Arginine metabolism : nitric oxide and beyond
TL;DR: Physiological roles and relationships between the pathways of arginine synthesis and catabolism in vivo are complex and difficult to analyse, owing to compartmentalized expression of various enzymes at both organ and subcellular levels.
Abstract: Arginine is one of the most versatile amino acids in animal cells, serving as a precursor for the synthesis not only of proteins but also of nitric oxide, urea, polyamines, proline, glutamate, creatine and agmatine. Of the enzymes that catalyse rate-controlling steps in arginine synthesis and catabolism, argininosuccinate synthase, the two arginase isoenzymes, the three nitric oxide synthase isoenzymes and arginine decarboxylase have been recognized in recent years as key factors in regulating newly identified aspects of arginine metabolism. In particular, changes in the activities of argininosuccinate synthase, the arginases, the inducible isoenzyme of nitric oxide synthase and also cationic amino acid transporters play major roles in determining the metabolic fates of arginine in health and disease, and recent studies have identified complex patterns of interaction among these enzymes. There is growing interest in the potential roles of the arginase isoenzymes as regulators of the synthesis of nitric oxide, polyamines, proline and glutamate. Physiological roles and relationships between the pathways of arginine synthesis and catabolism in v i v o are complex and difficult to analyse, owing to compartmentalized expression of various enzymes at both organ (e.g. liver, small intestine and kidney) and subcellular (cytosol and mitochondria) levels, as well as to changes in expression during development and in response to diet, hormones and cytokines. The ongoing development of new cell lines and animal models using cDNA clones and genes for key arginine metabolic enzymes will provide new approaches more clearly elucidating the physiological roles of these enzymes. Correspondence may be addressed to either Dr. G. Wu (e-mail g-wu@tamu.edu) or Dr. S. M. Morris, Jr. (e-mail sid@hoffman.mgen.pitt.edu) at the addresses given.
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TL;DR: Its striking inter- and intracellular signaling capacity makes it extremely difficult to predict the effect of NOS inhibitors and NO donors, which still hampers therapeutic applications.
Abstract: During the past two decades, nitric oxide (NO) has been recognized as one of the most versatile players in the immune system. It is involved in the pathogenesis and control of infectious diseases, tumors, autoimmune processes and chronic degenerative diseases. Because of its variety of reaction partners (DNA, proteins, low–molecular weight thiols, prosthetic groups, reactive oxygen intermediates), its widespread production (by three different NO synthases (NOS) and the fact that its activity is strongly influenced by its concentration, NO continues to surprise and perplex immunologists. Today, there is no simple, uniform picture of the function of NO in the immune system. Protective and toxic effects of NO are frequently seen in parallel. Its striking inter- and intracellular signaling capacity makes it extremely difficult to predict the effect of NOS inhibitors and NO donors, which still hampers therapeutic applications.
2,944 citations
Cites background from "Arginine metabolism : nitric oxide ..."
...Furthermore, N ω -hydroxy- l -arginine, which is secreted by cells and detectable in the plasma, can be oxidized to citrulline and NO by a number of hemoproteins (such as peroxidases and cytochrome P450) as well as superoxide anion...
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TL;DR: The results indicate that M-1- or M-2-dominant macrophage responses can influence whether Th1/Th2 or other types of inflammatory responses occur.
Abstract: Evidence is provided that macrophages can make M-1 or M-2 responses. The concept of M-1/M-2 fomented from observations that macrophages from prototypical Th1 strains (C57BL/6, B10D2) are more easily activated to produce NO with either IFN-g or LPS than macrophages from Th2 strains (BALB/c, DBA/2). In marked contrast, LPS stimulates Th2, but not Th1, macrophages to increase arginine metabolism to ornithine. Thus, M-1/M-2 does not simply describe activated or unactivated macrophages, but cells expressing distinct metabolic programs. Because NO inhibits cell division, while ornithine can stimulate cell division (via polyamines), these results also indicate that M-1 and M-2 responses can influence inflammatory reactions in opposite ways. Macrophage TGF-b1, which inhibits inducible NO synthase and stimulates arginase, appears to play an important role in regulating the balance between M-1 and M-2. M-1/M-2 phenotypes are independent of T or B lymphocytes because C57BL/6 and BALB/c NUDE or SCID macrophages also exhibit M-1/M-2. Indeed, M-1/M-2 proclivities are magnified in NUDE and SCID mice. Finally, C57BL/6 SCID macrophages cause CB6F1 lymphocytes to increase IFN-g production, while BALB/c SCID macrophages increase TGF-b production. Together, the results indicate that M-1- or M-2-dominant macrophage responses can influence whether Th1/Th2 or other types of inflammatory responses occur. The Journal of Immunology, 2000, 164: 6166 ‐ 6173.
2,501 citations
Cites background from "Arginine metabolism : nitric oxide ..."
...Because NO inhibits cell replication (7, 28, 29), while ornithine (as a precursor of polyamines) can stimulate replication, these results suggested that macrophages from Th1 and Th2 mice can influence immune reactions in opposite ways....
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...This pattern of arginine metabolism makes sense for constructive processes such as wound healing because excess NO would inhibit cell replication/healing, while ornithine could promote cell replication/healing because it is a precursor for polyamines and collagen (7, 28, 29)....
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TL;DR: In this paper, an optimal nutritional countermeasure against space radiation-induced cytotoxicity is designed for the biological safety of astronauts, where a large body of the literature supports the notion that dietary antioxidants are useful radioprotectors.
2,106 citations
TL;DR: Dietary supplementation with one or a mixture of these functional AA, which include arginine, cysteine, glutamine, leucine, proline, and tryptophan, may be beneficial for ameliorating health problems at various stages of the life cycle and optimizing efficiency of metabolic transformations to enhance muscle growth, milk production, egg and meat quality and athletic performance.
Abstract: Recent years have witnessed the discovery that amino acids (AA) are not only cell signaling molecules but are also regulators of gene expression and the protein phosphorylation cascade. Additionally, AA are key precursors for syntheses of hormones and low-molecular weight nitrogenous substances with each having enormous biological importance. Physiological concentrations of AA and their metabolites (e.g., nitric oxide, polyamines, glutathione, taurine, thyroid hormones, and serotonin) are required for the functions. However, elevated levels of AA and their products (e.g., ammonia, homocysteine, and asymmetric dimethylarginine) are pathogenic factors for neurological disorders, oxidative stress, and cardiovascular disease. Thus, an optimal balance among AA in the diet and circulation is crucial for whole body homeostasis. There is growing recognition that besides their role as building blocks of proteins and polypeptides, some AA regulate key metabolic pathways that are necessary for maintenance, growth, reproduction, and immunity. They are called functional AA, which include arginine, cysteine, glutamine, leucine, proline, and tryptophan. Dietary supplementation with one or a mixture of these AA may be beneficial for (1) ameliorating health problems at various stages of the life cycle (e.g., fetal growth restriction, neonatal morbidity and mortality, weaning-associated intestinal dysfunction and wasting syndrome, obesity, diabetes, cardiovascular disease, the metabolic syndrome, and infertility); (2) optimizing efficiency of metabolic transformations to enhance muscle growth, milk production, egg and meat quality and athletic performance, while preventing excess fat deposition and reducing adiposity. Thus, AA have important functions in both nutrition and health.
2,047 citations
Cites background from "Arginine metabolism : nitric oxide ..."
...In adult mammals, the citrulline released from the small intestine is converted into arginine primarily in kidneys and, to a lesser extent, in other cell types (including endothelial cells, leukocytes, and smooth muscle cells) (Fig. 1). However, in neonates, most of the gut-derived citrulline is utilized locally for arginine synthesis ( Wu and Morris 1998 )....
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...For example, arginine is an allosteric activator of N-acetylglutamate synthase, a mitochondrial enzyme that converts glutamate and acetyl-CoA into N-acetylglutamate (an allosteric activator of carbamoylphosphate synthase I) ( Wu and Morris 1998 )....
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TL;DR: Metabolic tracer analysis revealed a Myc-dependent metabolic pathway linking glutaminolysis to the biosynthesis of polyamines, which may represent a general mechanism for metabolic reprogramming under patho-physiological conditions.
1,632 citations