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Substitution of Five Essential Amino Acids by their Alpha-keto Analogues in the Diet of Rats¹

Departments of Pharmacology and Experimental Therapeutics and Medicine, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205

Weanling male rats were fed diets containing essential amino acids as the sole source of nitrogen. Individual amino acids were replaced by equimolar quantities of their alpha-keto analogues (as sodium or calcium salts), with and without sufficient glutamate to make the diets isonitrogenous. Growth and feed efficiency in rats receiving the keto analogue of methionine were the same as in controls receiving L-methionine or DL-methionine with or without neomycin. Urea excretion increased compared with controls fed L-methionine. Substitution of L-phenylalanine, L-leucine or L-valine by its keto analogue reduced feed efficiency by approximately 24%, 33%, and 50%, respectively; urea excretion rose correspondingly. In the case of the keto derivative of leucine, urea clearance doubled. When L-methionine, L-phenylalanine, L-leucine, L-isoleucine, and L-valine were simultaneously replaced by their keto analogues (as calcium salts) isonitrogenously, growth and feed efficiency were reduced 48% and 41%, respectively. Addition of neomycin to the diet did not alter these results significantly, suggesting that intestinal bacteria may not be important in ketoacid utilization. Although nitrogen excretion as a fraction of dietary nitrogen was increased, blood urea fell sharply; urea clearance again doubled. Plasma amino acid concentrations showed depression of valine and leucine, maintenance of phenylalanine, methionine, and isoleucine, and the appearance of alloisoleucine. The activities of urea cycle enzymes measured in liver homogenates were unchanged except for increased carbamyl phosphate synthetase and ornithine transcarbamylase in those rats given neomycin plus the keto analogues. The results show that these analogues can, with varying degrees of efficiency, replace the corresponding amino acids in the diet, even in the presence of intestinal bacteriostasis. The keto analogue of leucine appears to increase the renal clearance of urea.

KEY WORDS: • -keto analogues • amino acids • growth

¹ Supported by USPHS/NIH Research Grant AM 15603, Training Grant GM 01183 from the United States Public Health Service, and by a grant-in-aid from Merck Sharp & Dohme, Inc.

Manuscript received 22 April 1974.

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