbal supplements such as L-arginine. Learn the facts about this supplement. Your body can also make arginine in addition to getting it from food sources, so deficiencies are rare. However, a person can become deficient in…. For mild cases of erectile dysfunction ED , the amino acid supplement L-citrulline may be a possible treatment. L-arginine and nitric oxide may be linked to bipolar disorder, but research about this topic is limited.
Nitric oxide is a molecule produced in your body that may offer various health benefits — from improved exercise performance to better brain function…. Maintaining optimal levels of nitric oxide in your body is essential for your overall health. Agmatine can be found in some foods, particularly those that are products of fermentation, such as cheeses and some spirits 45 , 46 , but it is unlikely that the small amounts found in such foods contribute significantly to the total agmatine present in the body.
Although this article will not discuss the role of arginine and its posttranslational modifications in the function of proteins, it should be appreciated that these modifications include not only methylation of arginine residues 47 but also conversion to citrulline 48 or ornithine 49 Figure 2.
The modified arginine residues are released as free amino acids during protein turnover, and elevated concentrations of at least one of them ADMA represent a risk factor for cardiovascular disease 50 , probably through its inhibition of the NOS enzymes 27 , as indicated in Figure 2.
Because homocysteine can inhibit the activity of dimethylarginine dimethylaminohydrolase 51 , the enzyme that degrades ADMA 52 , a complex interplay exists between metabolism of the sulfur-containing amino acids and arginine metabolism.
At the whole-body level, the fraction of free citrulline and ornithine derived from protein turnover is probably quite small. However, because recent studies indicate that multiple intracellular pools of arginine can exist in at least some cell types 23 , arginine derived from protein turnover may therefore represent a not insignificant fraction of at least one of these pools within specific cells.
Investigators have only recently become aware that protein turnover can release various arginine derivatives; thus, the potential effect of this process on arginine metabolism remains to be evaluated. Reduced arginine availability, as can occur during catabolic stress, can preferentially alter the expression of specific proteins beyond what might be anticipated merely as a consequence of changes in rates of global protein synthesis.
Not surprisingly, most of the affected proteins are themselves involved in some aspect of arginine metabolism. Argenomics can be considered to have originated in the early s when Robert Schimke showed that activities of argininosuccinate synthetase and argininosuccinate lyase in several mammalian cell lines are repressed by arginine and increase when arginine is replaced by citrulline 53 , The mechanisms underlying such changes were not known at the time but were later shown to involve regulation at both the transcriptional and the posttranscriptional level of the argininosuccinate synthetase gene 55 , However, the precise mechanisms whereby the changes in transcription occur still remain to be elucidated some 40 y later.
More recently, the expression of several other genes was also shown to be preferentially affected by reductions in arginine availability, which can occur as the result of increased arginase activity. Intriguingly, the effects of arginine deprivation are not identical for these genes nor are the mechanisms that are involved.
Arginine deprivation results in decreased expression of iNOS 57 , 58 and the T cell receptor zeta-chain 59 , 60 but results in increased expression of CAT-1 61 — Some of the regulatory effects of arginine deprivation also can be cell-type-specific. For example, arginine deprivation results in reduced iNOS protein stability in macrophages 58 but not in astrocytes Because the molecules that sense changes in arginine concentration and the signal transduction pathways that link the sensors to the end effects are not known, their identification represents a challenging aspect of ongoing research in arginine metabolism.
Effects of limiting arginine availability on gene expression. Block arrows signify increases or decreases in the indicated features.
Pathways that have not yet been characterized are indicated by dotted lines and question marks. It is clear that our knowledge regarding the identities of the arginine metabolites and the enzymes that use or produce arginine has advanced greatly in recent years, and separate chapters could easily be written or already have been, in some cases for each of the enzymes and metabolites described here.
At the same time, it also is apparent that much remains to be done, including expansion of our knowledge regarding the dynamic state of arginine metabolism in vivo, especially within local anatomic sites, and characterization of the roles and regulation of the many arginine metabolic enzymes and transport systems in health and disease. This is an encouraging state of affairs not only for those of us who already have succumbed to fascination with the metabolic intricacies of this remarkable amino acid but also for those who are seeking new challenges.
SMM conducted the literature review and was solely responsible for drafting the manuscript. The author had no conflicts of interest. Morris SM Jr. Regulation of enzymes of the urea cycle and arginine metabolism. Annu Rev Nutr ; 22 : 87 — Google Scholar.
Recent advances in arginine metabolism. Arginine metabolism in mammals. In: Cynober LA , ed. Metabolic and therapeutic aspects of amino acids in clinical nutrition. Google Preview. Arginine metabolism: enzymology, nutrition, and clinical significance. Proceedings of a symposium dedicated to the memory of Vernon R Young. April 5—6, J Nutr ; suppl : S — S. The metabolic basis of arginine nutrition and pharmacotherapy. Biomed Pharmacother ; 56 : — Satriano J.
Arginine pathways and the inflammatory response: interregulation of nitric oxide and polyamines: review article. Amino Acids ; 26 : — 9. Plasma membrane transporters for arginine. J Nutr ; : S — 9S. Arginine metabolism: nitric oxide and beyond. Biochem J ; : 1 — Rabier D , Kamoun P. Metabolism of citrulline in man. Amino Acids ; 9 : — Almost all about citrulline in mammals.
Amino Acids ; 29 : — Abumrad NN , Barbul A. The use of arginine in clinical practice. Plasma arginine and citrulline kinetics in adults given adequate and arginine-free diets. Generation of a mouse model for arginase II deficiency by targeted disruption of the arginase II gene.
Mol Cell Biol ; 21 : — 3. Eagle H. Amino acid metabolism in mammalian cell cultures. Science ; : — 7. Mammalian urea cycle enzymes. Annu Rev Genet ; 20 : — Arginine synthesis, metabolism, and transport: regulators of nitric oxide synthesis. Cellular and molecular biology of nitric oxide. Regulation of arginine availability and its impact on NO synthesis. In: Ignarro LJ , ed. Nitric oxide. Biology and pathobiology. Mori M , Gotoh T. Regulation of nitric oxide production by arginine metabolic enzymes.
Biochem Biophys Res Commun ; : — 9. Sources of arginine for induced nitric oxide synthesis in the isolated perfused liver. Am J Physiol ; : G — 6. Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions. Hypertension ; 23 : — Kurz S , Harrison DG.
Insulin and the arginine paradox. J Clin Invest ; 99 : — Xie L , Gross SS. Argininosuccinate synthetase overexpression in vascular smooth muscle cells potentiates immunostimulant-induced NO production. J Biol Chem ; : — Role of neutral amino acid transport and protein breakdown for substrate supply of nitric oxide synthase in human endothelial cells.
0コメント