Propionic Acid Pathway

Introduction

The propionic acid pathway is a metabolic pathway that plays an important role in the catabolism (breakdown) of certain amino acids and fatty acids in the body. This pathway is important for the generation of energy in cells, as well as for the production of important compounds such as glucose and ketone bodies.

The propionic acid pathway is also known as the propionate pathway or the methylmalonyl-CoA pathway, named after the key intermediate metabolites involved in the pathway. The pathway begins with the breakdown of certain amino acids, including valine, isoleucine, threonine, and methionine, as well as odd-chain fatty acids. These molecules are converted into propionyl-CoA, which is then converted into methylmalonyl-CoA.

Overview

•  Production
  • β-oxidation of odd-numbered fatty acids
    • 2 carbon acetyl-CoA groups removed from chain until there are 5 carbons remaining
    • 5 carbon chain split into 1 acetyl-CoA (2C) + 1 propionyl-CoA (3C)
• Pathway
  • propionyl-CoA → methylmalonyl-CoA
    • catalyzed by propionyl-CoA carboxylase
      • requires biotin (B7)
  • methylmalonyl-CoA → succinyl-CoA 
    • catalyzed by methylmalonyl-CoA mutase
      • requires B₁₂
    • deficiency of B₁₂ results in a blockage of this step
      • result is ↑↑↑ methylmalonate
      • can cause irreversible neuropathy
        • due to pathologic synthesis of myelin with methylmalonate
      • a means to determine whether a patient with megaloblastic anemia is deficient in folate or B₁₂
        • methylmalonic aciduria not see in folate deficiencies
  • succinyl-CoA → citric acid cycle
    • can be converted to malate
      • is gluconeogenic
• exception to rule that fatty acids can be converted to glucose

Types

The propionic acid pathway can be classified into two main types based on the type of molecule that is being metabolized:

1. Amino acid pathway: This pathway involves the breakdown of certain amino acids, including valine, isoleucine, threonine, and methionine. These amino acids are converted into propionyl-CoA through a series of enzymatic reactions, which is then further metabolized through the propionic acid pathway.
2. Fatty acid pathway: This pathway involves the breakdown of odd-chain fatty acids, which contain an odd number of carbon atoms. These fatty acids are broken down into propionyl-CoA, which is then metabolized through the propionic acid pathway.

Both pathways converge at the point where propionyl-CoA is converted into methylmalonyl-CoA, which is an intermediate metabolite in the pathway. Methylmalonyl-CoA can then be converted into succinyl-CoA, which enters the citric acid cycle and contributes to energy production, or it can be converted back into propionyl-CoA, which can be used in gluconeogenesis or the production of ketone bodies.

Deficiencies in enzymes involved in the propionic acid pathway can lead to a group of inherited metabolic disorders known as propionic acidemia, which can affect both the amino acid and fatty acid pathways. In these disorders, there is a buildup of propionic acid and other toxic metabolites in the body, which can cause a range of symptoms including developmental delays, seizures, and organ damage.

Studies

The propionic acid pathway has been the subject of extensive research over the years, with studies exploring various aspects of its regulation, function, and clinical significance. Here are some examples of studies related to the propionic acid pathway:

1. Regulation of the propionic acid pathway: Researchers have studied the enzymes and other factors involved in the regulation of the propionic acid pathway, as well as the cellular and molecular mechanisms that control the flow of metabolites through the pathway. For example, a study published in the Journal of Biological Chemistry in 2017 identified a novel enzyme called PMVK that plays a key role in the regulation of the pathway by modulating the conversion of propionyl-CoA to methylmalonyl-CoA.
2. Clinical significance of the propionic acid pathway: The propionic acid pathway is clinically significant because of its role in propionic acidemia, a rare inherited disorder that affects the breakdown of certain amino acids and fatty acids. Researchers have studied the genetics, biochemistry, and clinical manifestations of propionic acidemia, as well as the development of new diagnostic and therapeutic strategies. For example, a study published in the journal Molecular Genetics and Metabolism in 2019 described a new diagnostic approach using whole-exome sequencing to identify genetic mutations associated with propionic acidemia.
3. Role of the propionic acid pathway in disease: Researchers have also explored the potential role of the propionic acid pathway in the pathogenesis of other diseases, including cancer, diabetes, and neurological disorders. For example, a study published in the journal Cell Reports in 2019 suggested that dysregulation of the propionic acid pathway may contribute to the development of colorectal cancer by altering the balance of cellular energy metabolism.

Overall, research on the propionic acid pathway has advanced our understanding of the complex metabolic processes that underlie cellular function and disease, and may lead to new treatments and interventions for a range of conditions.

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