PMC:6194691 / 104432-107822 JSONTXT

{"project":"MyTest","denotations":[{"id":"30340614-14400-30706304","span":{"begin":456,"end":459},"obj":"14400"},{"id":"30340614-9419373-30706305","span":{"begin":1005,"end":1008},"obj":"9419373"},{"id":"30340614-23104556-30706306","span":{"begin":1409,"end":1412},"obj":"23104556"},{"id":"30340614-27023624-30706307","span":{"begin":1414,"end":1417},"obj":"27023624"},{"id":"30340614-27696119-30706308","span":{"begin":1419,"end":1422},"obj":"27696119"},{"id":"30340614-24989463-30706309","span":{"begin":1699,"end":1702},"obj":"24989463"},{"id":"30340614-18486589-30706310","span":{"begin":1704,"end":1707},"obj":"18486589"},{"id":"30340614-24436052-30706311","span":{"begin":1709,"end":1712},"obj":"24436052"},{"id":"30340614-11320540-30706312","span":{"begin":1903,"end":1906},"obj":"11320540"},{"id":"30340614-16407855-30706313","span":{"begin":1908,"end":1911},"obj":"16407855"},{"id":"30340614-14720211-30706314","span":{"begin":2593,"end":2596},"obj":"14720211"},{"id":"30340614-27023624-30706315","span":{"begin":2598,"end":2601},"obj":"27023624"},{"id":"30340614-27696119-30706316","span":{"begin":2603,"end":2606},"obj":"27696119"},{"id":"30340614-9298851-30706317","span":{"begin":2608,"end":2611},"obj":"9298851"},{"id":"30340614-36379-30706318","span":{"begin":2640,"end":2643},"obj":"36379"},{"id":"30340614-2882529-30706319","span":{"begin":2735,"end":2738},"obj":"2882529"},{"id":"30340614-36379-30706320","span":{"begin":2740,"end":2743},"obj":"36379"},{"id":"30340614-27023624-30706321","span":{"begin":2745,"end":2748},"obj":"27023624"},{"id":"30340614-11880482-30706322","span":{"begin":2977,"end":2980},"obj":"11880482"},{"id":"30340614-17076763-30706323","span":{"begin":2982,"end":2985},"obj":"17076763"},{"id":"30340614-12524459-30706324","span":{"begin":3105,"end":3108},"obj":"12524459"},{"id":"30340614-21882281-30706325","span":{"begin":3110,"end":3113},"obj":"21882281"},{"id":"30340614-23043456-30706326","span":{"begin":3210,"end":3213},"obj":"23043456"},{"id":"30340614-27885628-30706327","span":{"begin":3215,"end":3218},"obj":"27885628"},{"id":"30340614-28417264-30706328","span":{"begin":3376,"end":3379},"obj":"28417264"},{"id":"30340614-27023624-30706329","span":{"begin":3381,"end":3384},"obj":"27023624"},{"id":"30340614-27696119-30706330","span":{"begin":3386,"end":3389},"obj":"27696119"}],"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":"The glutamate/glutamine cycle shown in bold with indication of some of the losses and of replenishment of glutamate by denovo synthesis. Glutamate (Glu) in the presynaptic neuron is packaged into vesicles and released into the ISF during neurotransmission. Most of the glutamate is taken up into the astrocytes by the transporter Eaat1 (glast, Slc1a3) where it is converted to glutamine (Gln) by addition of an NH4+ by the enzyme glutamine synthase (g.s) [642, 643]. The glutamine is transported into the ISF by Snat3 and/or Snat5 (Slc38a3 and Slc38a5) from which it is taken up into the presynaptic terminals again by a transporter that may be a Snat. The glutamate is then regenerated by glutaminase (g.a). This cycle represents a large turnover of the amide group at the end of the side chain in glutamine, estimated to be 55% of the CMRglc (cerebral metabolic rate of glucose, see Sect. 5.3) for the entire brain in rats amounting to 490 nmol g−1 min−1 (estimated value in humans 280 nmol g−1 min−1) [644] (G. A. Dienel, personal communication). However the requirement for NH4+ consumed in the conversion of glutamate to glutamine within the astrocytes is balanced by an equal release of NH4+ in the reverse conversion in neurons. Whether diffusion of NH4+ itself is adequate to transfer the nitrogen from neurons to astrocytes as shown or some other form of N carrier is required remains controversial [385, 641, 645]. Regardless, if there were no losses of glutamine or glutamate from the cycle, there would be no need for any fluxes of amino acids into or out of the parenchyma to support glutaminergic neurotransmission. However, there are losses of glutamate and glutamine from the cycle [347, 646, 647]. At least in rodents, such losses are made good by de novo synthesis of glutamate in the astrocytes. Estimates of the total rate of loss and of de novo synthesis are around 11% of CMRglc ([648, 649] (G. A. Dienel, personal communication), i.e. about 0.11 × 0.9 µmol g−1 min−1 ≅ 100 nmol g−1 min−1. The carbon skeletons for the de novo synthesis are derived ultimately from glucose. Glucose is metabolized to two molecules of pyruvate one of which is carboxylated by pyruvate carboxylase (p.c) (thought to be present within the brain only in astrocytes) to form oxaloacetic acid (OAA) a component of the citric acid cycle. Addition of acetyl-CoA from the second pyruvate then forms citrate, which is decarboxylated to form α-ketoglutarate (α-KG). Glutamate is then formed either a by transamination (t.a) of α-ketoglutarate using leucine or other amino acids as source (see e.g. [383, 641, 645, 650], or b by addition of NH4+ [366] catalyzed by glutamate dehydrogenase (g.d). The latter is believed to be a minor pathway [359, 366, 641]. The source of the amino groups for transamination is considered further in Sect. 5.5.3 and Fig. 18. Data for the pathways involved in glutamate synthesis are much less extensive for human than for rat. Rothman and colleagues [651, 652] have argued that the α-ketoglutarate is synthesized in astrocytes based on measurements of incorporation of 13C (see [653, 654]). However, the failure to find a key transaminase in human astrocytes by immunohistochemistry [655, 656] has cast some doubt on astrocytes being the major site for the conversion from α-ketoglutarate to glutamate. For recent reviews of glutamate synthesis see [386, 641, 645]"}

{"project":"2_test","denotations":[{"id":"30340614-14400-30706304","span":{"begin":456,"end":459},"obj":"14400"},{"id":"30340614-9419373-30706305","span":{"begin":1005,"end":1008},"obj":"9419373"},{"id":"30340614-23104556-30706306","span":{"begin":1409,"end":1412},"obj":"23104556"},{"id":"30340614-27023624-30706307","span":{"begin":1414,"end":1417},"obj":"27023624"},{"id":"30340614-27696119-30706308","span":{"begin":1419,"end":1422},"obj":"27696119"},{"id":"30340614-24989463-30706309","span":{"begin":1699,"end":1702},"obj":"24989463"},{"id":"30340614-18486589-30706310","span":{"begin":1704,"end":1707},"obj":"18486589"},{"id":"30340614-24436052-30706311","span":{"begin":1709,"end":1712},"obj":"24436052"},{"id":"30340614-11320540-30706312","span":{"begin":1903,"end":1906},"obj":"11320540"},{"id":"30340614-16407855-30706313","span":{"begin":1908,"end":1911},"obj":"16407855"},{"id":"30340614-14720211-30706314","span":{"begin":2593,"end":2596},"obj":"14720211"},{"id":"30340614-27023624-30706315","span":{"begin":2598,"end":2601},"obj":"27023624"},{"id":"30340614-27696119-30706316","span":{"begin":2603,"end":2606},"obj":"27696119"},{"id":"30340614-9298851-30706317","span":{"begin":2608,"end":2611},"obj":"9298851"},{"id":"30340614-36379-30706318","span":{"begin":2640,"end":2643},"obj":"36379"},{"id":"30340614-2882529-30706319","span":{"begin":2735,"end":2738},"obj":"2882529"},{"id":"30340614-36379-30706320","span":{"begin":2740,"end":2743},"obj":"36379"},{"id":"30340614-27023624-30706321","span":{"begin":2745,"end":2748},"obj":"27023624"},{"id":"30340614-11880482-30706322","span":{"begin":2977,"end":2980},"obj":"11880482"},{"id":"30340614-17076763-30706323","span":{"begin":2982,"end":2985},"obj":"17076763"},{"id":"30340614-12524459-30706324","span":{"begin":3105,"end":3108},"obj":"12524459"},{"id":"30340614-21882281-30706325","span":{"begin":3110,"end":3113},"obj":"21882281"},{"id":"30340614-23043456-30706326","span":{"begin":3210,"end":3213},"obj":"23043456"},{"id":"30340614-27885628-30706327","span":{"begin":3215,"end":3218},"obj":"27885628"},{"id":"30340614-28417264-30706328","span":{"begin":3376,"end":3379},"obj":"28417264"},{"id":"30340614-27023624-30706329","span":{"begin":3381,"end":3384},"obj":"27023624"},{"id":"30340614-27696119-30706330","span":{"begin":3386,"end":3389},"obj":"27696119"}],"text":"The glutamate/glutamine cycle shown in bold with indication of some of the losses and of replenishment of glutamate by denovo synthesis. Glutamate (Glu) in the presynaptic neuron is packaged into vesicles and released into the ISF during neurotransmission. Most of the glutamate is taken up into the astrocytes by the transporter Eaat1 (glast, Slc1a3) where it is converted to glutamine (Gln) by addition of an NH4+ by the enzyme glutamine synthase (g.s) [642, 643]. The glutamine is transported into the ISF by Snat3 and/or Snat5 (Slc38a3 and Slc38a5) from which it is taken up into the presynaptic terminals again by a transporter that may be a Snat. The glutamate is then regenerated by glutaminase (g.a). This cycle represents a large turnover of the amide group at the end of the side chain in glutamine, estimated to be 55% of the CMRglc (cerebral metabolic rate of glucose, see Sect. 5.3) for the entire brain in rats amounting to 490 nmol g−1 min−1 (estimated value in humans 280 nmol g−1 min−1) [644] (G. A. Dienel, personal communication). However the requirement for NH4+ consumed in the conversion of glutamate to glutamine within the astrocytes is balanced by an equal release of NH4+ in the reverse conversion in neurons. Whether diffusion of NH4+ itself is adequate to transfer the nitrogen from neurons to astrocytes as shown or some other form of N carrier is required remains controversial [385, 641, 645]. Regardless, if there were no losses of glutamine or glutamate from the cycle, there would be no need for any fluxes of amino acids into or out of the parenchyma to support glutaminergic neurotransmission. However, there are losses of glutamate and glutamine from the cycle [347, 646, 647]. At least in rodents, such losses are made good by de novo synthesis of glutamate in the astrocytes. Estimates of the total rate of loss and of de novo synthesis are around 11% of CMRglc ([648, 649] (G. A. Dienel, personal communication), i.e. about 0.11 × 0.9 µmol g−1 min−1 ≅ 100 nmol g−1 min−1. The carbon skeletons for the de novo synthesis are derived ultimately from glucose. Glucose is metabolized to two molecules of pyruvate one of which is carboxylated by pyruvate carboxylase (p.c) (thought to be present within the brain only in astrocytes) to form oxaloacetic acid (OAA) a component of the citric acid cycle. Addition of acetyl-CoA from the second pyruvate then forms citrate, which is decarboxylated to form α-ketoglutarate (α-KG). Glutamate is then formed either a by transamination (t.a) of α-ketoglutarate using leucine or other amino acids as source (see e.g. [383, 641, 645, 650], or b by addition of NH4+ [366] catalyzed by glutamate dehydrogenase (g.d). The latter is believed to be a minor pathway [359, 366, 641]. The source of the amino groups for transamination is considered further in Sect. 5.5.3 and Fig. 18. Data for the pathways involved in glutamate synthesis are much less extensive for human than for rat. Rothman and colleagues [651, 652] have argued that the α-ketoglutarate is synthesized in astrocytes based on measurements of incorporation of 13C (see [653, 654]). However, the failure to find a key transaminase in human astrocytes by immunohistochemistry [655, 656] has cast some doubt on astrocytes being the major site for the conversion from α-ketoglutarate to glutamate. For recent reviews of glutamate synthesis see [386, 641, 645]"}