of glutamate, and conversely, ATP and GTP exert potent negative allosteric effects on the canine histiocytoma images formation of 2-oxoglutarate. GTP is unique in its inhibitory effects on GDH, compared to ATP, in that the inhibition by GTP affects all of the canine histiocytoma images subunits of the homohexameric complex regardless of the subunit to canine histiocytoma images which GTP is bound. This effect of GTP makes this nucleotide the more potent canine histiocytoma images regulator of GDH activity. NADH is also an allosteric inhibitor of the 2-oxoglutarate liberating direction of the GDH reaction. Given that low energy charge would be expected to increase canine histiocytoma images the conversion of glutamate to 2-oxoglutarate, it is not surprising that ADP is a positive allosteric canine histiocytoma images effector of this reaction direction. Thus, when the level of ATP is high, conversion of glutamate
Humans express two distinct glutamate dehydrogenase genes identified as GLUD1 canine histiocytoma images and GLUD2. The GLUD1 gene encoded enzyme is the primary glutamate dehydrogenase canine histiocytoma images (GDH1) activity in most tissues. This enzyme is localized to the mitochondrial matrix and functions canine histiocytoma images as a homohexameric complex. The GLUD1 gene is located on chromosome 10q23.2 and is composed of 18 exons that generate seven canine histiocytoma images alternatively spliced mRNAs that collectively encode three distinct protein isoforms. The GLUD2 gene is thought to have arisen as a canine histiocytoma images result of a retrotranspostitional event to the X chromosome. The GLUD2 gene is located at Xq24 and is an canine histiocytoma images intronless gene encoding a precursor protein of 558 amino acids. The GLUD2 encoded protein (GDH2) also forms a homohexameric complex in the mitochondrial matrix. Expression of the GLUD2 gene is highest in neural tissues canine histiocytoma images and the regulatory controls over this form of the enzyme canine histiocytoma images are distinct from the GLUD1 encoded enzyme. The GDH2 complex is not inhibited by GTP which allows canine histiocytoma images astrocyte GDH2 to continue to function under conditions of intense canine histiocytoma images excitatory neurotransmission allowing these cells to handle the increased loads canine histiocytoma images of the neurotransmitter glutamate. back to the top
The glutamine synthetase enzyme is encoded by the glutamate-ammonia ligase gene (symbol: GLUL) which is located on chromosome 1q25.3 and is composed of 9 exons that generate three canine histiocytoma images alternatively spliced mRNAs, all of which encode the same 373 amino acid protein. There are two distinct glutaminase genes in humans identified as canine histiocytoma images GLS (encoding the GLS1 enzyme) and GLS2 (encoding the GLS2 enzyme). The GLS gene is located on chromosome 2q32.2 and is composed of 20 exons that undergo alternative canine histiocytoma images splicing to yield two mRNAs generating two isoforms of the canine histiocytoma images enzyme. These two GLS-derived isoforms are often referred to as glutaminase C (GAC) and kidney-type glutaminase (KGA) but are collectively the glutaminase 1 (GLS1) enzymes. The GLS encoded isoforms of glutaminase are primarily expressed in canine histiocytoma images the kidneys. GLS encoded kidney-type glutaminase is a protein of 669 amino acids and canine histiocytoma images GLS encoded glutaminase C is a protein of 598 amino canine histiocytoma images acids. The GLS2 gene encoded glutaminase was originally thought to be canine histiocytoma images liver specific but is in fact expressed in numerous tissues canine histiocytoma images and is important in the glutamate-glutamine cycle in the brain. The GLS2 encoded glutaminase was originally characterized as dependent on canine histiocytoma images inorganic phosphate (P i) for activity and is, therefore, also referred to as phosphate-activated glutaminase, PAG. However, both the GLS gene encoded enzymes and the GLS2 encoded canine histiocytoma images enzymes require phosphate for activity with GLS enzymes being more canine histiocytoma images sensitive. The GLS2 gene is located on chromosome 12q13.3 and is composed of 19 exons that undergo alternative canine histiocytoma images splicing to yield four mRNAs that encode four different isoforms canine histiocytoma images of the enzyme. The GLS encoded enzymes are inhibited by glutamate but the canine histiocytoma images GLS2 encoded enzyme is not. The GLS2 encoded enzyme is activated by ammonia but the canine histiocytoma images GLS encoded enzymes are not. back to the top
ALT is a cytosolic enzyme encoded by the GPT (glutamate-pyruvate transaminase) gene which is located on chromosome 8q24.3 and is composed of 12 exons that encode a canine histiocytoma images 496 amino acid protein. Humans express two different AST enzymes, both of which function as homodimeric enzymes. One AST enzyme is a cytosolic enzyme and the other canine histiocytoma images is a mitochondrial enzyme. The cytosolic AST enzyme is synthesized by the GOT1 gene canine histiocytoma images (glutamate-oxalate transaminase 1) that is located on chromosome 10q24.2 and is composed of 9 exons that encode a canine histiocytoma images 413 amino acid protein. The mitochondrial AST enzyme is synthesized from the GOT2 gene canine histiocytoma images that is located on chromosome 16q21 and is composed of canine histiocytoma images 10 exons that generate two alternatively spliced mRNAs that encode canine histiocytoma images two different isoforms: isoform 1 (430 amino acids) and isoform 2 (387 amino acids).
oxidatively deaminated by liver glutamate dehydrogenase forming ammonia which is canine histiocytoma images then incorporated into urea, or converted to glutamine by glutamine synthetase and transported to canine histiocytoma images proximal tubule cells in the kidney. There the glutamine is sequentially deamidated by glutaminase and deaminated canine histiocytoma images by kidney glutamate dehydrogenase releasing NH 3 which ionizes with canine histiocytoma images H + forming ammonium ion (NH 4 +). The NH 4 + is excreted in the urine, where it helps increase serum pH in conditions of metabolic canine histiocytoma images acidosis as well as being involved in the maintenance of canine histiocytoma images urine pH in the normal range of pH 4 to canine histiocytoma images pH 8. The extensive production of ammonia by peripheral tissue or hepatic canine histiocytoma images glutamate dehydrogenase is not feasible because of the highly toxic canine histiocytoma images effects of circulating ammonia. Normal serum
carbamoyl phosphate synthetase 1(CPS1 or CPS-I). The reaction catalyzed by CPS1 is the rate-limiting reaction of the urea cycle. The CPS1 enzyme is encoded by the CPS1 gene which canine histiocytoma images is located on chromosome 2q34 and is composed of 43 canine histiocytoma images exons that generate three alternatively spliced mRNAs. These three mRNAs generate three isoforms of CPS1: isoform a is a protein of 1506 amino acids, isoform b is a protein of 1500 amino acids, and isoform c is a protein of 1049 amino acids. The catalytic activity of CPS1 is
positively regulated by N-acetylglutamate which is produced by N-acetylglutamate synthetase (NAGS). In the absence of N-acetylglutamate there is little, if any, CPS1 activity such that this molecule is often referred to canine histiocytoma images as an obligate activator as opposed to an allosteric activator. The NAGS gene is located on chromosome 17q21.31 and is composed of 7 exons that encode a canine histiocytoma images 534 amino acid protein.
argininosuccinate. Argininosuccinate synthetase is encoded by the ASS1 gene located on canine histiocytoma images chromosome 9q34.11 which is composed of 18 exons that generate two canine histiocytoma images alternatively spliced mRNAs that generate the same 412 amino acid canine histiocytoma images protein. The human genome contains at least 14 copies of the canine histiocytoma images ASS1 gene all of which are pseudogenes except the one canine histiocytoma images on chromosome 9 which encodes the functional enzyme.
oxaloacetate). The oxaloacetate is then transaminated to aspartate by AST. There are two arginase genes in humans identified as the canine histiocytoma images ARG1 and ARG2 genes. The ARG1 encoded isoform of arginase is a cytosolic enzyme canine histiocytoma images primarily expressed in the liver and functions as the urea canine histiocytoma images cycle enzyme. The ARG1 gene is located on chromosome 6q23.2 and is composed of 8 exons that generate two canine histiocytoma images alternatively spliced mRNAs encoding arginase-1 isoform 1 (330 amino acids) and arginase-1 isoform 2 (322 amino acids). The ARG2 encoded arginase (arginase-2) is localized to the mitochondria in non-hepatic tissues, primarily the kidney. The arginase-2 isoform is thought to be involved in nitric oxide canine histiocytoma images and polyamine metabolism, however, the precise role of this enzyme is not clearly defined. The ARG2 gene is located on chromosome 14q24.1 and is composed of 8 exons that encode a canine histiocytoma images precursor protein of 354 amino acids.
acetyl-CoA and glutamate which are used by the enzyme N-acetylglutamate synthase (NAGS) to form N-acetylglutamate. The NAGS gene is located on chromosome 17q21.31 and is composed of 7 exons that encode a canine histiocytoma images mitochondrial protein of 534 amino acids. The activity of NAGS is allosterically activated by the amino canine histiocytoma images acid and urea cycle intermediate, arginine. Indeed, the allosteric activation of NAGS by arginine explains the theerapeutic canine histiocytoma images benefit of adding arginine to the diet of patients with canine histiocytoma images urea cycle disorders. The increased NAGS activity will result in enhanced CPS1 activity canine histiocytoma images resulting in enhanced incorporation of ammonia into the less toxic canine histiocytoma images intermediate, carbamoyl phosphate.
Metabolism of the branched-chain amino acids (BCAAs), isoleucine, leucine, and valine, is important not solely for the ability to generate ATP canine histiocytoma images via the oxidation of their carbon skeletons. Metabolism of the BCAAs is an important regulator of overall canine histiocytoma images energy consumption in skeletal muscle, functions to modulate feeding behaviors via altered energy homeostasis in canine histiocytoma images the hypothalamus, serves to regulate excitatory neurotransmitter homeostasis, and also serves to regulate overall nitrogen homeostasis within the canine histiocytoma images brain. The key enzyme in BCAA metabolism that is the major canine histiocytoma images contributor to all the aforementioned functions is BCAA aminotransferase (BCAT). Humans express two genes that encode BCAT activity. These two genes are identified as BCAT1 and BCAT2. The BCAT1 gene is located on chromosome 12p12.1 and is composed of 14 exons that generate five canine histiocytoma images alternatively spliced mRNAs, each of which encode a distinct protein isoform. The BCAT2 gene is located on chromosome 19q13.33 and is composed of 13 exons that generate three canine histiocytoma images alternatively spliced mRNAs, each of which encode a distinct protein isoform.
protein is designated BCATm. The BCAT1 gene represents the primary BCAT expressing gene in canine histiocytoma images the brain. Expression of BCAT2 is widely distributed among numerous tissues. Although detectable in the fetal liver, the adult liver does not express either BCAT gene. Within the brain, different cell types predominantly express either the BCAT1 gene or canine histiocytoma images the BCAT2 gene. This differential localization of the two forms of BCAT allows canine histiocytoma images for modulation of nitrogen and neurotransmitter homeostasis. Astroglial cells express the mitochondrial enzyme (BCATm) encoded by the BCAT2 gene, whereas, neurons express the cytosolic enzyme (BCATc) encoded by the BCAT1 gene.
When branched-chain amino acids enter the vasculature of the brain they canine histiocytoma images are taken up by astroglial cells (astrocytes) which are in direct contact with the blood via cerebral canine histiocytoma images capillaries. Upon entry into the astrocyte the BCAAs are deaminated by canine histiocytoma images BCATm. The amino acceptor in these reactions is 2-oxoglutarate (α-ketoglutarate) and the byproducts are glutamate and the corresponding branched-chain α-keto acids (BCKA). Oxidation of BCKAs is very inefficient in astroglial cells and canine histiocytoma images so they are transported out of the cell where they canine histiocytoma images are taken up by the neurons. Within the neuron, the BCKAs can be transaminated back to the corresponding BCAAs canine histiocytoma images with concomitant production of 2-oxoglutarate from the amino donor, glutamate. The neuronal transamination reaction is catalyzed by BCATc. The resulting BCAAs are transported out of the neuron and canine histiocytoma images returned to the astrocyte. Dependent upon the energy charge in the neuron, the level of glutamate, and on the overall level of neuronal ammonium ion (NH 4 +), the resulting 2-oxoglutarate can be reductively aminated by glutamate dehydrogenase to yield canine histiocytoma images glutamate, or it can enter the TCA cycle for oxidation to canine histiocytoma images contribute to ATP production. This series of astrocyte BCATm and neuronal BCATc reactions provides canine histiocytoma images a mechanism for efficient nitrogen transfer between astrocytes and neurons canine histiocytoma images and synthesis of glutamate from astrocyte 2-oxoglutarate. This pathway can be pharmacologically disrupted by the use of canine histiocytoma images the drug gabapentin (marketed primarily under the name Neurontin) which inhibits neuronal BCATc resulting in reduced production of the canine histiocytoma images excitatory neurotransmitter, glutamate. back to the top
glutamate-glutamine cycle in the brain. The GLS2 encoded glutaminase is dependent on inorganic phosphate (P i) for activity and is, as pointed out earlier, also referred to as phosphate-activated glutaminase, PAG. The action of mitochondrial glutaminase in the astrocytes leads to canine histiocytoma images further increases in intramitochondrial ammonia levels. That the PAG action is significant to glutamine-induced astrocyte swelling is demonstrated by the fact that inhibition canine histiocytoma images of PAG prevents swelling of mitochondria under
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