Hypothesis: Where the Depleted Plasma Amino Acids Go in Phenylketonuria, and Why

HYPOTHESIS: WHERE THE DEPLETED PLASMA AMINO ACIDS GO IN PHENYLKETONURIA, AND WHY HALVOR N. CHRISTENSEN* Introduction One of the principal merits of our paying attention to each other's work is that our attention is occasionally refocused on our own findings, so that we may come ultimately to understand them. I develop here an instance in which formerly puzzling aspects of older results seem finally to fall into place. I was brought in 1948 [2] to a perception of the plasma amino acid levels as representing the balance in the amino acid traffic among tissues consequent to the competition of tissues for the several amino acids. These are pumped uphill into the tissues, as Van Slyke and Meyer predicted [3], with the exception, however, of the brain, most of which is kept relatively deprived of amino acids—to the obvious advantage of the presumed function of some of them as neurotransmitters. On the basis of observed competition among amino acids for transport into cells, I predicted in 1953 [4, p. 235] that the phenylalanine accumulation in phenylketonuria would surely handicap the flow of some amino acids to the brain. It was not clear to me at the time why the brain might be particularly sensitive to that competitive action, although it was logical to expect a special sensitivity because of continued neural development during infancy. Development When a description of the Na"""-independent transport system's preferring bulky dipolar amino acids was achieved [5], and this system was Support is acknowledged from grant HDO 1233, the Institute for Child Health and Human Development, National Institute of Health, USPHS. A preliminary publication has been presented [I]. *Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109.© 1987 by The University of Chicago. AU rights reserved. 003 1 -5982/87/3002-0524$0 1 .00 186 I Halvor N. Christensen ¦ Amino Acids in Phenylketonuria later identified as the predominant one supplying amino acids across the blood-brain barrier [6], my prediction that the high concentrations of phenylalanine in plasma might lead to nutritional deprivation of the brain could be narrowed, at least temporarily, to the several bulkier amino acids such as tyrosine, tryptophan, leucine, isoleucine, methionine , and valine. A special inhibition of tyrosine entry into the brain by administered phenylalanine and other amino acids was shown in 1962 [7], and the brain levels of several of the bulkier (not necessarily larger) amino acids later were found diminished in experimental hyperphenylalaninemia and in PKU [8, 9]. Conceivably, this transport inhibition might cause the plasma levels of these bulkier amino acids to rise slightly. Paradoxically, however, the circulating levels of a somewhat different group of amino acids were shown to fall rather than to rise, both in clinical and in experimental hyperphenylalaninemia. In his review [10], Knox records the early history of this paradox, which is the particular subject of this paper. Threonine, glutamine, asparagine, proline, alanine, and leucine were included in lists of the affected amino acids [11, 12]. The investigators tried to explain the paradox by proposing that excess phenylalanine may interfere with net movements from the intestine in the intact rat [11, 12], although this suggestion was not regarded as fully solving the problem [12]. In discussing a probably parallel action of orally administered leucine loads in lowering the plasma levels of valine, serine, and isoleucine, not arising from losses of these amino acids into the urine, Nyhan, Borden, and Childs [13] made this plausible statement: ". . . it seems likely that transport of amino acids into cells is responsible for their decreased concentration in the serum." These authors did not explain, however, why amino acids might accumulate in cells in this situation. Phenylalanine in excess was shown rather specifically in suckling rats to stimulate "accumulation and use of amino acids in [various] developing tissues" (including in some instances the brain) [14, 15], although the authors have not made clear to me why phenylalanine should do this, or why the effect should show so much more intensely in the tiny tissue samples from suckling rats a few days old (fig. 1). Nevertheless , these authors concluded (see their title [15]) that amino acid competition for transport was without physiological significance in this situation...