a-Ketoadipic Acid

α-Ketoadipic acid (α-KA), also known as 2-oxoadipic acid, is a crucial intermediate in the catabolism of the amino acids lysine and tryptophan.  

It undergoes oxidative decarboxylation facilitated by α-ketoadipic acid dehydrogenase, converting into glutaryl-CoA, which is essential for energy production and other metabolic functions. 

This metabolic process requires several cofactors including vitamins B1, B2, and lipoic acid. Proper functioning of this pathway is vital for maintaining metabolic balance, and disruptions can lead to elevated levels of α-KA, observed in metabolic disorders such as α-ketoadipic aciduria. 

Elevated α-KA can indicate metabolic defects and contribute to various clinical manifestations, including developmental and neurological issues, highlighting the importance of this metabolite in health and disease.

Elevated levels of α-ketoadipic acid (AKAA) can be a biomarker for several metabolic disorders, including α-ketoadipic aciduria and conditions related to oxidative stress and lipoprotein dysregulation.  It's also linked to the risk of type 2 diabetes and cardiovascular diseases.

Testing AKAA levels, along with related biomarkers like α-aminoadipic acid and cofactors (vitamins B1, B2, NAD, lipoic acid), provides a comprehensive view of metabolic health. Additionally, yeast and fungal infections may elevate AKAA levels, indicating broader metabolic disturbances. 

Understanding these associations helps in diagnosing and managing metabolic conditions more effectively.

What is a-Ketoadipic Acid?  [10.] 

α-Ketoadipic acid (α-KA), also known as 2-oxoadipic acid, is an organic acid metabolite in the lysine and tryptophan catabolic pathways.  It is normally involved in the conversion processes that break down these amino acids for energy production and other metabolic functions. 

Specifically, α-KA undergoes oxidative decarboxylation by α-ketoadipic acid dehydrogenase to form glutaryl-CoA, a critical step in the degradation pathway of lysine and tryptophan. 

This process involves several cofactors, including CoA, NAD, thiamine pyrophosphate (vitamin B1), lipoic acid, and FAD (vitamin B2), which facilitate the transformation of α-KA into usable energy substrates.

The proper functioning of α-ketoadipic acid dehydrogenase is essential for maintaining normal levels of α-KA and its upstream metabolites. Any disruption in this enzyme's activity can lead to the accumulation of α-KA, which is seen in metabolic disorders such as α-ketoadipic aciduria. 

This accumulation can be indicative of metabolic defects and can lead to various clinical manifestations, including developmental and neurological issues.  Regular metabolic functions involving α-KA ensure that amino acids are effectively broken down, contributing to overall metabolic balance and energy homeostasis.

a-Ketoadipic acid is also formed as a byproduct of metabolism in some strains of yeast.  [6.] 

What Are Organic Acids?  [2., 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., 8.]

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.

a-Ketoadipic Acid Clinical Significance

a-Ketoadipic acid (AKAA) has gained considerable attention due to its potential as a biomarker for various metabolic disorders and diseases, particularly those related to lipoprotein dysregulation and oxidative stress.  It has also been studied alongside its precursor, a-aminoadipic acid (AAA).  

a-Ketoadipic Aciduria

α-Ketoadipic aciduria is a metabolic disorder resulting from a defect in α-ketoadipic acid dehydrogenase.  This leads to the accumulation of AKAA and AAA, which can be detected through urine and serum analysis. 

The condition may present with severe developmental delays, although some individuals with the metabolic defect may be asymptomatic. 

Understanding and diagnosing α-ketoadipic aciduria involves identifying elevated metabolites and assessing enzyme activity, which provides insights into lysine and tryptophan metabolism.

a-Ketoadipic Acid and Diabetes

a-Ketoadipic Acid (AKAA) and its precursor a-aminoadipic acid (AAA) have been associated with an increased risk of developing type 2 diabetes. 

Elevated levels of AKAA have been observed in individuals with insulin resistance and glucose intolerance, even before the onset of overt diabetes. [9.]  This suggests that AKAA may serve as an early biomarker for metabolic dysregulation and could potentially aid in the identification of individuals at risk for developing these conditions.

A study involving 188 individuals who developed diabetes and 188 matched controls from the Framingham Heart Study (FHS) highlighted that high levels of AAA were associated with a greater than four-fold risk of developing diabetes.  This finding was validated in the Malmö Diet and Cancer Study (MDC), where similar results were observed.  [9.] 

AAA, produced during lysine degradation, was found to correlate with insulin resistance and β-cell function.  Higher AAA levels were associated with increased fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and β-cell function (HOMA-B). 

Experimental studies showed that AAA administration in mice lowered fasting plasma glucose levels and enhanced insulin secretion, suggesting a direct role in glucose homeostasis.

In mice, AAA treatment resulted in lower fasting glucose levels and higher insulin secretion, both in standard and high-fat diet conditions.  Additionally, AAA increased insulin secretion from pancreatic β-cells and isolated human islets, indicating its potential as a modulator of insulin release.

a-Ketoadipic Acid and Cardiovascular Disease  [5.] 

Furthermore, AKAA has been implicated in the pathogenesis of cardiovascular disease due to its potential role in atherosclerosis.  Studies have shown that higher levels of AKAA are associated with increased inflammation and atherosclerosis development.  

a-Aminoadipic acid (AAA) and lysine nitrile (LysCN) are formed through myeloperoxidase (MPO)-mediated oxidation of protein-bound lysyl residues.  This process is linked to inflammatory diseases and may contribute to cardiovascular disease (CVD) risk.

Elevated levels of AAA and LysCN were found in atherosclerotic plaques compared to healthy aortic tissues, linking these oxidation products to CVD.

Lab Testing for a-Ketoadipic Acid

Test Information, Sample Type and Preparation

Laboratory testing for organic acids including a-ketoadipic 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-Ketoadipic Acid Results

Optimal Range for a-Ketoadipic 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-Ketoadipic Acid.  

One company reports the following reference range for a-Ketoadipic Acid:  </= 1.7 mmol/mol creatinine.  [7.]

Clinical Significance of Elevated Levels of a-Ketoadipic Acid

Elevated levels of a-Ketoadipic Acid are seen in the rare metabolic disorder a-ketoadipic aciduria.  

Apart from that, elevated levels may be seen in conditions including prediabetes or diabetes, cardiovascular disease, atherosclerotic disease, or in the setting of cofactor nutrient deficiencies including Coenzyme A, NAD, thiamine pyrophosphate (vitamin B1), lipoic acid, and riboflavin (vitamin B2).  

Elevated levels of a-ketoadipic acid may also be seen in some yeast and fungal infections, as it is a metabolite of certain yeast and fungal organisms.  [6.] 

Clinical Significance of Low Levels of a-Ketoadipic Acid

Low levels of a-Ketoadipic Acid are not considered clinically relevant. 

Related Biomarkers to Test

While AKAA itself is a valuable biomarker, its interpretation can be enhanced by considering other related biomarkers that provide insights into the underlying metabolic pathways and potential contributing factors.

α-Aminoadipic Acid

α-Aminoadipic acid is the direct precursor of AKAA in the lysine degradation pathway. Measuring the levels of α-aminoadipic acid can provide additional information about the metabolic flux through this pathway and may help differentiate between potential causes of elevated AKAA levels, such as cofactor deficiencies or enzymatic impairments.

Elevated levels of a-aminoadipic acid can also signal early metabolic disorders such as insulin resistance or prediabetes.  [3.] 

Cofactor Levels  [10.] 

As mentioned earlier, the formation of AKAA is dependent on various cofactors, including NAD, thiamine pyrophosphate (vitamin B1), lipoic acid, and FAD (vitamin B2).

Measuring the levels of these cofactors can provide insights into potential deficiencies or imbalances that may contribute to the accumulation of AKAA or its precursors.

Yeast or Fungal Infections

Some studies have suggested that yeast or fungal infections may contribute to elevated levels of AKAA. These microorganisms can produce enzymes that interfere with the normal metabolism of lysine and tryptophan, potentially leading to the accumulation of AKAA or related metabolites.

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