The Metabolism and Clinical Relevance of the Keto Acid Analogues of Essential Amino Acids

Richards, Peter

doi:10.1042/cs0540589

Cited by 6 publications

(7 citation statements)

References 30 publications

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“…7). BCOA salts have been used before to decrease the dietary nitrogen load given to uremic patients (69,88). With BCOA given 20 mm prior to exercise, plasma ammonia concentration rose slightly less than in a control experiment in the postabsorptive state, and exhaustion (maximal heart rate) was reached after 4 mm at the 100-W level (exhaustion after 1 mm at 100 W in the control experiment).…”

Section: New Observationsmentioning

confidence: 99%

Metabolism of Branched-Chain Amino Acids and Ammonia During Exercise: Clues from McArdle's Disease*

1990

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Patients with McArdle's disease (myophosphorylase deficiency) cannot use muscle glycogen as an energy source during exercise. They therefore are an ideal model to learn about the metabolic adaptations which develop during endurance exercise leading to glycogen depletion. This review summarizes the current knowledge of ammonia and amino acid metabolism in these patients and also adds several new data. During incremental exercise tests in patients with McArdle's disease, forearm venous plasma ammonia concentration rises to a value between 200 and 500 microM. Femoral arteriovenous difference studies show that muscle produces the ammonia. The leg release of both ammonia and glutamine (in mumol/min) has been estimated to be five- to tenfold larger in one of these patients than in healthy individuals exercising at comparable relative work load. Patients with McArdle's disease have a larger uptake of branched-chain amino acids (BCAA) by exercising leg muscles and show a more rapid activation of the muscle branched-chain 2-oxo acid dehydrogenase complex, a key enzyme in the degradation of the BCAA. In general, supplements of BCAA taken before the exercise test lead to a deterioration of exercise performance and a higher increase in heart rate and plasma ammonia during exercise, whereas supplements of branched-chain 2-oxo acids improve exercise performance and lead to a smaller increase in heart rate and plasma ammonia. At constant power output, patients with McArdle's disease show a rapid increase in heart rate and exertion perceived in the exercising muscles, which peak within 10 min after the start of exercise and then fall again ("second wind"). Peak heart rate and peak exertion coincide with a peak in plasma ammonia. Ammonia production during exercise in these patients is estimated to exceed the reported breakdown of ATP to IMP and therefore most likely originates from the metabolism of amino acids. Deamination of amino acids via the reactions of the purine nucleotide cycle and glutamate dehydrogenase are possible pathways. Deamination of glutamine, released by muscle, by glutaminase present in the endothelial cells of the vascular system may also contribute to the ammonia production. The observations made in these patients have led to the hypothesis that excessive acceleration of the metabolism of BCAA drains 2-oxoglutarate in the primary aminotransferase reaction and thus reduces flux in the citric acid cycle and impedes aerobic oxidation of glucose and fatty acids. This draining effect is normally counteracted by the anaplerotic conversion of muscle glycogen to citric acid cycle intermediates, a reaction which is severely hampered in these patients due to the glycogen breakdown defect.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: New Observationsmentioning

confidence: 99%

Metabolism of Branched-Chain Amino Acids and Ammonia During Exercise: Clues from McArdle's Disease*

1990

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“…24 As our previous published data show that patients in group sLP preserve residual renal function better, 13 the increase of E/NEAA ratio may suggest an improved release of NEAA accumulation in group sLP. On the other hand, the use of keto acids in uremic patients could supply EAA for protein synthesis at the expense of endogenous nonessential nitrogen, 12 which may also explain the decrease of NEAA in patients on keto acids-supplemented diets. According to our original study design, we may provide further evidence of it in this study by looking at the difference between groups LP and sLP.…”

Section: Discussionmentioning

confidence: 99%

“…10 In addition, keto acids are of therapeutic value in uremia by supplying EAA for protein synthesis at the expense of endogenous nonessential nitrogen, thus release the kidney burden. 12 It is now unknown whether dietary intervention, which is low in protein and supplemented with keto acids, would do favor for AA metabolism in PD patients. We recently published data 13 suggesting that supplemented low-protein diet is associated with maintenance of residual renal function without altering nutritional status in a randomized controlled trial of PD patients, which did not directly measure plasma AA levels.…”

Section: Introductionmentioning

confidence: 99%

Improved plasma amino acids pattern following 12 months of supplemented low-protein diet in peritoneal dialysis patients

et al. 2010

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Background: Decreased plasma essential amino acid (EAA) levels, increased nonessential amino acid (NEAA) levels, and low EAA to NEAA ratio (E/NEAA) are common in peritoneal dialysis (PD) patients and may impact uremic complications. In the present study, we investigate the impact of keto acids-supplemented lowprotein (sLP) diet on plasma amino acids (AAs) patterns in stable PD patients. Methods: This is a supplemental analysis of a previously published prospective and randomized trial. Thirty-nine PD patients selected from the original population were divided to receive either low (LP: 0.6-0.8 g/kg ideal body weight [IBW]/d, n = 13), keto acids-supplemented low-(sLP: 0.6-0.8 g/kg IBW/d + 0.12 g/kg IBW/d of keto acids, n = 12), or high-(HP: 1.0-1.2 g/kg IBW/d, n = 14) protein diets and followed for 1 year. Plasma AA patterns were assessed at baseline and 12 months using high-performance liquid chromatography. Results: Whereas there were no significant differences between the three groups at baseline, following 12 months, the E/NEAA had increased significantly in group sLP (0.58 ± 0.16 to 0.83 ± 0.20, p < 0.05), but was not different in either LP (0.62 ± 0.20 to 0.72 ± 0.13, p = ns) or HP (0.66 ± 0.14 to 0.74 ± 0.12, p = ns) group. This change in E/NEAA in group sLP was due to a significant decrease in NEAA concomitantly with maintained EAA levels, whereas in the other two groups, neither EAA nor NEAA changed significantly. Conclusions: A low-protein diet supplemented with keto acids significantly improved the pattern of plasma AA in prevalent PD patients.

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“…Much information about the mechanisms of ketoacid utilization has accumulated in the last four decades, mostly as a result of carefully conducted studies performed by Dr Walser in Baltimore, Maryland, and Peter Richards in London. 10,19,20 Together with Peter Richard's group in Stockholm we investigated the extent of utilization of IV or oral 13 C-labeled keto analogues of valine and phenylalanine in three healthy individuals and four uremic patients. (The healthy subjects were Drs Dave Halliday, Susanne Ell, from Australia, and Peter Richards himself.)…”

Section: Proteins Amino Acids and Ketoacids In Uremiamentioning

confidence: 99%

A Thirty‐Year Odyssey in Nitrogen Metabolism: From Ammonium to Dipeptides

Fürst

2000

J Parenter Enteral Nutr

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The Metabolism and Clinical Relevance of the Keto Acid Analogues of Essential Amino Acids

Cited by 6 publications

References 30 publications

Metabolism of Branched-Chain Amino Acids and Ammonia During Exercise: Clues from McArdle's Disease*

Metabolism of Branched-Chain Amino Acids and Ammonia During Exercise: Clues from McArdle's Disease*

Improved plasma amino acids pattern following 12 months of supplemented low-protein diet in peritoneal dialysis patients

A Thirty‐Year Odyssey in Nitrogen Metabolism: From Ammonium to Dipeptides

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