2-Oxoglutaric Acid

2-Oxoglutaric acid, also known as alpha-ketoglutaric acid or α-ketoglutarate, is a key intermediate in the tricarboxylic acid (TCA) or Krebs cycle, which plays a crucial role in cellular energy production and metabolism. 

It also has many implications for human health, as its presence is associated with benefits including reduced cancer risk, optimal energy production, and bone health.  

As a biomarker, the levels of 2-oxoglutaric acid in biological samples can provide valuable insights into various metabolic processes and conditions, particularly those related to mitochondrial function and energy metabolism.

What is 2-Oxoglutaric Acid, or Alpha-Ketoglutarate?  [15.] 

2-oxoglutaric acid is more commonly known as alpha-ketoglucaric acid or alpha-ketoglutarate (AKG).  AKG is a vital intermediary metabolite in the Krebs cycle with multifaceted roles in cellular and metabolic pathways. 

It functions as an energy donor, a precursor in amino acid biosynthesis, a signaling molecule, and a regulator of epigenetic processes through protein binding. 

As an essential co-substrate for 2-oxoglutarate-dependent dioxygenases (2-OGDDs), AKG is crucial in hydroxylation reactions that affect collagen biosynthesis and the hypoxia-inducible factor (HIF) involved in cancer progression.

Key Functions of 2-Oxoglutaric Acid, or Alpha-Ketoglutarate  [15., 16.] 

Energy Metabolism and Amino Acid Synthesis

AKG is integral to the Krebs cycle, facilitating ATP production, amino acid synthesis, and the regulation of reactive oxygen species (ROS). It helps maintain energy balance and cellular function by converting nutrients into usable energy.

Epigenetic Regulation

AKG plays a significant role in epigenetic modifications by serving as a substrate for enzymes like prolyl-4 hydroxylase, which synthesizes collagen, and prolyl hydroxylases that stabilize HIF-1, influencing cancer development. 

It also affects DNA and histone demethylation through its involvement with lysine demethylases.

Signaling and Cellular Functions

AKG binds to specific G protein-coupled receptors, influencing intracellular calcium levels and various cellular regulation functions such as metabolism, growth, and differentiation.  

Clinical and Therapeutic Applications of 2-Oxoglutaric Acid, or Alpha-Ketoglutarate  [15., 16.] 

Antioxidant and Protective Roles

AKG exhibits antioxidant properties, protecting cells from oxidative stress by scavenging free radicals. It has been shown to prevent mitochondrial DNA damage and oxidative stress-induced conditions in animal models, highlighting its potential in managing oxidative damage.

Immunomodulation and Protein Metabolism

As a precursor of glutamine, AKG supports the immune system and helps regulate protein metabolism, making it beneficial in states of increased protein catabolism, such as recovery from trauma or surgery. 

Clinical studies indicate its effectiveness in improving protein metabolism and reducing muscle proteolysis.  [2.] 

Bone Health  [13.] 

AKG has anabolic effects on bone tissue, promoting collagen synthesis and improving bone mineral density and strength.  Studies suggest its potential in treating osteoporosis and other bone disorders by enhancing the structural integrity of bones.

Cancer Therapy  [9., 11.]

Research indicates that AKG can inhibit HIF-1 activity, reducing angiogenesis and tumor growth. It shows promise as an anti-tumor agent, particularly in cancers with metabolic reprogramming and pseudohypoxia. AKG's ability to influence epigenetic modifications further supports its potential in cancer treatment.

What Are Organic Acids?  [3., 5.]

Organic acids are organic compounds with acidic properties.  They include a variety of functional groups like carboxyl, phenol, enol, and thiol, with carboxylic acids having the strongest acidity.

Organic acids are considered weak acids, with those containing phenol, enol, alcohol, or thiol groups being even weaker.  

Their structures vary in terms of carbon chain types—aromatic, aliphatic, alicyclic, heterocyclic—saturation, substitutions, and the number of functional groups. 

These acids play critical roles in metabolic and catabolic pathways, notably in the tricarboxylic acid cycle inside mitochondria, which is central to energy production in eukaryotes.  They are also pivotal in determining the sensory properties of fruits and vegetables.

Organic Acid Disorders  [1., 12.]

Organic acid disorders are inherited metabolic conditions that affect the enzymes or transport proteins essential for the breakdown of amino acids, lipids, or carbohydrates. They are marked by the excessive excretion of non-amino organic acids in urine, primarily due to defects in specific enzymes involved in amino acid breakdown that cause buildup of organic acids in tissues.

Conditions can manifest as inborn metabolic disorders of organic acids and amino acids, urea cycle anomalies, and mitochondrial respiratory chain deficiencies.

These disorders are typically passed down through autosomal recessive inheritance.  They often present in newborns with symptoms like vomiting and lethargy, progressing to more severe neurological symptoms. 

Early diagnosis and intervention are critical and can improve outcomes. Diagnostic methods include urine organic acid analysis via gas chromatography-mass spectrometry (GC/MS). 

Current treatments focus on managing symptoms and preventing complications, although definitive therapies are still under research.  Treatment focuses may include dietary management, detoxifying harmful metabolites, and in severe cases, organ transplantation. 

Continuous monitoring and management are essential for managing symptoms and preventing complications.

Organic Acids and the Microbiome  [7.]

Increasingly, research highlights new relationships between the microbiome and human health.  Many organisms that comprise the microbiome produce organic acids that can then be tested for additional diagnostic capability.  

Certain organic acids in urine like hippuric acid, benzoic acid, and indoleacetic acid are metabolites produced by gut bacteria from the breakdown of amino acids, dietary polyphenols, and other substances. 

These acids provide insights into gut health and metabolic functions.  For example, elevated levels of certain acids may indicate gut dysbiosis or specific metabolic imbalances, such as phenylketonuria. 

Some organic acids known to be produced by the microbiome include: 

Benzoic Acid (BA): 

Produced from phenylalanine and polyphenol metabolism by intestinal bacteria. High levels in urine can indicate glycine deficiency or liver dysfunction.

Hippuric Acid (HA):

Formed in the liver by conjugation of benzoic acid with glycine. Elevated levels may indicate exposure to environmental toxins like toluene.

Phenylacetic Acid (PAA) and Phenylpropionic Acid (PPA): 

These acids result from phenylalanine metabolism by gut bacteria. High urinary levels can suggest dysbiosis or disorders like phenylketonuria. PAA is also associated with depression markers.

4-Hydroxybenzoic Acid (4-HBA) and 4-Hydroxyphenylacetic Acid (4-HPAA): 

Derivatives of tyrosine metabolism. 4-HBA is linked to catechin (green tea) metabolism, and 4-HPAA is useful in diagnosing small bowel diseases related to bacterial overgrowth.

3-Hydroxyphenylpropionic Acid (3-HPPA): 

A metabolite from dietary polyphenols like proanthocyanidins, indicative of robust bacterial metabolism in the intestines.

3,4-Dihydroxyphenyl Propionic Acid (3,4-DHPPA): 

Produced from dietary quinolones by clostridial species, with high levels suggesting an overgrowth.

3-Indoleacetic Acid (IAA): A breakdown product of tryptophan by gut bacteria such as Bifidobacterium and Bacteroides. Elevated levels are seen in conditions like phenylketonuria or dietary changes.

These organic acids are important markers in clinical diagnostics, helping to monitor metabolic disturbances, gut microbiota balance, and exposure to environmental toxins.

Their presence and concentration are influenced by diet, gut microbiota composition, and overall metabolic health, making them valuable indicators in clinical settings for assessing both metabolic and gastrointestinal conditions.

Organic Acid Testing in Functional Medicine

Organic Acid Testing in Functional Medicine

In functional medicine, organic acid testing is utilized to evaluate a patient's metabolic function through a simple urine test. This testing can identify metabolic imbalances that may affect a patient’s mood, energy, and overall health. 

Testing provides insights into nutrient deficiencies, dietary habits, toxic exposures, and gut microbiome activity. 

The results assist practitioners in customizing treatment plans to address specific metabolic dysfunctions and improve health outcomes. 

Additionally, it helps in assessing the impact of microbial metabolism and the efficiency of the Krebs Cycle, aiding in personalized healthcare.

Laboratory Testing for 2-Oxoglutaric Acid, or Alpha-Ketoglutarate

Test Information, Sampling Methods and Preparation

Laboratory testing for organic acids including Alpha-Ketoglutarate is typically done in urine, although it can also be tested in blood.  Testing may be ordered to diagnose an inborn metabolic disorder, or to assess metabolic function and gastrointestinal health in a functional medicine setting.  

Urine samples may be collected in a clinical setting; they can also be collected at home.  Some labs recommend or require a first morning void sample, to provide a concentrated sample. 

Interpreting 2-Oxoglutaric Acid, or Alpha-Ketoglutarate Results

Optimal Range for 2-Oxoglutaric Acid, or Alpha-Ketoglutarate Testing

Generally, falling within reference ranges for organic acids is recommended, although for many of these organic acids, a level towards the lower end of the reference range is considered optimal.  

It is essential to consult with the laboratory company used for their recommended reference range for Alpha-Ketoglutarate. 

One company reports the following reference range for 2-Oxoglutaric Acid, or Alpha-Ketoglutarate:  <18.94 mcg/mg creatinine  [10.]

Clinical Significance of Elevated Levels of 2-Oxoglutaric Acid, or Alpha-Ketoglutarate

Elevated levels of alpha-ketoglutarate (AKG) can occur in the setting of deficiencies in cofactors needed for the enzymatic conversion of alpha-ketoglutarate to succinyl CoA, such as B vitamins, magnesium, manganese, and zinc.  

Genetic deficiencies can also cause elevations in alpha-ketoglutarate.  This can occur in the setting of various genetic deficiencies including hyperinsulinism-hyperammonemia syndrome (HHS).  [8., 14.]

High glucose conditions in diabetes also promote elevated levels of AKG.  [6.] 

Clinical Significance of Low Levels of 2-Oxoglutaric Acid, or Alpha-Ketoglutarate

Low levels of Alpha-Ketoglutarate may reflect nutrient deficiencies in enzymatic cofactors or Krebs cycle substrates.  

Also, since AKG is essential for the Krebs cycle which generates ATP (the primary energy currency of cells), low α-KG levels can lead to reduced ATP production, resulting in fatigue, weakness, and overall decreased cellular function.

An in-depth nutritional assessment including levels of B vitamins, magnesium, manganese and zinc may be warranted.  

2-Oxoglutaric Acid/Alpha-Ketoglutarate Related Biomarkers and Comparative Analysis

Alpha-ketoglutarate is typically tested along with other organic acids to gain deeper insights into metabolic pathways and physiological processes.

Organic acids that may be tested as part of a panel include: 

2-Hydroxybutyric Acid: this acid is a marker for insulin resistance and increased oxidative stress.

2-Hydroxyphenylacetic Acid: derived from phenylalanine metabolism, this acid is used as a biomarker in various metabolic assessments.

3-Hydroxybutyric Acid: a ketone body produced during fat metabolism, indicative of carbohydrate deprivation or ketogenic conditions.

3-Hydroxyisovaleric Acid: an organic acid that accumulates in leucine catabolism disorders, often elevated in maple syrup urine disease.

3-Indoleacetic Acid: a metabolite of tryptophan, it is significant in the study of serotonin pathways and plant growth regulation.

4-Hydroxybenzoic Acid: a derivative of tyrosine metabolism, it is linked to catechin (green tea) metabolism and may be produced by some intestinal bacteria.

4-Hydroxyphenylacetic Acid: a breakdown product of tyrosine, used in diagnosing disorders involving the degradation of aromatic amino acids.

5-Hydroxyindoleacetic Acid: the main metabolite of serotonin, used as a marker in the diagnosis of carcinoid syndrome.

Adipic Acid: a dicarboxylic acid that can also be formed metabolically in humans through the oxidation of certain fatty acids.

‍a-Keto-b-Methylvaleric Acid: an intermediate in isoleucine metabolism, which can accumulate in certain metabolic disorders.

a-Ketoisocaproic Acid: an intermediate in the metabolism of leucine, elevated in maple syrup urine disease.

a-Ketoisovaleric Acid: a breakdown product of valine metabolism, also linked to maple syrup urine disease.

a-Ketoglutaric Acid: a key intermediate in the citric acid cycle, essential for energy production and nitrogen transport.

Benzoic Acid: produced from phenylalanine and polyphenol metabolism by intestinal bacteria. High levels in urine can indicate glycine deficiency or liver dysfunction.

Cis-Aconitic Acid: an intermediate in the tricarboxylic acid cycle, formed by the dehydration of citric acid.

Citric Acid: a central compound in the citric acid cycle, crucial for energy production in cells.

Ethylmalonic Acid: this acid accumulates in ethylmalonic encephalopathy and is involved in fatty acid metabolism.

Fumaric Acid: an intermediate in the tricarboxylic acid (TCA) cycle, participating in energy production through its conversion to malate and subsequent participation in the generation of ATP.

Homovanillic Acid: a major metabolite of dopamine, used as a marker to monitor dopamine levels.

Hippuric Acid: formed from the conjugation of benzoic acid and glycine; elevated levels can indicate exposure to certain environmental toxins.

‍Hydroxymethylglutarate: an intermediate in leucine metabolism, also associated with disorders of ketogenesis and ketolysis.

‍Isocitric Acid: an isomer of citric acid and an important part of the citric acid cycle, pivotal in cellular energy production.

Kynurenic Acid: a product of tryptophan metabolism, known for its role as a neuroprotective agent.

Lactic Acid: produced from pyruvate via anaerobic metabolism, an indicator of hypoxia and strenuous exercise.

Malic Acid: a dicarboxylic acid found in fruits, and involved  in the citric acid cycle.

Methylmalonic Acid: an indicator of Vitamin B12 deficiency, it accumulates when the vitamin is deficient.

Methylsuccinic Acid: a dicarboxylic acid often involved in alternative pathways of fatty acid metabolism.

Orotic Acid: involved in the metabolism of pyrimidines, abnormalities in its levels can indicate metabolic disorders.

Pyroglutamic Acid: an uncommon amino acid derivative that can accumulate in glutathione synthesis disorders.

Pyruvic Acid: a key intersection in several metabolic pathways; its levels are crucial for assessing cellular respiration and metabolic function.

Quinolinic Acid: a neuroactive metabolite of the kynurenine pathway, elevated levels are associated with neurodegenerative diseases.

Suberic Acid: a dicarboxylic acid that is a biomarker in adipic aciduria, often studied in relation to fatty acid oxidation disorders.

Succinic Acid: a four-carbon dicarboxylic acid that plays a central role in the Krebs cycle, crucial for energy production.

Tricarballylic Acid: an organic acid that can inhibit aconitase in the citric acid cycle and is sometimes associated with glyphosate exposure.

Vanillylmandelic Acid: a metabolite of epinephrine and norepinephrine, used as a marker for neuroblastoma and other catecholamine-secreting tumors.

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