Oxaloacetate, a keto-acid vital to numerous cellular processes, plays a central role in human metabolism. Its involvement in regulating blood glutamate concentration, particularly in the context of brain tumors, has garnered significant attention. Specifically, oxaloacetate converts glutamate to α-ketoglutarate, effectively "scavenging" excess glutamate, which is beneficial in conditions like gliomas where extracellular brain glutamate levels are elevated.
Keto Acids: An Overview
In organic chemistry, keto acids, also known as ketoacids or oxo carboxylic acids, are organic compounds characterized by the presence of both a carboxylic acid group (−COOH) and a ketone group (>C=O). In some instances, the keto group may be hydrated. These compounds play crucial roles in various metabolic pathways.
Keto acids are classified based on the position of the ketone group relative to the carboxylic acid group:
- Alpha-keto acids (α-keto acids or 2-oxoacids): The keto group is located adjacent to the carboxylic acid. These acids are often produced through the oxidative deamination of amino acids and can also serve as precursors to amino acids. A prime example is alpha-ketoglutaric acid, a 5-carbon ketoacid derived from glutamic acid.
- Beta-keto acids (β-keto acids or 3-oxoacids): The ketone group is situated on the second carbon atom from the carboxylic acid. These acids are typically formed through Claisen condensation. Acetoacetic acid is a representative example.
- Gamma-keto acids (γ-keto acids or 4-oxoacids): The ketone group is located on the third carbon atom from the carboxylic acid.
Metabolic Significance of Keto Acids
Keto acids participate in a wide array of anabolic pathways within metabolism. During periods of low ingested sugar and carbohydrate levels, the body relies on stored fats and proteins for energy production. Glucogenic amino acids from proteins and Glycerol from Triglycerides are converted to glucose.
Oxaloacetate's Role in Glutamate Regulation
Oxaloacetate's ability to regulate blood glutamate concentration is of particular interest. By converting glutamate to α-ketoglutarate, it helps maintain glutamate homeostasis, which is crucial for neuronal health. Elevated extracellular glutamate levels, as seen in conditions like gliomas, can lead to excitotoxicity and neuronal damage. Oxaloacetate's "glutamate scavenging" action can mitigate these harmful effects.
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Oxaloacetate Keto-Enol-Tautomerase Activity
Two highly purified proteins with oxaloacetate keto-enol-tautomerase activity (oxaloacetate keto-enol-isomerase, EC 5.3.2.2) have been isolated from the bovine heart mitochondrial matrix.
The first protein has a molecular mass of 37 kDa (SDS-gel electrophoresis and Sephacryl SF-200 gel filtration). It is stable at 40 degrees C and has maximal catalytic activity at pH 8.5, with half-maximal activity at pH 7.0. The enzyme is specifically inhibited by oxalate and diethyloxaloacetate. When assayed in the enol----ketone direction at 25 degrees C (pH 9.0), the enzyme obeys simple substrate saturation kinetics with Km and Vmax values of 45 microM and 74 units per mg of protein, respectively; the latter value corresponds to the turnover number of 2700 min-1.
The second protein has a molecular mass of 80 kDa (SDS-gel electrophoresis and Sephacryl SF-300 gel filtration). The enzyme is rapidly inactivated at 40 degrees C and shows a sharp pH optimum of activity at pH 9.0. The enzyme can be completely protected from thermal inactivation by oxaloacetate and dithiothreitol. The kinetic parameters of the enzyme as assayed in the enol----ketone direction at 25 degrees C (pH 9.0) are: Km = 220 microM and Vmax = 20 units per mg of protein; the latter corresponds to the turnover number of 1600 min-1. The enzyme activity is specifically inhibited by maleate and pyrophosphate.
Oxaloacetate and Glioblastoma Multiforme: An In Vivo Study
To investigate the potential therapeutic effects of oxaloacetate, a dose-ranging study was conducted in mice implanted with glioblastoma multiforme cells. A human primary glioblastoma cell line, U87MG, was implanted intracranially into female athymic nude mice. The mice were then administered daily oral gavage doses of oxaloacetate at human equivalent (HEQ) doses of 480, 1500, 3000, and 11,200 mg. The impact on survival was measured and compared to a vehicle control group. Time to endpoint (TTE) was recorded for each animal. The logrank test was used to assess the significance of the difference between the overall survival experiences of two groups. The logrank test analyzed the individual TTEs for all animals in a group, except those lost to the study due to non-treatment related (NTR) deaths.
The results showed that daily doses of 1500 and 3000 mg of oxaloacetate led to a statistically significant increase in survival compared to the vehicle control group (p≤0.05). The hazard ratios (logrank) for the 1500 and 3000 mg dose groups were 2.527 and 2.218, respectively.
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In a comparative group study, the same daily doses of oxaloacetate were given with temozolomide 7.5 mg/kg for 5 days. All combination groups demonstrated a highly significant increase in survival compared to the vehicle control (p<0.001). 1500 mg oxaloacetate combined with temozolomide further increased TTE survival by an additional 15%, compared to temozolomide treatment alone, however this group did not reach statistical significance.
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