Free <scp>d</scp>-amino acids in human plasma in relation to senescence and renal diseases

Nagata, Yoko; Akino, Toyoaki; Ohno, Kimiyoshi; Kataoka, Yoshimitsu; Ueda, Takahiro; Sakurai, Takao; Shiroshita, Koh-Ichi; Yasuda, Takuji

doi:10.1042/cs0730105

Cited by 89 publications

(47 citation statements)

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“…Because DAO is present at the highest activity in the kidney compared with the other organs, injury to the kidney may cause accumulation of Damino acids. Increasing evidence that plasma levels of D-amino acids were significantly higher in patients with renal diseases than in healthy subjects (1,18) suggests that renal DAO plays a prominent role in elimination of D-amino acids. However, little information is available on the contribution of renal DAO to the elimination of D-amino acids, because the ␣-keto acid and L-amino acid formed are indistinguishable from the endogenous ␣-keto acid and L-amino acid.…”

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confidence: 99%

Role of renald-amino-acid oxidase in pharmacokinetics ofd-leucine

Hasegawa¹,

Matsukawa²,

Shinohara³

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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Amino acids are now recognized to be widely present in mammals. Renal D-amino-acid oxidase (DAO) is associated with conversion of D-amino acids to the corresponding ␣-keto acids, but its contribution in vivo is poorly understood because the ␣-keto acids and/or L-amino acids formed are indistinguishable from endogenous compounds. First, we examined whether DAO is indispensable for conversion of D-amino ]leucine observed in rats suggested that kidney was the principal organ responsible for converting D-leucine to KIC. ␣-ketoisocaproic acid; kidney; nephrectomy ALL AMINO ACIDS, EXCEPT FOR GLYCINE, occur as optically active isomers. Amino acids used in protein synthesis are of the L-configuration, whereas D-amino acids rarely occur in proteins. Recent progress in chromatography on the separation of DL-amino acids reveals that significant amounts of several free D-amino acids are present in higher animals (5). A number of studies have indicated that D-amino acids play essential roles in several physiological functions (2, 9, 17). Because D-amino acids have also been found in foods and beverage drinks (3), it is considered that quite a few D-amino acids are taken into the body via these diets. Thus it has become important to understand how their levels are controlled.D-Amino-acid oxidase (DAO; EC 1.4.3.3) is a flavoenzyme that catalyzes the oxidation of D-amino acids to the corresponding ␣-keto acids (15). These ␣-keto acids are stereospecifically converted to their corresponding L-amino acids by transaminases. Almost all higher animals have DAO in their kidney, liver, and brain, although the mouse is an exception and does not have the enzyme in the liver (11). Because DAO is present at the highest activity in the kidney compared with the other organs, injury to the kidney may cause accumulation of Damino acids. Increasing evidence that plasma levels of D-amino acids were significantly higher in patients with renal diseases than in healthy subjects (1, 18) suggests that renal DAO plays a prominent role in elimination of D-amino acids. However, little information is available on the contribution of renal DAO to the elimination of D-amino acids, because the ␣-keto acid and L-amino acid formed are indistinguishable from the endogenous ␣-keto acid and L-amino acid.One of the unique advantages of the use of a stable isotopelabeled compound as a tracer is that an endogenous compound and its exogenously administered labeled analog are separately measurable by using gas chromatography-mass spectrometry (GC-MS). Our recent use of stable isotope-labeled D-leucine (D-[ 2 H 7 ]leucine) has proved a powerful methodology for examining the pharmacokinetic behavior of exogenously administered D-leucine and studying the conversion of D-leucine to the corresponding ␣-keto acid, ␣-ketoisocaproic acid (KIC), and L-leucine (6 -8, 16 To confirm the role of DAO, we investigated by using the stable isotope tracer technique whether mutant mice lacking DAO activity (ddY/DAO Ϫ ) are able to convert D-leucine to KIC and/or L-leucine. We furthe...

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Role of renald-amino-acid oxidase in pharmacokinetics ofd-leucine

Hasegawa¹,

Matsukawa²,

Shinohara³

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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“…D-AAO is the only enzyme known to metabolize D-amino acids in the kidney (29) and seems to be the main mechanism by which the kidney eliminates D-serine (32). D-AAO metabolizes D-amino acids into their corresponding ␣-keto acids and NH 3 ( Fig.…”

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confidence: 99%

Why isd-serine nephrotoxic and α-aminoisobutyric acid protective?

Krug¹,

Völker²,

Dantzler³

et al. 2007

American Journal of Physiology-Renal Physiology

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d-Serine selectively causes necrosis of S3 segments of proximal tubules in rats. This leads to aminoaciduria and glucosuria. Coinjection of the nonmetabolizable amino acid α-aminoisobutyric acid (AIB) prevents the tubulopathy. d-serine is selectively reabsorbed in S3, thereby gaining access to peroxisomal d-amino acid oxidase (d-AAO). d-AAO-mediated metabolism produces reactive oxygen species. We determined the fractional excretion of amino acids and glucose in rats after intraperitoneal injection of d-serine alone or together with reduced glutathione (GSH) or AIB. Both compounds prevented the hyperaminoaciduria. We measured GSH concentrations in renal tissue before (control) and after d-serine injection and found that GSH levels decreased to ∼30% of control. This decrease was prevented when equimolar GSH was coinjected with d-serine. To find out why AIB protected the tubule from d-serine toxicity, we microinfused d-[14C]serine or [14C]AIB (0.36 mmol/l) together with [3H]inulin in late proximal tubules in vivo and measured the radioactivity in the final urine. Fractional reabsorption of d-[14C]serine and [14C]AIB amounted to 55 and 70%, respectively, and 80 mmol/l of AIB or d-serine mutually prevented reabsorption to a great extent. d-AAO activity measured in vitro (using d-serine as substrate) was not influenced by a 10-fold higher AIB concentration. We conclude from these results that 1) d-AAO-mediated d-serine metabolism lowers renal GSH concentrations and thereby provokes tubular damage because reduction of reactive oxygen species by GSH is diminished and 2) AIB prevents d-serine-induced tubulopathy by inhibition of d-serine uptake in S3 segments rather than by interfering with intracellular d-AAO-mediated d-serine metabolism.

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“…Furthermore, dietary casein contains very small quantities of Damino acids (Man and Bada, 1987) (Nagata et al, 1987). In addition, in mutant mice lactating D -AAOX, D -amino acids seem to be concentrated in many tissues, including the liver and kidney (Nagata et al, 1989;Nagata et al, 1994 (Ohno, 1985).…”

Section: Resultsmentioning

confidence: 99%

Hepatic and renal D-amino acid oxidase activities in the growing rat after ten days of protein undernutrition and refeeding

Carreira

Brun-Achirou²,

Brachet³

et al. 1996

Reprod. Nutr. Dev.

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Summary ― The activity levels of hepatic and renal D -amino acid oxidase (EC 1.4.3.3), a key enzyme for D -amino acid utilization in mammals, were determined in growing rats after a 10 day period of protein undernutrition and subsequent refeeding. Reducing the protein intake for 10 days (3% casein diet) resulted in an 8% loss of the animals' mean body weight and a 50% decrease in the mean size of the liver and kidney as compared to the control animals fed on a 22% casein diet during the same period. When the undernourished rats were refed with the normal protein diet, their weight increased about four fold as compared with that of the control animals, and after a ten day period of refeeding, the lost body and tissue weights were completely recovered. As far as the specific activity of D -amino acid oxidase was concerned, a 44% reduction took place in the liver of rats subjected to protein undernutrition for 10 days. During the period of refeeding, however, the enzyme activity level increased slowly in comparison with the overall hepatic protein level, since its specific activity on day 10 was still 28% below that of the control rats. In sharp contrast, no significant change in the kidney enzyme level was observed throughout these nutritional manipulations. This

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Free d-amino acids in human plasma in relation to senescence and renal diseases

Cited by 89 publications

References 0 publications

Role of renald-amino-acid oxidase in pharmacokinetics ofd-leucine

Role of renald-amino-acid oxidase in pharmacokinetics ofd-leucine

Why isd-serine nephrotoxic and α-aminoisobutyric acid protective?

Hepatic and renal D-amino acid oxidase activities in the growing rat after ten days of protein undernutrition and refeeding

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