Nick E. Flynn

The metabolic basis of arginine nutrition and pharmacotherapy

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.

Glucocorticoid regulation of amino acid and polyamine metabolism in the small intestine

Several factors (including diets, changes in intestinal fluora, and hormones) regulate postnatal intestinal growth and development. Based on the early studies involving modification of the adrenal gland, pituitary gland or hypothalamus, exogenous glucocorticoids and glucocorticoid receptor antagonists are now used to study glucocorticoid-mediated metabolism of amino acids in the small intestine. Findings from these studies indicate that physiological levels of glucocorticoids stimulate the catabolism of glutamine and proline for the synthesis of citrulline and arginine in enterocytes during weaning. In addition, increases in circulating levels of glucocorticoids enhance expression of arginase, proline oxidase and ornithine decarboxylase, as well as polyamine synthesis from arginine and proline in enterocytes. These actions of the hormones promote intestinal maturation and may have therapeutic effects on intestinal disease (e.g., necrotizing enterocolitis). Molecular aspects, species-specific effects, and developmental responsiveness to glucocorticoids should be taken into consideration in designing both experimental and clinical studies.

Regulation of glutamine and glucose metabolism by cell volume in lymphocytes and macrophages

The effects of osmotically and sucrose-induced cell volume changes on glutamine and glucose metabolism were investigated in rat lymphocytes and macrophages incubated for 10-60 min at 37 degrees C in Krebs-Henseleit bicarbonate buffer (pH 7.4). Decreasing extracellular osmolarity from 336 to 286 mOsmol by decreasing medium NaCl from 119 to 94 mM increased cell volume and the rates of glutamine metabolism and glycolysis in both cell types. Conversely, increasing extracellular osmolarity from 286 to 386 mOsmol by the addition of 50 and 100 mM D-mannitol progressively decreased both cell volume and the rates of glutamine and glucose metabolism in lymphocytes and macrophages. At the same medium osmolarity of 336 mOsmol, the rates of glutamine metabolism and glycolysis were greater with the addition of 50 mM sucrose than with that of 25 mM NaCl. The sucrose-induced increase in cell volume, which is due to the uptake of sucrose by lymphocytes and macrophages via pinocytosis, is associated with enhanced rates of glutamine metabolism and glycolysis. Our findings suggest that cell volume change may be a hitherto unrecognized mechanism for regulating metabolism in lymphocytes and macrophages. The enhanced glutamine and glucose metabolism in these cells in response to mitogenic stimulation or immunological activation may result, at least in part, from the concomitant increase in cell volume.

Chapter 5 Amino acid metabolism in the small intestine: biochemical bases and nutritional significance

Publisher Summary This chapter reviews recent work on intestinal amino acid metabolism, with an emphasis on its biochemical bases and nutritional significance. The small intestine is a highly differentiated and complex organ, responsible for the terminal digestion and absorption of nutrients, and also plays an important role in amino acid metabolism. Most of glutamine and almost all of glutamate and aspartate in the diet are catabolized by the small intestinal mucosa in the first pass. The small intestinal mucosa also degrades enteral arginine, ornithine, proline, branched-chain amino acids, and lysine. In the postabsorptive state, the small intestine takes up arterial glutamine and releases ammonia, alanine, citrulline, and proline as the major nitrogenous products. The intestine-derived citrulline is effectively utilized for arginine synthesis by extrahepatic cells and organs. The extensive catabolism of enteral amino acids by the small intestine substantially reduces their availability to extraintestinal tissues and alters the patterns of amino acids that enter the systemic circulation. It has important practical implications for the utilization efficiency and recommended requirements of dietary protein and amino acids by animals, including humans.

Glycine oxidation and conversion into amino acids in Saccharomyces cerevisiae and Candida albicans

Humans are exposed much more often to exogenous Saccharomyces cerevisiae (a baker’s yeast) than exogenous Candida albicans (a highly infectious yeast) but suffer no apparent complications from S. cerevisiae. We hypothesize that variations in characteristics between these two species may be due, in part, to differences in glycine metabolism. In this study, we examined differences in glycine oxidation between C. albicans and S. cerevisiae. Both C. albicans and S. cerevisiae were cultured in glycine enriched media, followed by determination of glycine oxidation and amino acid concentrations in cells. Glycine was degraded to a much greater extent in C. albicans than in S. cerevisiae. Threonine concentrations and glycine oxidation were also elevated in C. albicans. Almost all of the disappearance of glycine from incubation media was accounted for by the formation of serine, threonine, and CO2 in S. cerevisiae, whereas these products represented only 50% of the metabolized glycine in C. albicans. The unidentified metabolites of glycine in C. albicans, presumably purines, could contribute to its infectious capacity and this warrants further study.

Effect of HCO3− on glutamine and glucose metabolism in lymphocytes

Lymphocytes play a quantitatively important role in glutamine utilization in the body. We hypothesized that in metabolic acidosis characterized by decreased extracellular HCO3- concentration ([HCO3-]), glutamine utilization by lymphocytes may decrease to compensate partially for the increased uptake of glutamine by the kidneys for ammoniagenesis. This study was therefore designed to quantify the effect of extracellular [HCO3-] on glutamine metabolism in lymphocytes relative to glucose utilization. Mesenteric lymph node lymphocytes were incubated at 37 degrees C for 1 hour in Krebs-Henseleit buffer containing 0, 12.5, and 25 mmol/L HCO3- at a constant pH of 7.4 or 15.7 and 25 mmol/L HCO3- at a constant CO2 concentration of 1.25 mmol/L. Reducing extracellular [HCO3-] from 25 to 12.5 mmol/L at constant pH or from 25 to 15.7 mmol/L at constant CO2 concentration decreased glutamine utilization and the production of glutamate and ammonia. A reduction in [HCO3-] from 12.5 to 0 mmol/L further decreased glutamine utilization, as well as the production of all measured glutamine metabolites. Interestingly, decreasing [HCO3-] from 25 to 0 mmol/L had no significant effect on glucose metabolism, although the production of pyruvate (a minor product of glucose in lymphocytes) was decreased in the absence of medium HCO3-. The contribution of glutamine but not of glucose to lymphocyte adenosine triphosphate (ATP) production was decreased with reduced extracellular [HCO3-]. Thus, glucose was a more important fuel for lymphocytes than was glutamine at low [HCO3-].(ABSTRACT TRUNCATED AT 250 WORDS)