PMC:6194691 / 123746-127168 JSONTXT

{"project":"MyTest","denotations":[{"id":"30340614-7906717-30706384","span":{"begin":1377,"end":1380},"obj":"7906717"},{"id":"30340614-8780046-30706384","span":{"begin":1377,"end":1380},"obj":"8780046"},{"id":"30340614-9681479-30706384","span":{"begin":1377,"end":1380},"obj":"9681479"},{"id":"30340614-14720211-30706384","span":{"begin":1377,"end":1380},"obj":"14720211"},{"id":"30340614-9681479-30706385","span":{"begin":1621,"end":1624},"obj":"9681479"},{"id":"30340614-11238772-30706386","span":{"begin":1626,"end":1629},"obj":"11238772"},{"id":"30340614-23104556-30706387","span":{"begin":1645,"end":1648},"obj":"23104556"},{"id":"30340614-11238772-30706388","span":{"begin":2088,"end":2091},"obj":"11238772"},{"id":"30340614-28417264-30706389","span":{"begin":2093,"end":2096},"obj":"28417264"},{"id":"30340614-11238772-30706390","span":{"begin":3417,"end":3420},"obj":"11238772"}],"namespaces":[{"prefix":"_base","uri":"https://www.uniprot.org/uniprot/testbase"},{"prefix":"UniProtKB","uri":"https://www.uniprot.org/uniprot/"},{"prefix":"uniprot","uri":"https://www.uniprot.org/uniprotkb/"}],"text":"Observed fluxes of neutral amino acids compared with their requirement in glutamate synthesis\nA major difficulty is revealed by comparison of the small net fluxes for the large, essential neutral amino acids and the large provision of these amino acids required for transamination to convert α-ketoglutarate into glutamate (see Figs. 16 and 17). For this requirement to be satisfied by influx across the blood–brain barrier of leucine, isoleucine and valine, their combined net influx would need to be \u003e 100 nmol min−1 g−1 (see Sect. 5.5.1). For a cerebral blood flow of 0.57 mL min−1 g−1 (see e.g. Sect. 5.3) that would correspond to an A − V difference \u003e 175 µM. Given that the total of the arterial plasma concentrations for these amino acids is only 392 µM (see Table 3), this A − V difference and hence net rate of transport should have been well above the “noise” in all of the studies, even that in rats (see Table 4).\nIf, as indicated by all available studies, sufficient net inward flux of amino acids does not in fact exist, the amino groups for synthesis of glutamate in the astrocytes must be obtained from sources within the brain. Independent evidence that such a source is available comes from studies comparing isotope dilution in the brain when plasma leucine was labeled with 13C or 15N. 62% of the N in brain leucine was derived from reverse transamination [380–383].\nOne detailed suggestion (see Fig. 18) is that loss of the branched chain α-ketoacids (BCKA), e.g. α-ketoisocaproate, generated in the transamination in the astrocytes is prevented by using a branched chain amino acid (BCAA) shuttle ([382, 384], reviewed in [385]). In this scheme instead of being further metabolized within the astrocytes as shown in Fig. 17, the BCKA are transferred to neurons where the branched chain amino acids (BCAA), e.g. leucine, can be regenerated by transamination from glutamate producing α-ketoglutarate. The leucine is then exported back to the astrocytes while the glutamate within the neuron is regenerated by glutamate dehydrogenase from NH4+ and the α-ketoglutarate [384, 386]. In this scheme NH4+ is taken from the neuron where it is released from glutamine and will be at relatively high concentration. This is shifted to the astrocyte by the BCAA shuttle where it can be combined with new α-ketoglutarate to complete the de novo synthesis of glutamate. This scheme greatly reduces the need for net flux of BCAA across the blood–brain barrier.\nFig. 18 The branched chain amino acid shuttle for provision of branched chain amino acids (BCAA) in the astrocytes to allow de novo synthesis of glutamate. Leucine (Leu) is used as example of a BCAA. α-KG α-ketoglutarate, α-KIC α-ketoisocaproic acid, Gln glutamine, Glu glutamate, g.a glutaminase, g.d glutamate dehydrogenase, g.s glutamine synthetase, t.a transaminase. Losses of Gln, primarily by efflux, and of Glc, primarily by catabolism are replaced by de novo synthesis of α-KG in astrocytes and transamination using Leu producing α-KIC. Leu is regenerated from α-KIC in the neuron by transamination from Glu producing α-KG. The Glu is in turn regenerated from the α-KG and NH4+ by gdh. Loss of N via efflux of Gln, Glu, and Leu is made good by net inward flux of Leu and NH4+. The BCAA shuttle greatly reduces the need for net inward flux of Leu as this is only required to make good the metabolic loss of α-KIC\n(Based on Figure 1 in Hutson [384])"}

{"project":"2_test","denotations":[{"id":"30340614-7906717-30706384","span":{"begin":1377,"end":1380},"obj":"7906717"},{"id":"30340614-8780046-30706384","span":{"begin":1377,"end":1380},"obj":"8780046"},{"id":"30340614-9681479-30706384","span":{"begin":1377,"end":1380},"obj":"9681479"},{"id":"30340614-14720211-30706384","span":{"begin":1377,"end":1380},"obj":"14720211"},{"id":"30340614-9681479-30706385","span":{"begin":1621,"end":1624},"obj":"9681479"},{"id":"30340614-11238772-30706386","span":{"begin":1626,"end":1629},"obj":"11238772"},{"id":"30340614-23104556-30706387","span":{"begin":1645,"end":1648},"obj":"23104556"},{"id":"30340614-11238772-30706388","span":{"begin":2088,"end":2091},"obj":"11238772"},{"id":"30340614-28417264-30706389","span":{"begin":2093,"end":2096},"obj":"28417264"},{"id":"30340614-11238772-30706390","span":{"begin":3417,"end":3420},"obj":"11238772"}],"text":"Observed fluxes of neutral amino acids compared with their requirement in glutamate synthesis\nA major difficulty is revealed by comparison of the small net fluxes for the large, essential neutral amino acids and the large provision of these amino acids required for transamination to convert α-ketoglutarate into glutamate (see Figs. 16 and 17). For this requirement to be satisfied by influx across the blood–brain barrier of leucine, isoleucine and valine, their combined net influx would need to be \u003e 100 nmol min−1 g−1 (see Sect. 5.5.1). For a cerebral blood flow of 0.57 mL min−1 g−1 (see e.g. Sect. 5.3) that would correspond to an A − V difference \u003e 175 µM. Given that the total of the arterial plasma concentrations for these amino acids is only 392 µM (see Table 3), this A − V difference and hence net rate of transport should have been well above the “noise” in all of the studies, even that in rats (see Table 4).\nIf, as indicated by all available studies, sufficient net inward flux of amino acids does not in fact exist, the amino groups for synthesis of glutamate in the astrocytes must be obtained from sources within the brain. Independent evidence that such a source is available comes from studies comparing isotope dilution in the brain when plasma leucine was labeled with 13C or 15N. 62% of the N in brain leucine was derived from reverse transamination [380–383].\nOne detailed suggestion (see Fig. 18) is that loss of the branched chain α-ketoacids (BCKA), e.g. α-ketoisocaproate, generated in the transamination in the astrocytes is prevented by using a branched chain amino acid (BCAA) shuttle ([382, 384], reviewed in [385]). In this scheme instead of being further metabolized within the astrocytes as shown in Fig. 17, the BCKA are transferred to neurons where the branched chain amino acids (BCAA), e.g. leucine, can be regenerated by transamination from glutamate producing α-ketoglutarate. The leucine is then exported back to the astrocytes while the glutamate within the neuron is regenerated by glutamate dehydrogenase from NH4+ and the α-ketoglutarate [384, 386]. In this scheme NH4+ is taken from the neuron where it is released from glutamine and will be at relatively high concentration. This is shifted to the astrocyte by the BCAA shuttle where it can be combined with new α-ketoglutarate to complete the de novo synthesis of glutamate. This scheme greatly reduces the need for net flux of BCAA across the blood–brain barrier.\nFig. 18 The branched chain amino acid shuttle for provision of branched chain amino acids (BCAA) in the astrocytes to allow de novo synthesis of glutamate. Leucine (Leu) is used as example of a BCAA. α-KG α-ketoglutarate, α-KIC α-ketoisocaproic acid, Gln glutamine, Glu glutamate, g.a glutaminase, g.d glutamate dehydrogenase, g.s glutamine synthetase, t.a transaminase. Losses of Gln, primarily by efflux, and of Glc, primarily by catabolism are replaced by de novo synthesis of α-KG in astrocytes and transamination using Leu producing α-KIC. Leu is regenerated from α-KIC in the neuron by transamination from Glu producing α-KG. The Glu is in turn regenerated from the α-KG and NH4+ by gdh. Loss of N via efflux of Gln, Glu, and Leu is made good by net inward flux of Leu and NH4+. The BCAA shuttle greatly reduces the need for net inward flux of Leu as this is only required to make good the metabolic loss of α-KIC\n(Based on Figure 1 in Hutson [384])"}