Glutamine Transports Ammonia in Blood
Free ammonia is toxic to the central nervous system and must be transported in a nontoxic form to the liver, where it can enter the urea cycle and eventually be excreted in the urine. The catabolism of proteins in muscle produces nitrogen that is then incorporated to form glutamine, a nontoxic transport form of ammonia . It is estimated that 30 to 35% of amino acid nitrogen is transported in the plasma in the form of glutamine . The formation of glutamine primarily takes place in peripheral muscle tissue from glutamate (Figure 5.3). However, glutamine metabolism in the liver and central nervous system serves as an important mechanism for decreasing ammonia levels. Once glutamine reaches the liver, it is ultimately converted from the transport form of ammonia to the disposal form of ammonia — urea. Thus, glutamine acts as a nitrogen "shuttle" or "buffer" by either accepting excess ammonia or liberating it to form other amino acids, nucleotides, or urea. The capacity of glutamine to perform these essential actions makes it the major nitrogen transporter between tissues of the human body .
FIGURE 5.2 Molecular structure of glutamate.
Intercellular Glutamine Cycle of the Liver
The liver is the principal location of nitrogen metabolism in the body, and it plays a fundamental role in glutamine homeostasis. The liver contains glutamine syn-thetase and glutaminase but is neither a net consumer nor a net producer of glutamine. Due to their distinct functions, these two enzymes are confined to different regions of the liver. Glutaminase and the urea cycle enzymes are concentrated in the periportal hepatocytes that surround the portal system as it branches throughout the liver. Glutamine enters the periportal cells and is hydrolyzed to contribute an ammonium ion for urea synthesis . Glutamate formed in this process can either be metabolized into other amino acids or enter the route of gluconeogenesis. Glutamine synthetase is highly concentrated in the perivenous region of the liver, which drains the venous blood from the systemic circulation. This enzyme scavenges free ammonia in the plasma by joining it to glutamate to form glutamine . Glutamine formed from this reaction is released into the blood, where it circulates back to the liver only to be taken up by the periportal cells that can process the nitrogen into urea for disposal. Therefore the liver plays a vital role in maintaining low blood ammonia levels by apprehending free ammonia molecules from the plasma as well as by producing urea. Glutamine and its associated enzymes are integral to both processes.
Glutamine Plays a Critical Role in Acid-Base Regulation
Regulation of acid-base balance, like that of nitrogen excretion, is shared by the liver and kidney, with glutamine playing a vital role. Complete catabolism of most amino acids derived from proteins yields carbon dioxide, water, and urea, which are neutral products. However, the breakdown of the positively charged amino acids arginine, lysine, and histidine and the sulfur-containing amino acids methionine and cysteine results in the net formation of protons (acid). Catabolism of the negatively charged amino acids glutamate and aspartate results in net utilization of protons but is only able to consume a portion of the protons produced by catabolism of the positively charged and sulfur-containing amino acids. In order for the body to remain in acid-base balance, the excess acid produced each day by the catabolism of proteins must be matched by an equivalent amount of a base. The kidney is able to produce this base in the form of bicarbonate by metabolizing glutamine, and thus maintaining acid-base neutrality. Glutamine taken up by the kidneys is deaminated by glutaminase to produce glutamate, which can then enter the tricarboxylic acid cycle after being metabolized into a-ketoglutarate. The metabolism of one molecule of glutamine by the kidney yields two bicarbonate molecules and two ammonium molecules (Figure 5.4). This can be represented as follows:
This is an entirely neutral reaction, but the ammonium produced is secreted into the lumen of the kidney tubules and taken away by the urine. The bicarbonate, on the other hand, enters the peritubular capillaries and corresponds to a net gain of base for the body. The protons produced by amino acid catabolism are thus balanced by the bicarbonate manufactured by glutamine metabolism in the kidney . This renal metabolism of glutamine assumes even greater importance in metabolic acidosis, a condition associated with excessive acid production in the body. Certain pathologic conditions such as lactic acidosis, ketogenesis, or ingestion of certain chemicals can cause metabolic acidosis. Renal enzymes involved in glutamine metabolism are increased during times when the body is subjected to states of metabolic acidosis in order to generate more bicarbonate and neutralize the insult. The liver also contributes to neutralizing the blood during times of metabolic acidosis by decreasing the conversion of glutamine into urea. This increases the available pool of glutamine the kidney can metabolize into bicarbonate.
Gluconeogenesis during a Fasting State Requires Glutamine from Skeletal Muscle
Skeletal muscle tissue contains over 90% of the glutamine pool in the body and is the major site of glutamine synthesis. During the fasting or catabolic state, the body attempts to maintain plasma glucose levels in order to sustain glucose-requiring tissues such as the brain . The breakdown of liver glycogen to glucose is an early response to starvation but is transient, as liver glycogen stores are depleted after 10 to 18 h of fasting. As glycogen stores decrease, gluconeogenesis in the liver and kidney intensifies, as these are the only two organs that contain the necessary gluconeogenesis enzyme glucose-6-phosphatase . During the starvation period, alanine and glutamine are released after the breakdown of skeletal muscle and account for 40 to 70% of amino acids that are converted to glucose . Alanine has long been considered the predominant amino acid substrate for gluconeogenesis, but recent evidence shows that glutamine makes a significant contribution. Furthermore, studies have shown that alanine and glutamine have particular inclinations toward one organ over the other. Alanine is predominantly metabolized by the liver into glucose, while glutamine is the preferred substrate in the kidney .
Glutamine Is Essential for Cells of the Immune System
Although the immune system is composed of a diverse line of cells with different functions, they share a common goal of providing a cellular defense against infection. Until recently, little was known about the metabolism or preferred fuel source of these cells that include lymphocytes, macrophages, and neutrophils. Abundant evidence has shown that glutamine is the principal energy source for white blood cells of the immune system, and that they may utilize it at a rate greater than glucose . Not only does glutamine serve as an energy source, but it also supplies the nitrogen to synthesize new purines and pyrimidines in lymphocytes . These nucleotides are the building blocks of DNA and RNA that must be replicated in order for cell proliferation to occur. Tissue culture studies have demonstrated that failure to supplement culture media with glutamine severely limits the ability of lymphocytes to respond to mitogenic stimulation, which is probably related to its use as a precursor for nucleotide synthesis and as a source of energy . In addition to providing energy and the ability to proliferate, glutamine has been shown to be involved in the specific functions of immune cells. Neutrophils, which engulf and digest foreign material, have been shown to increase phagocytic activity, increase superoxide production, and resist apoptosis when supplemented with glutamine . Macrophages deprived of glutamine expressed less human leukocyte antigen DR, a critical gene product used by the macrophage for antigen presentation . In trauma patients as well as surgery patients, human leukocyte antigen DR was increased with parenteral supplementation of glutamine [15,16].
The role of the lungs in maintaining glutamine homeostasis has only recently been appreciated. Similar to skeletal muscle, the lungs are glutamine donors with high levels of glutamine synthetase that release glutamine in response to endotoxin or glucocorticoid administration. Although the lung does not have the same tissue mass as skeletal muscle, it contains an equivalent concentration of glutamine synthetase and receives a greater proportion of the total circulation. Therefore, the lung is able to release a significant amount of glutamine and may increase glutamine output up to six times following major surgery, trauma, sepsis, starvation, or acidosis due to the upregulation of glutamine synthetase .
Glutamine is an important respiratory fuel for the exocrine and endocrine pancreas with arteriovenous differences in glutamine concentration indicative of glutamine extraction rates near 50%. Use of glutamine-enriched total parenteral nutrition (TPN) in rats before and after small bowel resection significantly increased pancreatic weight, DNA content, protein content, total trypsinogen, and lipase content . Microscopic analysis of pancreatic sections demonstrated that exogenous glutamine resulted in pancreatic acinar hyperplasia. These investigators also demonstrated that glutamine supports pancreatic growth and function during elemental enteral feeding. Glutamine may also influence pancreatic endocrine function by enhancing P-cell secretion of insulin in response to glucose . There is also evidence that glutamate dehydrogenase may have a regulatory role in the pancreatic P-cell, as individuals with a mutation in this enzyme have elevated insulin secretion .
Glutamate is the main neurotransmitter at excitatory synapses in the central nervous system, and y-amino butyric acid (GABA) provides inhibitory signals . Experiments have shown that glutamate and GABA are collected by astroglia in the synaptic space after nerve depolarization. Once contained within the astroglia, glutamate and GABA are ultimately converted to glutamine that is transported back into the neuron and modified to become glutamate again . Researchers recently concluded that this glutamine-glutamate cycle in the brain "plays a central role in the normal functional energetics of the cerebral cortex" .
Glutamine Is the Precursor to Purines and Pyrimidines
Glutamine is partially oxidized by glutaminolysis in enterocytes and lymphocytes to supply energy and precursor molecules for the synthesis of purines and pyrimidines that are used by these rapidly dividing cells for the synthesis of RNA and DNA. As the nitrogen donor in the formation of carbamoyl phosphate, glutamine in conjunction with aspartic acid is required for the committed step in pyrimidine synthesis (formation of N-carbamoylaspartate). A transamination reaction involving glutamine is again used in the synthesis of the pyrimidine nucleotide cytosine triphosphate (CTP) from uridine triphosphate (UTP). In the purine biosynthetic pathway, glutamine contributes two amine groups in reactions leading to the synthesis of inosine monophosphate (IMP) and donates a third amine group in the conversion of IMP to guanosine monophosphate (GMP). Thus glutamine is an essential building block of DNA and RNA, which are required by the rapidly dividing cells of the intestine and immune system.
Glutamine and Its Relation to Glutathione, a Powerful Antioxidant
Glutathione is a y-glutamylcysteinylglycine tripeptide important in the detoxification of endogenously generated peroxides and exogenous chemical compounds. It is found in nearly all cells and is critical in stabilizing erythrocyte membranes, conjugating drugs to make them more water soluble, transporting amino acids across cell membranes, and acting as a cofactor for enzyme reactions. Glutamine is the precursor to glutamate (Figure 5.3), which is combined with cysteine and glycine in two separate reactions that both require adenosine triphosphate (ATP) . Oxygen free radicals and peroxides are known to be harmful to the body on the molecular level. The glutathione formed from glutamine is the most important free radical scavenger in the body that can neutralize the oxidative threat . Recent data suggest that glutamine is intimately involved in regulating glutathione levels, as shown in experiments in a human neuroblastoma cell line . Furthermore, glutathione has been shown to preserve proteins in their reduced form, which ensures that certain enzymes function properly .
The intestines consume the largest amount of glutamine of any organ in the body, and it is their preferred fuel source. Glutamine can either be taken up by the intestinal epithelial cells (enterocytes) from the lumen or be delivered via the bloodstream. Once the glutamine has gone into the enterocyte, it is taken up by the mitochondria and converted into ATP via the following reactions:
glutamine -> glutamate -> a-ketoglutarate -> Krebs cycle -> ATP
Because the enterocytes contain little glutamine synthetase and have an abundance of glutaminase, they are unable to synthesize glutamine from other molecules and must depend on a preformed supply of glutamine . It will be shown later that glutamine is essential to maintain the integrity of the intestinal lining and prevent pathogens from violating it and entering surrounding tissues.
Taurine is a unique amino acid that possesses antioxidant as well as osmoregulatory properties. Inflammatory cells, especially neutrophils, contain an abundance of taurine in their cytosol. The major function of taurine is to travel with the neutrophils to wounded tissue and trap chlorinated oxidants and transform them into the nontoxic taurine chloramine form . This has been shown to be important in maintaining the cell membrane and preventing self-destruction of the cell . Glutamine is important in the regulation of taurine metabolism, as shown experimentally in rats fed a glutamine-enriched diet that increased taurine uptake in the kidneys. This increase in taurine concentration was also seen in trauma patients who were supplemented with glutamine . Taurine is also important in maintaining intracellular osmolarity, as it can remain at high intracellular concentrations with minimal expenditure of energy and respond to osmotic changes rapidly . It is believed that the decreased extracellular water retention seen with glutamine supplementation during a stressed state is mediated through taurine .
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