a-Keto-b-Methylvaleric Acid

α-Keto-β-Methylvaleric Acid (α-KBMVA) is a critical intermediate in the breakdown of the branched-chain amino acid isoleucine, produced through transamination and oxidative decarboxylation. 

It is a substrate for the branched-chain alpha-keto acid dehydrogenase (BCKDH) enzyme complex, converting α-KBMVA to isovaleryl-CoA, a vital step in isoleucine catabolism. 

Proper metabolism of α-KBMVA relies on cofactors like lipoic acid and various B vitamins; deficiencies can lead to its accumulation, indicating metabolic issues.  Elevated α-KBMVA levels can suggest conditions like maple syrup urine disease (MSUD), a genetic disorder resulting from BCKDH deficiency.

Branched-chain amino acids (BCAAs) including isoleucine, leucine, and valine are essential for protein synthesis, energy production, and metabolic regulation.  These amino acids are primarily catabolized in skeletal muscle and further metabolized in the liver. 

Impaired BCAA metabolism can lead to serious health issues, underscoring the importance of understanding intermediates like α-KBMVA in maintaining metabolic balance.

What is a-Keto-b-Methylvaleric Acid?  [1., 8.] 

Alpha-keto-beta-methylvaleric acid (α-KBMVA) is an organic compound with the molecular formula C6H10O3.  It is an alpha-keto acid.  α-KBMVA is an important intermediate metabolite formed during the catabolic breakdown of the branched-chain amino acid isoleucine. 

Three of the essential amino acids are branched-chain amino acids (BCAAs): leucine, isoleucine, and valine.   A-keto-b-methylvaleric acid is an intermediate metabolite of the breakdown of isoleucine.  

It is produced from isoleucine via transamination and oxidative decarboxylation reactions. α-KBMVA is a substrate for the branched-chain alpha-keto acid dehydrogenase (BCKDH) enzyme complex, which converts it to isovaleryl-CoA, a further step in isoleucine catabolism. 

Impaired metabolism of α-KBMVA can lead to its accumulation in the body, indicating potential deficiencies in cofactors like lipoic acid, thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), pantothenic acid, and coenzyme A needed for BCKDH activity.  [9.] 

Moderately elevated levels may suggest impaired conversion to isovaleryl-CoA, while very high elevations along with other keto acids are characteristic of maple syrup urine disease (MSUD), a rare inherited metabolic disorder.  

Branched Chain Amino Acid Metabolism

After protein intake, BCAAs quickly enter systemic circulation and are readily available for use. 

While most amino acids are initially catabolized in the liver, the initial catabolism of BCAAs primarily takes place in skeletal muscle.  In skeletal muscle, branched-chain aminotransferase enzymes convert BCAAs into α-ketoacids. 

Then these α-ketoacids are then released into the blood for further metabolism, mainly in the liver. BCAAs serve as substrates for protein synthesis, energy production, regulation of mammalian target of rapamycin (mTOR) signaling pathway, and other metabolic processes.  [9.] 

What is Maple Syrup Urine Disease?  [6.] 

Maple Syrup Urine Disease (MSUD) is a rare genetic disorder caused by a deficiency in the branched-chain alpha-ketoacid dehydrogenase complex, leading to the accumulation of branched-chain amino acids and their toxic byproducts. 

This condition is detectable in newborn screenings due to its severe impact on development if left untreated. 

MSUD presents in the neonatal period with symptoms such as poor feeding, lethargy, irritability, and a characteristic maple syrup odor in urine.  Without intervention, it can lead to irreversible brain damage, seizures, coma, and death. 

Early diagnosis and management, including dietary restrictions and metabolic monitoring, are crucial for improving outcomes and quality of life. 

Acute episodes require emergency treatment to manage metabolic crises and prevent complications like cerebral edema.  Long-term care involves a specialized diet and regular health monitoring to manage the disorder effectively.

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  [2., 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.

Laboratory Testing for a-Keto-b-Methylvaleric Acid

Test Information, Sampling Methods and Preparation

Laboratory testing for organic acids including a-Keto-b-Methylvaleric 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 a-Keto-b-Methylvaleric Acid Results

Optimal Range for a-Keto-b-Methylvaleric 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 a-Keto-b-Methylvaleric Acid.  

One company reports the following reference range for a-Keto-b-Methylvaleric Acid: </= 2.1 mmol/mol creatinine   [10.]

Clinical Significance of Elevated Levels of a-Keto-b-Methylvaleric Acid

Elevations of a-Keto-b-Methylvaleric Acid often indicate a deficiency in an enzymatic cofactor such as a member of the B vitamin complex or lipoic acid.  

Alternatively, levels of a-Keto-b-Methylvaleric Acid may rise with certain genetic deficiencies, which often manifest as maple syrup urine disease.  

Clinical Significance of Low Levels of a-Keto-b-Methylvaleric Acid

Low levels of a-Keto-b-Methylvaleric Acid are not considered clinically relevant.

Related Biomarkers to Test Alongside a-Keto-b-Methylvaleric Acid

Branched-chain Amino Acids  [7.]

Given that a-KMVA is a metabolic product of isoleucine, assessing levels of branched-chain amino acids (BCAAs) such as leucine, isoleucine, and valine may also be clinically important.

Elevated levels of these amino acids, along with a-KMVA, can indicate a disruption in their catabolism, often seen in conditions like Maple Syrup Urine Disease (MSUD). 

Acylcarnitines Profile  [12.] 

Acylcarnitines are derivatives of fatty acids and amino acids that are essential for transporting fatty acids into the mitochondria for energy production. 

A comprehensive acylcarnitines profile can help detect abnormalities in fatty acid and amino acid metabolism, which are often linked to the same metabolic pathways that involve a-KMVA. 

This profile provides a broader insight into mitochondrial health and function, complementing the data obtained from a-KMVA levels.

Organic Acids

Organic acids, including lactic acid and pyruvic acid, are further metabolites that should be measured to assess the completeness of the metabolic cycle in which a-KMVA is involved. 

Their levels can provide additional clues about the efficiency of cellular energy production and the presence of metabolic blockages. 

Like a-KMVA, these compounds are typically analyzed using chromatographic techniques that ensure detailed and accurate metabolic profiling.

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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