Biochemical Markers of Bone Metabolism: An Overview

Glycine is a major amino acid in mammals and other animals It is synthesized from serine, threonine, choline, and hydroxyproline via inter-organ metabolism involving primarily the liver and kidneys Under normal feeding conditions, glycine is not adequately synthesized in birds or in other animals, particularly in a diseased state Glycine degradation occurs through three pathways: the glycine cleavage system (GCS), serine hydroxymethyltransferase, and conversion to glyoxylate by peroxisomal d-amino acid oxidase Among these pathways, GCS is the major enzyme to initiate glycine degradation to form ammonia and CO2 in animals In addition, glycine is utilized for the biosynthesis of glutathione, heme, creatine, nucleic acids, and uric acid Furthermore, glycine is a significant component of bile acids secreted into the lumen of the small intestine that is necessary for the digestion of dietary fat and the absorption of long-chain fatty acids Glycine plays an important role in metabolic regulation, anti-oxidative reactions, and neurological function Thus, this nutrient has been used to: (1) prevent tissue injury; (2) enhance anti-oxidative capacity; (3) promote protein synthesis and wound healing; (4) improve immunity; and (5) treat metabolic disorders in obesity, diabetes, cardiovascular disease, ischemia-reperfusion injuries, cancers, and various inflammatory diseases These multiple beneficial effects of glycine, coupled with its insufficient de novo synthesis, support the notion that it is a conditionally essential and also a functional amino acid for mammals (including pigs and humans)

Glycine metabolism in animals and humans: implications for nutrition and health

The noninvasive assessment of bone turnover has received increasing attention over the past few years because of the need for sensitive markers in the clinical investigation of osteoporosis. Markers of bone formation include the serum measurement of total and bone-specific alkaline phosphatase, osteocalcin, and type I collagen extension peptides. Assessment of bone resorption can be achieved with measurement of fasting urinary calcium and hydroxyproline, urinary hydroxylysine glycosides, urinary excretion of the pyridinium cross-links (pyridinoline and deoxypyridinoline), and plasma tartrate-resistant acid phosphatase activity. Several studies performed in a variety of metabolic bone diseases have shown these markers to be of unequal sensitivity and specificity. In addition, some of them are not fully characterized. For assessment of the level of bone turnover in women with vertebral osteoporosis, serum osteocalcin and urinary pyridinoline appear to be the most sensitive markers so far. Programs combining bone mass measurement and assessment of bone turnover by several markers in women at the time of menopause are being developed in an attempt to improve the assessment of the risk for osteoporosis. Efforts are being made to develop more convenient assays and to identify other markers of bone turnover. A battery of various specific markers is likely to improve the assessment of the complex and subtle abnormalities of bone metabolism that characterize metabolic bone diseases, especially the various aspects of osteoporosis.

Biochemical markers of bone turnover.

Glutamine utilization by the small intestine.

The net renal metabolism of amino acids and ammonia in the post absorptive state was evaluated in subjects with normal renal function and in patients with chronic renal insufficiency by measuring renal uptake and release, and urinary excretion of free amino acids and ammonia. In normal subjects the kidney extracts glutamine, proline, citrulline, and phenylalanine and releases serine, arginine, taurine, threonine, tyrosine, ornithine, lysine, and perhaps alanine. The renal uptake of amino acids from arterial blood occurs by way of plasma only, whereas approximately a half of amino acid release takes place by way of blood cells. Glycine is taken up from arterial plasma, while similar amounts of this amino acid are released by way of blood cells. In the same subjects total renal ammonia production can be largely accounted for by glutamine extracted. In patients with chronic renal insufficiency (a) the renal uptake of phenylalanine and the release of taurine and ornithine disappear; (b) the uptake of glutamine and proline, and the release of serine and threonine are reduced by 80--90%; (c) the uptake of citrulline and the release of alanine, arginine, tyrosine, and lysine are reduced by 60--70%; (d) no exchange of glycine is detectable either by way of plasma or by way of blood cells; (e) exchange of any other amino acid via blood cells disappears, and (f) total renal ammonia production is reduced and not more than 35% of such production can be accounted for by glutamine extracted, so that alternative precursors must be used. A 140% excess of nitrogen release found in the same patients suggests an intrarenal protein and peptide breakdown, which eventually provides free amino acids for ammonia production.

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Renal metabolism of amino acids and ammonia in subjects with normal renal function and in patients with chronic renal insufficiency.

1 Arteriovenous differences fro amino acids across kidneys of normal and chronically acidotic rats were measured Glutamine was the only amino acid extracted in increased amounts in acidosis There was a considerable production of serine by kidneys from both normal and acidotic rats 2 The arterial blood concentration of glutamine was significantly decreased in acidotic animals 3 The glutamine extracted by kidneys of acidotic rats was largely and probably exclusively derived from the plasma 4 The blood lactate concentration was unchanged in acidosis, as was the uptake of lactate by the kidney

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Arteriovenous differences for amino acids and lactate across kidneys of normal and acidotic rats.

The metabolism of hydroxyproline by the rat kidney leads to the production of significant quantities of both glycine and serine. This process was observed in both the isolated perfused kidney and in isolated cortical tubule suspensions. The rate of hydroxyproline metabolism was increased in both preparations by the addition of alanine. The distribution of hydroxyproline oxidase, hydroxyoxoglutarate aldolase and alanine-glyoxalate transaminase were determined in detail. All three enzymes were found exclusively in the renal cortex where they were restricted to the mitochondria. Cortical tubule fractionation studies indicated that the enzymes are located in the proximal convoluted and proximal straight segments at the nephron. The results suggest that hydroxyproline degradation could contribute significantly to the renal synthesis of serine.

Hydroxyproline metabolism by the rat kidney: Distribution of renal enzymes of hydroxyproline catabolism and renal conversion of hydroxyproline to glycine and serine

Insensitivity of the amino acids of canola and rapeseed to methanol-ammonia extraction and commercial processing.

1. Concentrations of polyamines, amino acids, glycogen, nucleic acids and protein, and activities of ornithine decarboxylase and S-adenosylmethionine decarboxylase, were measured in livers from control, streptozotocin-diabetic and insulin-treated diabetic rats. 2. Total DNA per liver and protein per mg of DNA were unaffected by diabetes, whereas RNA per mg of DNA and glycogen per g of liver were decreased. Insulin treatment of diabetic rats induced both hypertrophy and hyperplasia, as indicated by an increase in all four of these constituents to or above control values. 3. Spermidine content was increased in the livers of diabetic rats, despite the decrease in RNA, but it was further increased by insulin treatment. Spermine content was decreased by diabetes, but was unchanged by insulin treatment. Thus the ratio spermidine/spermine in the adult diabetic rat was more typical of that seen in younger rats, whereas insulin treatment resulted in a ratio similar to that seen in rapidly growing tissues. 4. Ornithine decarboxylase activity was variable in the diabetic rat, showing a positive correlation with endogenous ornithine concentrations. This correlation was not seen in control or insulin-treated rats. Insulin caused a significant increase in ornithine decarboxylase activity relative to control or diabetic rats. 5. S-Adenosylmethionine decarboxylase activity was increased approx. 2-fold by diabetes and was not further affected by insulin. 6. Hepatic concentrations of the glucogenic amino acids, alanine, glutamine and glycine were decreased by diabetes. Their concentrations and that of glutamate were increased by injection of insulin. Concentrations of ornithine, proline, leucine, isoleucine and valine were increased in livers of diabetic rats and were decreased by insulin. Diabetes caused a decrease in hepatic concentration of serine, threonine, lysine and histidine. Insulin had no effect on serine, lysine and histidine, but caused a further fall in the concentration of threonine.

Polyamine and amino acid content, and activity of polyamine-synthesizing decarboxylases, in liver of streptozotocin-induced diabetic and insulin-treated diabetic rats.

Glycine is metabolized in isolated renal cortical tubules to stochiometric qualities of ammonia, CO2 and serine by the combined actions of the glycine-cleavage-enzyme complex and serine hydroxymethyltransferase. The rate of renal glycine metabolism by this route is increased in tubules from acidotic rats, but is not affected in vitro by decreasing the incubation pH from 7.4 to 7.1. Metabolic acidosis caused an increase in the renal activity of the glycine-cleavage-enzyme complex, but there were no changes in the activity of serine hydroxymethyltransferase or of methylenetetrahydrofolate dehydrogenase. This enzymic adaptation permits increased ammoniagenesis from glycine during acidosis. The physiological implications are discussed.

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Douglas E. Hall

Papers

Arteriovenous differences for amino acids and lactate across kidneys of normal and acidotic rats.

Hydroxyproline metabolism by the rat kidney: Distribution of renal enzymes of hydroxyproline catabolism and renal conversion of hydroxyproline to glycine and serine

Insensitivity of the amino acids of canola and rapeseed to methanol-ammonia extraction and commercial processing.

Polyamine and amino acid content, and activity of polyamine-synthesizing decarboxylases, in liver of streptozotocin-induced diabetic and insulin-treated diabetic rats.

Increased activity of renal glycine-cleavage-enzyme complex in metabolic acidosis.