Some recent developments in the study of amino acid metabolism

I 946-47), that amino acids must be channelled preferentially into pathways for the synthesis of tissue proteins.Only when the quantities of amino acids consumed exceed the requirements for protein synthesis are appreciable amounts of amino acids oxidized for energy (Kang-Lee & Harper, 1978; Patterson & Harper, 1982).Among the factors that contribute to the efficiency of this channelling are: ( I ) the enzymes for degradation of essential amino acids, other than the BCAA, are confined almost exclusively to the liver (Miller, 1962); (2) the K,,,s of the aminoacyl-tRNA synthetases are much lower than those of the amino-aciddegrading enzymes so, when tissue amino acid concentrations are low, the former should be saturated with substrate and be fully active, whereas the rates of reaction of the latter will be low (Harper, 1971(Harper, , 1974;;Krebs, 1972;Rogers, 1976);(3) insulin released after ingestion of a meal stimulates uptake of amino acids into cells of tissues such as muscle in which few essential amino acids are degraded and also stimulates protein synthesis (Harper, 1974).Yet, Jefferson & Korner (1969) observed maximum rates of protein synthesis in an in vitro system from perfused liver only when amino acid concentrations in the perfusate were increased several-fold above post-prandial arterial concentrations.A logical inference from these Observations was that amino acids exerted control over the rate of protein synthesis in ways other than by serving as substrates for aminoacyl-tRNA synthetases. Amino acids in the control of protein synthesis and degradationCurrent knowledge of nutritional control of protein synthesis has been summarized by Henshaw (1980) and Austin & Clemens (1981).In starved animals and in animals deprived of protein or a single amino acid, the rate of protein synthesis in several tissues, but especially in muscle, falls.This is associated with disaggregation of polysomes and an accumulation of ribosomal subunits.In mammalian cells in tissue culture, these responses to amino acid deprivation are rapid and recovery occurs equally rapidly when the missing amino acid is provided.Recovery occurs even if new RNA synthesis is inhibited by actinomycin D, indicating that control by amino acid supply is exerted at the level of translation of mRNA rather than at the level of transcription.The presence of uncharged tRNA or depletion of ATP has been shown in cultured cells to depress protein synthesis.Measurements made in starved animals, nevertheless, indicate that starvation will depress protein synthesis even when tRNA is almost all acylated; depression of protein synthesis is also observed under conditions in which ATP is not depleted.Pain & Henshaw (1975) and Pain et al. (1980) observed that, in Ehrlich cells deprived of lysine, the number of initiation complexes (40s Met t R N 4 ) was substantially reduced, and that protein synthesis was stimulated by addition of initiation factor eIF-2.Taken altogether these observations suggest that the block in protein synthesis in response to deprivation of one or more amino acids occurs in reactions involved in the attachment of ribosomes to mRNA and is the result of a reduced rate of initiation.