The metabolic basis of arginine nutrition and pharmacotherapy

doi:10.1016/S0753-3322(02)00273-1

Biomedicine & Pharmacotherapy

Volume 56, Issue 9, November 2002, Pages 427-438

https://doi.org/10.1016/S0753-3322(02)00273-1 Get rights and content

Abstract

As an essential precursor for the synthesis of proteins and other molecules with enormous biological importance (including nitric oxide, urea, ornithine, proline, polyamines, glutamate, creatine, agmatine, and dimethylarginines), arginine displays remarkable metabolic and regulatory versatility. Evidence available to date provides a sound reason to classify arginine as an essential amino acid for young mammals (including parenterally fed human infants) and as a conditionally essential amino acid for adults under such conditions as trauma, burn injury, massive small-bowel resection, and renal failure. Arginine administration reverses endothelial dysfunction, enhances wound healing, prevents the early stages of tumorigenesis, and improves cardiovascular, reproductive, pulmonary, renal, digestive, and immune functions. Arginine or its effective precursor citrulline may hold great promise as a nutritional or pharmacotherapeutic treatment for a wide array of human diseases.

Introduction

A century after its first isolation from lupin seedlings, L-arginine (2-amino-5-guanidinovaleric acid) was identified in 1988 as the physiological precursor for nitric oxide (NO) synthesis in animal cells 〚1〛. NO is the major endothelium-derived relaxing factor, a mediator of immune responses, a neurotransmitter, a cytotoxic free radical, and a widespread signaling molecule in the body 〚2〛. The discovery of NO synthesis has stimulated an enormous interest in the biochemistry, nutrition, and pharmacology of arginine over the past 15 years. As such, extensive studies have been conducted to explore nutritional or therapeutic roles of arginine to treat a wide array of human diseases that are associated with a relative or absolute deficiency of arginine or with a reduced bioavailability of NO 〚3〛, 〚4〛, 〚5〛. In addition to NO, other products of arginine catabolism, such as ornithine, proline, polyamines (putrescine, spermidine and spermine), creatine, agmatine, and glutamate (Fig. 1), may also mediate the beneficial effects of arginine 〚6〛, thus extending its physiological roles to virtually every cellular and organ function in the body. The major objective of this article is to examine the metabolic basis of arginine nutrition and pharmacotherapy.

Section snippets

Arginine synthesis and catabolism

A brief summary of arginine metabolism is necessary to appreciate the broad implications of arginine for health, disease, and clinical applications. For a general knowledge of mammalian arginine metabolism and its molecular regulation, readers are referred to the recent comprehensive reviews by Wu and Morris 〚6〛 and Morris 〚7〛. Here, we will focus on the salient features of arginine synthesis and catabolism that are most pertinent to this article.

Roles of arginine in hormone secretion, proteolysis, gene expression, and oxidative defenses

Arginine stimulates the secretion of pancreatic hormones (insulin and glucagon), anterior pituitary hormones (growth hormone and prolactin), and placental lactogen in humans and animals 〚37〛, thereby regulating the metabolism of protein, amino acids, glucose, and fatty acids, as well as conceptus development. Also, arginyl-tRNA is not only an immediate precursor for protein synthesis but participates in the posttranslational conjugation of arginine with the N-termini of proteins bearing

Bioavailability and safety of arginine administration

Dietary arginine intake by the average American adult has been estimated to be 5.4 g/day 〚45〛. In both humans and animals, owing to a relatively high arginase activity in the small intestinal mucosa, ∼40% of dietary arginine is degraded during absorption and the remainder enters the portal vein 〚54〛, 〚76〛. Because the amino acid transport system y⁺ is virtually absent from hepatocytes, > 85% of the arginine delivered to the liver is not taken up by this organ 〚6〛. On the basis of the

Clinical applications of arginine

The knowledge of arginine metabolism has provided a biochemical basis for its use to prevent and treat a wide array of human diseases and to develop pharmacotherapeutic strategy. A defect in NO synthesis from arginine results in abnormalities in nervous, muscular, circulatory, respiratory, digestive, urinary, reproductive, endocrine, and immune systems 〚3〛, 〚4〛, 〚5〛. As such, increasing arginine provision is likely beneficial for patients with these disorders. In contrast, excessive production

Concluding remarks and perspectives

An important concept that has emerged from this review is that arginine displays remarkable metabolic and regulatory versatility in mammals. Thus, the beneficial or destructive roles of arginine critically depend on the relative activities of arginine-catabolizing enzymes, and precise regulation of these enzymes has important implications for health and disease. Much of the data regarding the role of arginases in regulating NO, polyamine, proline and glutamate synthesis have been generated from

Acknowledgements

Work in our laboratories is supported, in part, by grants from the United State Department of Agriculture, the American Heart Association, and Juvenile Diabetes Research Foundation, by a Hatch project from the Texas Agricultural Experiment Station, and by a Texas A&M University Faculty Fellowship. We thank Frances Mutscher for office support.

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Biomedicine & Pharmacotherapy

Dossier: Free amino acids in human health and pathologiesThe metabolic basis of arginine nutrition and pharmacotherapy☆

Abstract

Introduction

Section snippets

Arginine synthesis and catabolism

Roles of arginine in hormone secretion, proteolysis, gene expression, and oxidative defenses

Bioavailability and safety of arginine administration

Clinical applications of arginine

Concluding remarks and perspectives

Acknowledgements

Regulation of hyperglycemia and dyslipidemia by exogenous L-arginine in diabetic rats

Biochimie

Nitrogen metabolism in sickle cell anemia—free amino acids in plasma and urine

Am J Med Sci

Arginine supplementation prevents necrotizing enterocolitis in the premature infant

J Pediatr

Reduced serum amino acid concentrations in infants with necrotizing enterocolitis

J Pediatr

Plasma L-arginine concentrations in premature infants with necrotizing enterocolitis

J Pediatr

Hyperammonemia resulting from intravenous alimentation using a mixture of synthetic L-amino acids: a preliminary report

J Pediatr

Dietary L-arginine prevents fetal growth restriction in rats

Am J Obstet Gynecol

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Dossier: Free amino acids in human health and pathologies
The metabolic basis of arginine nutrition and pharmacotherapy☆

Purification and properties of a new enzyme, N^G,N^G-dimethylarginine dimethylaminohydrolase, from rat kidney