Glutamine metabolism
Glutamine is an amino acid classified as L-alpha, containing five carbon atoms. It consists of carbon (41.09%), hydrogen (6.90%), oxygen (32.84%), and nitrogen (19.17%). In terms of its physiological pH, glutamine falls into the neutral amino acid category, while from a nutritional standpoint, it’s considered a non-essential amino acid. Glutamine exhibits two amino groups — the alpha-amino group and the readily hydrolysable side-chain amide group. These distinct characteristics empower glutamine’s pivotal role as a nitrogen transporter and carrier of NH3. [1]
The body produces 40–80 g of glutamine per day
The natural synthesis of glutamine, as determined through isotopic methodologies, is estimated to range between 40 to 80 grams per 24 hours. Similar rates of production within this range are also observed when employing pharmacokinetic techniques to assess glutamine synthesis. [2]
How much glutamine do we consume with food?
The average daily ingestion of glutamine acquired from dietary protein typically ranges from 3 to 6 grams per day. This estimation is based on a presumed daily protein intake of 0.8 to 1.6 grams per kilogram of body mass for a person weighing 70 kilograms. [3]
The Upper Tolerable Intake Level of glutamine
In study conducted by Walsh et al., participants consumed 3 grams of glutamine every 15 minutes within the last 30 minutes of a 2-hour exercise session. This intake was continued every 15 minutes throughout a subsequent 2-hour recovery period, totaling an intake of 30 grams of glutamine. [4]
Runners, whose body mass ranged from 69.9 kg with a deviation of ± 2.8 kg, were given 0.1 grams of L-glutamine per kilogram of body weight, mixed with sugar-free lemonade or a placebo (sugar-free lemonade only). This dosage was administered four times daily over a span of 14 days, commencing on the initial day of their training. This supplementation regimen equated to an approximate intake of 28 grams of glutamine per day. [5]
The administration of doses at 0.35, 0.5, and 0.65 grams per kilogram were well tolerated by the subjects in the study by Ward et al., showing no adverse effects on plasma glutamine and ammonia levels. As a result, it was determined that a dosage of 0.65 grams per kilogram is deemed safe for the use of glutamine in clinical studies involving pediatric oncology patients. That is approximately 45 grams of glutamine per day for 70kg person. [6]
Synthesis and utilization of glutamine
In the human body, the concentration and accessibility of glutamine rely on a delicate equilibrium between its synthesis and/or release, as well as its uptake by various organs and tissues. Specific organs such as the lungs, liver, brain, skeletal muscles, and adipose tissue exhibit distinct activities related to the synthesis/production of glutamine within their respective tissues. Conversely, tissues that predominantly consume glutamine, such as the intestinal mucosa, leukocytes, and renal tubule cells, showcase elevated levels of glutaminase activity. [1]
The primary enzymes involved in glutamine metabolism are glutaminase (GA) and glutamine synthetase (GS), which facilitate the crucial steps in glutamine utilization and synthesis, respectively. GA, located in mitochondria, hydrolyzes glutamine to generate glutamate and ammonia. This process effectively retains glutamine within the cell for intracellular metabolism since glutamate, which carries a negative charge, cannot freely traverse the plasma membrane. Following the conversion of glutamine to glutamate, subsequent enzymatic actions involving glutamate dehydrogenase (GDH) and aminotransferases, such as glutamate-oxaloacetate transaminase, transform glutamate into 2-oxoglutarate. This 2-oxoglutarate is then able to enter the tricarboxylic acid (TCA) cycle, a process referred to as glutamine-dependent anaplerosis. This step is vital for the synthesis of crucial building blocks required for biomass production, including nucleotides, lipids, and amino acids. Conversely, high activity of GS characterizes ammonia-producing tissues, playing a critical role in net glutamine generation. Tissues undergoing catabolic states, such as skeletal muscle, rely significantly on GS activity to facilitate the production of glutamine. [7]
Glutaminase (GA) and glutamine synthetase (GS) are enzymes present in various tissues, but they typically exhibit distinct cellular expressions within these tissues. Glutaminase is responsible for catalyzing the hydrolysis of glutamine, breaking it down into glutamate and ammonia. Conversely, glutamine synthetase functions in the biosynthesis of glutamine by combining glutamate with ammonia. These enzymes are often found in different types of cells within the same tissue, indicating their specific roles in regulating the levels of glutamine and its derivatives within different cellular environments. [8]
Indeed, the enzymes glutamine synthetase (GS) and glutaminase (GA) exhibit differences in their intracellular localization within cells. Glutamine synthetase predominantly resides in the cytosol, while GA, particularly in its active state, is primarily found within mitochondria. These distinct locations align with the specific functions of these enzymes: GA facilitates the breakdown of glutamine, contributing to its utilization as an energy source, whereas GS operates in the cytosol to generate glutamine, crucial for protein and nucleotide synthesis within the cell. [8]
Connection of glutamine to other metabolic products
Glutamine serves as a crucial precursor to various essential metabolic products within the body. When glutamine undergoes deamination through the action of glutaminase, it generates glutamate, a precursor to γ-aminobutyric acid (GABA), an important neurotransmitter with inhibitory functions. Additionally, proline, vital for collagen and connective tissue, is produced via the cyclization of glutamate. Through transamination, glutamine facilitates the transfer of ammonia between different tissues. Moreover, the amide nitrogen from glutamine is involved in the biosynthesis of purines and pyrimidines, fundamental building blocks of DNA and RNA. Metabolic reactions of glutamine contribute to the production of hexosamines, critical components for maintaining mucosal surfaces. Glutathione, an antioxidant shielding against free radical damage, includes glutamate derived from glutamine, along with cystine and glycine. Glutamate is also integral to folic acid, a cofactor in numerous enzymatic processes. Folic acid deficiency can lead to conditions such as megaloblastic anemia and fetal abnormalities like neural tube defects. Glutamine’s entry into the citric acid cycle via alpha-ketoglutarate is a vital pathway for energy production. This carbon skeleton of glutamine serves as a principal fuel source for small intestinal epithelial cells and lymphocytes. Furthermore, the conversion of glutamine to glutamate and subsequently to alpha-ketoglutarate can provide critical citric acid cycle intermediates, generating NADPH through the malate:pyruvate reaction catalyzed by malic enzyme.NADPH derived from this reaction serves as a significant cofactor in lipid and steroid biosynthesis, particularly in tissues like the placenta where the pentose phosphate shunt, another significant NADPH source, is limited. [8]
Glutamine’s inter-tissue metabolic interactions
Tissues that predominantly consume glutamine, such as intestinal mucosal cells, lymphocytes, and renal tubular cells, exhibit high levels of glutaminase (GA) activity. These cells are involved in utilizing glutamine for various metabolic processes. On the other hand, tissues that are primary producers of glutamine, like skeletal muscle cells and glial cells, demonstrate elevated activity of glutamine synthetase (GS). These cells play a role in generating glutamine, which is then released for use by other parts of the body. The liver, a versatile organ, can function either as a glutamine consumer or producer based on the glutamine requirements of other organs. Consequently, the liver regulates the activities of both glutamine synthetase (GS) and glutaminase (GA) accordingly, balancing glutamine synthesis or breakdown to meet the needs of the body. [8]
The skeletal muscle glutamate-glutamine synthesis axis represents a remarkable interplay between tissues, profoundly impacting understanding of physiological function and disease. This axis involves skeletal muscle synthesizing glutamine from glutamate, which is then utilized by immune cells, including lymphocytes, neutrophils, and macrophages. Together, muscle and immune cells collaborate to ensure adequate glutamine synthesis and utilization. Active skeletal muscle cells continually release glutamine into the bloodstream by utilizing the latter part of the tricarboxylic acid (TCA) cycle, producing 2-oxoglutarate. This compound can be transaminated to form glutamate, eventually leading to glutamine synthesis via the action of glutamine synthetase. Subsequently, glutamine travels in the bloodstream to target cells where it enters their TCA cycle at the 2-oxoglutarate point. This process facilitates the generation of precursors required for lipid, RNA, and signaling molecule synthesis in these cells.Physical inactivity may reduce the supply of glutamine in the blood, a situation particularly exacerbated in critically ill patients. This circumstance justifies the consideration of glutamine supplementation for this specific group of individuals.Another example of inter-tissue metabolic collaboration involving glutamine is observed between muscle and kidneys. Glutamine derived from muscle can be utilized by the kidneys, where each glutamine molecule’s metabolism into NH4+ and glucose via gluconeogenesis aids in eliminating two protons from the body. Eric Newsholme speculated that under maximal rates of glutamine utilization by the kidney, all the glutamine in the bloodstream would be consumed in less than 30 minutes if no additional glutamine were released from the muscle. This dynamic highlights the intricate and essential nature of glutamine’s inter-tissue metabolic interactions in maintaining physiological balance. [7]
Indeed, upon deeper examination of the glutamine-synthesis and glutamine-utilization pathways, it becomes evident that the inclusion of toxic ammonium ions, produced during amino acid metabolism in muscle cells, into the synthesis of glutamine serves a crucial role. This incorporation enables the transport of toxic ammonium in a non-toxic form across cell compartments and tissues throughout the body. By utilizing the toxic ammonium ions in the synthesis of glutamine, cells transform these harmful substances into a non-toxic and more transportable form. Glutamine acts as a carrier, facilitating the safe movement of ammonium ions between different cell compartments and tissues in the body. This process effectively mitigates the toxic effects of ammonium ions by converting them into a less harmful and more manageable substance during their transit between various cellular environments. [7]
What happens to glutamine when we are sick or under stress
Glutamine concentrations in both tissues and blood are regulated by the activities of enzymes like GS (glutamine synthetase) or GA (glutaminase). During catabolic conditions such as cancer, sepsis, infections, surgeries, traumas, or intense physical exercise, the body’s natural production of glutamine falls short of meeting demands. In these situations, glutamine behaves as a conditionally essential amino acid. It assumes this role by triggering an increase in GA expression and hindering GS action. Despite a decrease in plasma glutamine levels from the normal range (500–800 micromol/L) to lower levels (300–400 micromol/L), immune cells, which heavily rely on glutamine, surprisingly exhibit minimal impacts on their proliferation and function. However, heightened tissue breakdown leads to diminished glutamine stores, primarily in muscle and liver tissues. This reduction in tissue glutamine levels has widespread effects on the body as this amino acid is vital for nitrogen supply in the synthesis of essential components like purines, pyrimidines, and amino sugars. Persistent high levels of glutamine degradation in tissues disrupt numerous metabolic pathways and mechanisms reliant on glutamine availability. This disturbance can lead to immunosuppression. [1]
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