a-Ketobutyric Acid

α-Ketobutyric acid is a key intermediate in the metabolism of several amino acids including glycine, cysteine, methionine, and isoleucine.  

It is also involved in amino acid metabolism and the transsulfuration pathway, essential for glutathione synthesis.  Glutathione is a crucial antioxidant that helps maintain cellular redox balance and detoxify reactive oxygen species. 

Elevated levels of α-ketobutyric acid are often observed in metabolic disorders such as maple syrup urine disease (MSUD) and are also associated with conditions like acute coronary syndrome and muscle mass loss in liver cirrhosis. 

This highlights its significance as a biomarker for various metabolic disturbances, offering potential diagnostic and prognostic applications in clinical practice.

What is α-Ketobutyric Acid? 

α-Ketobutyric acid, also known as 2-ketobutyric acid or 2-oxobutyric acid, is an organic acid belonging to the class of short-chain keto acids.  It plays a crucial role in the metabolism of several amino acids including glycine, cysteine, methionine, valine, leucine, serine, threonine, and isoleucine.  [7., 9.]

Vitamin B3 is required as a cofactor for α-Ketobutyric Acid processing.  

Role in Glutathione Synthesis and Cysteine Metabolism  [6.] 

α-Ketobutyric acid is a byproduct of cysteine metabolism and plays a role in the transsulfuration pathway, which is critical for the synthesis of glutathione (GSH).  Glutathione is the primary non-protein antioxidant in cells, crucial for maintaining redox balance and detoxifying reactive oxygen species.

α-Ketobutyric Acid as a Biomarker for Disease

α-Ketobutyric Acid in Maple Syrup Urine Disease  [2.]

Maple syrup urine disease (MSUD) is a genetic disorder affecting branched-chain amino acid metabolism; consequently, certain metabolites of branched-chain amino acids can be significantly elevated in blood and urine.  [2.]

MSUD results from deficiencies in the branched-chain α-ketoacid dehydrogenase complex, which metabolizes leucine, isoleucine and valine.

Newborns with classical MSUD present within days of birth with metabolic ketoacidosis and progressive neurological decline.  Diagnosis requires quantitative amino acid analysis, which shows elevated branched-chain amino acids and the presence of alloisoleucine, a non-proteinogenic amino acid pathognomonic for MSUD. 

α-Ketobutyric acid is an intermediate in the metabolism of isoleucine, one of the BCAAs.  In MSUD, the accumulation of α-ketobutyric acid, along with other α-ketoacids, contributes to the metabolic disturbances observed in patients. 

Elevated levels of α-ketobutyric acid can lead to metabolic acidosis, which is a critical concern in managing MSUD.

α-Ketobutyric Acid and Acute Coronary Syndrome (ACS)  [5.]

α-Ketobutyric acid has shown promising results as a biomarker for acute coronary syndrome (ACS), a term that encompasses conditions such as unstable angina and acute myocardial infarction (AMI). 

Studies have demonstrated that higher levels of 2-ketobutyric acid are significantly correlated with an increased risk of ACS and the burden of atherosclerotic plaque.  [5.]

Specifically, 2-ketobutyric acid, identified through serum and urinary metabolomics, is noted for its contribution to the multiclass metabolic diagnostic model (MDM) used to distinguish between healthy controls (HC), unstable angina (UA), and acute myocardial infarction (AMI). 

As a biomarker, 2-ketobutyric acid reflects disruptions in metabolic pathways such as the tricarboxylic acid (TCA) cycle and oxidative phosphorylation.  Elevated 2-ketobutyric acid levels are linked to the progression of ACS, indicating its potential utility in early diagnosis and risk stratification in clinical settings.

Muscle Mass Loss in Liver Cirrhosis

In patients with liver cirrhosis, muscle wasting is a common complication that can significantly impact their quality of life and overall health. 

One study demonstrated that α-ketobutyric acid was upregulated in patients with muscle mass loss, indicating its potential role in the metabolic disturbances associated with sarcopenia in HBV-related decompensated liver cirrhosis.  [8.]

This finding suggests that α-ketobutyric acid could be an important marker for identifying and understanding muscle mass loss in cirrhotic patients.

What Are Organic Acids?  [3., 4.]

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., 11.]

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 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 α-Ketobutyric Acid

Test Information, Sampling Methods and Preparation

Laboratory testing for organic acids including α-Ketobutyric Acid 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 α-Ketobutyric Acid Results

Optimal Range for α-Ketobutyric Acid 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 α-Ketobutyric Acid.  

One company reports the following reference range for α-Ketobutyric Acid:  < 7.2

nmol/mg Creatinine  [10.]

Clinical Significance of Elevated Levels of α-Ketobutyric Acid

Elevated levels of α-Ketobutyric Acid in the body may indicate the presence of a rare metabolic disorder like Maple Syrup Urine Disease (MSUD).

MSUD leads to the accumulation of branched-chain amino acids and their metabolites, which can result in severe neurological damage if untreated. 

More commonly, mild elevations in the organic acid α-Ketobutyric Acid may indicate altered metabolic states or inefficiencies in protein metabolism.  It may also indicate a need for additional vitamin B3 supplementation. 

As discussed above, elevated levels of α-Ketobutyric Acid can also be seen in acute coronary syndrome and the muscle wasting seen in cirrhosis.

Clinical Significance of Low Levels of α-Ketobutyric Acid

Low levels of α-Ketobutyric Acid are not considered clinically relevant.

a-Ketobutyric Acid Related Biomarkers to Test

a-Ketobutyric Acid 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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