Editor’s Note: In this paper and in a review published in Nutrition Reviews thefollowing year (1956:14:225-7), Harper synthesized the concept of amino acid imbalance and thus enlarged our concepts of metabolism and expanded the basisfor evaluating the nutritional quality of proteins.



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IMPORTANCE OF AMINO ACID BALANCE IN NUTRITION A.E. HARPERAND C.A. ELVEHJEM During the early developments in nutrition there was a tendency to place certain nutrients in large groups, such as carbohydrates, minerals, and B-vitamins, and to deal with them in general terms. With progress in . . . biochemical research . . . it has become evident that each group consists of special components that . . . must be consided separately. Similarly we are inclined to think of protein as a single dietary component rather than as a group of specific compounds, but the time is rapidly approaching when it will be necessary to think . . . of the individual amino acids supplied by protein. . . During a study on the effect of amino acids on the deposition of liver fat in rats fed low-protein diets containingcholine, . . . supplementation of a low-protein diet, deficient primarily in methionine. with this amino acid precipitated a threonine deficiency that caused an increase in the deposition of liver fat. In other studies with other proteins, supplementation of the diet with amino acids that are not primarily limiting has been shown to increase the severity of the primary amino acid deficiency. The addition of tryptophandeficient proteins to diets low in tryptophan increased the requirement for tryptophan; the addition of lysine to a diet low in histidine caused a growth depression that was comcted only by the addition of histidine; and supplementation of certain ceml diets, deficient in threonine, with valine depressed growth. These observations are similar to the earlier observations that the inclusion of threonine in a low-protein diet deficient in niacin caused a severe growth depression that could be comted only by supplementing the diet with either niacin or its precursor tryptophan. Subsequently other amino acid supplements have been shown to produce similar effects. The severity of other vitamin deficiencies, such as the lack of sufficient pyridoxine and sufficient vitamin B,,, has been made greater by the addition of amino acids to the deficient diets. Toxic or other deleterious effects in laboratwy animals resulting from the addition of an excess of individual amino acids to diets that may or may not be particularly deficient,

have been reported from time to time. Recently it has been shown that the addition of ao excess of leucine to a diet that was not deficient in isoleucine depressed growth, and the growth depression was overc~mconly when the amount of isoleucine in the diet was increased. Although it has been thought that imbalancesarc unlikely to occur with natural foods and footstuffs, some evidence has been obtained that indicates that the level of leucine in corn and, in particular, in the corn protein zein, may be sufficiently high to increase the requirement for isoleucine. In a study with rice diets some preliminary results indicate that the balance of amino acids must be very delicate, because the addition of even a small amount of leucine to the diet depressed growth quite markedly. Another still different situation has come to light during the course of the studies on rice diets. Although a marked growth response has been observed in rats fed rice diets s u p plemented with lysine and threonine. the relatively small amounts of lysine and threonine that stimulated growth did not prevent the accumulation of fat in the livers of young rats fed diets composed almost entkly of rice. A further increasC in the level of lysine, which reduced the deposition of liver fat to normal, caused a growth depression that was comted only when the levels of several of the other essential amino acids in the diet were increased. These observations, which arc just a few among the many amino acid internlationship that have been studied, indicate that at least three types of amino acid imbalance may be encountered: I. When the most limiting amino acid in a diet generally poor in protein is increased, a deficiency of the next most limiting amino acid may occur, a situation that has its parallel in the early studies with the B vitamins, the coaverse of this, the addition of a small amount of the second most limiting amino acid, may increase the severity of the deficiency of the most limiting amino acid. 2. When an excess of an amino acid, which may or may not be limiting, is added to a diet that is marginal in certain of the B vitamins, the severity of the vitamin deficiency may be increased. 3. In some cases an excess of an amino acid may reduce the utilization of another amino acid that is provided in normally adequate amounts in the diet to such an extent that a deficiency occurs. Two other points arising from these studies should also be emphasized. Om is that what may be considered a satisfactory balance of amino acids by one criterion, e.g., growth, may be inadequate when judged by another criterion, e.g., the deposition of liver fat. The other is that unlike the B vitamins, which can be administered in amounts ranging from hundreds to thousands of times the known requirements, the toxic levels of many of the amino acids range from 2 to 10 timesthe requirements, depending on the dietary regimen. It is evident from a consideration of these facts that a thorough investigation of the effect of amino acid supplementation will be required before the addition of individual amino acids to diets that arc deficient in several respects cao be considered a safe procadurt.


Journal of the American Medical Association, Volume 158, 1955: Importance of amino acid balance in nutrition.

NUTRITION CLASSIC Editor’s Note: In this paper and in a review published in Nutrition Reviews thefollowing year (1956:14:225-7), Harper synthesized t...
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