This application is a request for funding to continue our research on the dynamic aspects of whole-body amino acid metabolism in adult humans, with particular reference to the nutritionally """"""""dispensable"""""""" (non-essential) amino acids. Our hypothesis is that, despite a constitutive capacity for de novo synthesis, the availability of the dispensable amino acids for meeting the needs for tissue/organ and whole-body protein synthesis and other metabolic functions in vivo is determined by the nitrogen and amino acid composition of the diet and other dietary factors and the relationship between the dynamic status of amino acid synthesis and degradation. The """"""""dispensable"""""""" amino acids of particular research interest here will be (a) arginine-ornithine-citrulline-proline """"""""tetrad"""""""", with additional emphasis on urea metabolism; (b) cysteine and (c) glycine. We have already made new and exciting progress in this area and sharpened our concepts of dispensable amino acids.
The specific aims are (1) (a) to continue to explore in vivo, whole-body metabolic and kinetic relationships among the urea cycle intermediates, arginine, ornithine and citrulline, under conditions of different intakes of total nitrogen and sources of amino acid nitrogen; (b) to supplement this with direct studies of urea kinetics and metabolism. (2) to determine the comparative, quantitative effects of dietary ornithine, citrulline or proline supplements on their metabolic status and on arginine and urea kinetics at adequate and low arginine intakes. (3) to examine the whole-body metabolic/kinetic interrelationships between methionine and cysteine as affected by level and route of methionine and cysteine intake and to explore in initial studies how these parameters affect glutathione status and metabolism. (4) to assess the effects of source and level of dispensable amino acid intake on threonine metabolism and threonine- glycine interrelationships, as a basis for understanding the potential role of glycine as a conditionally-dispensable amino acid. The proposed studies will help us further define the quantitative role played by dispensable amino acids in the maintenance of whole-body protein and amino acid homeostasis, and supplement and enhance emerging new knowledge concerning the molecular and cellular functions of amino acids. Our overall objective is to provide an integrative, biochemically-based definition of the nitrogen economy of the intact human organism.
