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The Secret Behind the Miracle Enzyme: Why is Glutamate Dehydrogenase Essential to Your Health?
Glutamate dehydrogenase (GLDH, GDH) is an enzyme that can be found in the mitochondria of both prokaryotes and eukaryotes. In addition to producing α-ketoglutarate, the reaction catalyzed by this enzyme also produces ammonia. In eukaryotes, this ammonia is generally processed as a substrate in the urea cycle. In mammals, the conversion of α-ketoglutarate to glutamate does not normally occur because the balance of glutamate dehydrogenase favors the production of ammonia and α-ketoglutarate.
In the brain, the NAD+/NADH ratio promotes oxidative deamination (i.e., conversion of glutamate to α-ketoglutarate and ammonia).
This enzyme works differently in microorganisms; it assimilates ammonia into amino acids, which are metabolized by glutamate and aminotransferase. In plants, the action of glutamate dehydrogenase will show different directional responses depending on the environment and pressure. When transgenic plants express microbial GLDH, they have higher tolerance to herbicides, water shortages, and infection by pathogens, and their nutritional value increases. This makes glutamate dehydrogenase a key link in the cellular catabolic and anabolic pathways and is therefore ubiquitous in eukaryotes.
In humans, the related genes are called GLUD1 (glutamate dehydrogenase 1) and GLUD2 (glutamate dehydrogenase 2), and there are at least five GLDH pseudogenes in the human genome.
Clinical Applications
GLDH can be measured in medical laboratories to assess liver function. Elevated serum GLDH levels indicate liver damage, and GLDH plays an important role in the differential diagnosis of liver disease, especially in combination with aminotransferases. Since GLDH is mainly present in mitochondria, it is almost undetectable in systemic inflammatory liver diseases such as viral hepatitis.
Some liver diseases characterized by hepatocellular necrosis, such as toxic liver injury or hypoxic liver disease, are often accompanied by high levels of serum GLDH. If extremely high aminotransferase levels are present at the same time, GLDH will play an important role in distinguishing acute viral hepatitis from acute toxic hepatic necrosis or acute anoxic liver disease. GLDH can also be used to measure the safety of drugs in clinical trials.
The enzyme immunoassay (EIA) for GLDH can be used as a screening tool for patients with Klebsiella infection.
Cofactors
NAD+ (or NADP+) is a cofactor in the glutamate dehydrogenase reaction, producing α-ketoglutarate and ammonia as byproducts. Depending on the cofactor used, glutamate dehydrogenases can be divided into the following three categories:
EC 1.4.1.2: L-glutamate + H2O + NAD+ ⇌ 2-ketoglutarate + NH3 + NADH + H+
EC 1.4.1.3: L-glutamate + H2O + NAD(P)+ ⇌ 2-ketoglutarate + NH3 + NAD(P)H + H+
EC 1.4.1.4: L-glutamate + H2O + NADP+ ⇌ 2-ketoglutarate + NH3 + NADPH + H+
Role of nitrogen flows
In animals and microorganisms, ammonia incorporation is achieved through the action of glutamate dehydrogenase and glutamine synthetase. Glutamate plays a central role in nitrogen flux in mammals and microorganisms, acting both as a nitrogen donor and a nitrogen acceptor.
Regulation of glutamate dehydrogenase
In humans, the activity of glutamate dehydrogenase is regulated by ADP-ribosylation, a covalent modification performed by the gene SIRT4. When calorie restriction and blood glucose are low, this regulation is relaxed to increase the production of α-ketoglutarate, making it available for the Krebs cycle and ultimately ATP production.
In microorganisms, activity is controlled by ammonia concentration and cognate rubidium ions, which alter the enzyme's Km (Michaelis constant) by binding to the allosteric site of GLDH.
In insulin-secreting β-cells, ADP-ribosylation is particularly important for the regulation of glutamate dehydrogenase. When the ATP:ADP ratio increases, beta cells secrete more insulin, and this increase in the ratio is related to the production of α-ketoglutarate from the breakdown of amino acids by GLDH. SIRT4 is essential in regulating insulin secretion and managing blood sugar levels.
Glutamate dehydrogenase from bovine liver was regulated by nucleotides in the late 1950s and early 1960s, a phenomenon described in detail by Karl Frieden. In addition to describing the effects of nucleotides such as ADP, ATP, and GTP, he also detailed the different kinetic behaviors between NADH and NADPH. This made it one of the first enzymes to display what was later described as allosteric behavior. Over time, researchers have used various testing methods to identify some amino acids that have long been known to activate transaminases, such as L-leucine.
These findings make us think about the impact of glutamate dehydrogenase on our health and how this amazing enzyme will once again change our understanding of the key role of biological metabolic chains. Will these focuses have a greater impact on human health in the future? Make a greater contribution?
