REGULATION OF CEREBRAL METABOLISM OF AMINO ACIDS—IV. INFLUENCE OF AMINO ACID LEVELS ON LEUCINE UPTAKE, UTILIZATION AND INCORPORATION INTO PROTEIN IN VZVO*

Abstract

THE relationship between intracerebral levels of free amino acids and the synthesis of brain proteins has not been elucidated. Evidence has been provided from experiments in ciuo that protein synthesis in the central nervous system may be limited by restricted passage of amino acids through the blood-brain barrier ( GAITONDE and RICHTER, 1956;WAELSCH and LAJTHA, 1961 ;RICHTER, 1962). In support of this view is the recent observation that the protein synthetic activities of microsomal and ribosomal preparations from rat cerebral cortex were equivalent under optimal conditions to those of similar preparations from rat liver (ZOMZELY, ROBERTS and RAPAPORT, 1964), whereas hepatic proteins were renewed much more rapidly in viva than brain proteins (LAJTHA, FURST, GERSTEIN and WAELSCH, 1957;LAJTHA, 1959). Studies with isolated cerebral microsomes and ribosomes (ZOMZELY et al., 1964) further indicated that protein synthesis in the brain may be unusually sensitive to alterations in levels of amino acids, ions, and other regulatory substances. Similar conclusions may be derived from studies of amino acid incorporation into proteins of brain cortex slices (FOLBERGROVA, 1961 ; MASE, TAKAHASHI and OGATA, 1962).Alterations in the free amino acid composition of cerebral cortex were induced in young adult rats fed diets differing in amino acid content for 4 days (ROBERTS, 1963). In some instances, the cerebral variations reflected differences in plasma levels of amino acids. Concomitant changes were not observed in the total protein content of the cerebral cortex or in the amino acidcomposition of totalcerebral protein. Although these results suggested that protein synthesis in the brain might be relatively independent of alterations in the intracellular pool of free amino acids, differences may have been produced in the rates of synthesis of individual proteins which were not detectable by the methods employed, The present investigations reveal that differences in the distribution of free amino acids in plasma and cerebral cortex, produced by dietary variations or amino acid injection, were accompanied by variations in cerebral protein turnover. METHODS Dietary dejciency.Male rats of an inbred Sprague-Dawley strain were maintained on Purina laboratory chow until they were about 6 weeks old and weighed 160-17Og. They were then fed

Glial Metabolism of Isoleucine

“…If the latter remains in the cycle its carbon chain will be converted to the symmetrical molecules succinate and fumarate and subsequently will give rise to [1,[2][3][4][5][6][7][8][9][10][11][12][13] C]malate and [3,4-13 C]malate as well as the corresponding isotopomers of oxaloacetate. These 13 Clabelled isotopomers of malate and oxaloacetate can be transformed under the influence of malic enzyme or phosphoenolpyruvate carboxykinase to [1,[2][3][4][5][6][7][8][9][10][11][12][13] C]pyruvate or [3-13 C]pyruvate, thereby leaving the cycle and serving as precursors of the corresponding lactate isotopomers (Fig. 2a).…”

“…[1,[2][3][4][5][6][7][8][9][10][11][12][13] C]acetyl-CoA entering the TCA cycle by citrate synthase gives rise to [4,[5][6][7][8][9][10][11][12][13] C]glutamine via [4,[5][6][7][8][9][10][11][12][13] C]2-oxoglutarate. If the latter remains in the cycle its carbon chain will be converted to the symmetrical molecules succinate and fumarate and subsequently will give rise to [1,[2][3][4][5][6][7][8][9][10][11][12][13] C]malate and [3,4-13 C]malate as well as the corresponding isotopomers of oxaloacetate. These 13 Clabelled isotopomers of malate and oxaloacetate can be transformed under the influence of malic enzyme or phosphoenolpyruvate carboxykinase to [1,[2]…”

“…13 C of pyruvate may re-enter the cycle by successive actions of the pyruvate dehydrogenase complex and citrate synthase. Indeed, labelled spin-offs from the TCA cycle were identified as [1,[2][3][4][5][6][7][8][9][10][11][12][13] Fig. 5b; Table 2).…”

“…BCAAs are easily transported through the blood-brain barrier into the brain parenchyma [1], where they fulfill several distinct tasks [2,3]: (1) As proteinogenic amino acids they are indispensable in protein synthesis; (2) together with their cognate branched-chain 2-oxo acids, BCAAs serve in maintaining the nitrogen balance in the glutamate/glutamine cycle [4,5]; (3) since, even in the presence of glucose, the BCAAs are rapidly degraded by brain slices [6], neuron-rich [7,8] and astroglia-rich primary cultures [7,9], they are considered as valuable fuel molecules in brain energy metabolism. Furthermore, degradation of BCAAs, especially leucine, provides carbon residues which enter the general metabolism of neural cells and thus are incorporated, e.g., into lipids [10,11] and amino acids [12,13]. The importance of BCAAs for brain metabolism is also stressed by the fact that disorders in their metabolism are associated with pathobiochemical conditions leading to metabolic diseases that are frequently coupled with neurological symptoms [14].…”

Alteration in Composition of Deoxyribonucleic Acid, Ribonucleic Acid, Proteins, and Amino Acids in Brain of Rats Fed High and Low Phenylalanine Diets

“…Cerebral protein synthesis appears to be particularly sensitive to changes in endogenous levels of amino acids [24,29]. Mase el al.…”