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Inborn Errors of Metabolism01:20

Inborn Errors of Metabolism

Phenylketonuria (PKU) is a protein metabolism disorder characterized by high blood levels of the amino acid phenylalanine. This results from a mutation in the gene responsible for phenylalanine hydroxylase, an enzyme that converts phenylalanine into tyrosine. When this enzyme is deficient, phenylalanine builds up in the blood, leading to symptoms such as vomiting, rashes, seizures, growth deficiency, and severe mental retardation. An early diagnosis and a diet restricting phenylalanine intake...
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Phase II biotransformation reactions are essential for detoxifying and eliminating xenobiotics, including many pharmaceutical compounds. These reactions typically involve conjugation, the covalent attachment of polar endogenous groups such as glucuronic acid, sulfate, methyl, or acetyl moieties to functional groups introduced during Phase I metabolism. The resulting conjugates are more water-soluble, enabling efficient renal or biliary excretion.The major classes of Phase II enzymes include...
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Hyperpolarized 13C Metabolic Magnetic Resonance Spectroscopy and Imaging
11:43

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Published on: December 30, 2016

Precision metabolic therapy for propionic acidemia.

Boopathi Subramaniyan1, Fang Lu2, Huan Li1

  • 1Surgical Research Lab, Department of Surgery, Cooper University Health Care, Camden, NJ 08103, USA.

Biochemical Pharmacology
|June 24, 2026
PubMed
Summary
This summary is machine-generated.

Propionic acidemia (PA) is a metabolic disorder where toxic buildup impairs cellular function. Combination therapies targeting short-chain fatty acid metabolism and CoA homeostasis offer a promising new strategy for treating PA.

Keywords:
ACSS2ACSS3AcetateAcetyl-CoACoANRF2PANKPropionic acidemiaPropionyl-CoA

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Area of Science:

  • Biochemistry
  • Metabolic Disorders
  • Genetics

Background:

  • Propionic acidemia (PA) is a rare genetic disorder caused by propionyl-CoA carboxylase deficiency.
  • Accumulation of propionyl-CoA and toxic metabolites disrupts cellular metabolism, leading to mitochondrial dysfunction and multi-organ pathology.
  • Current treatments like dietary restriction and supportive therapies have suboptimal long-term outcomes.

Purpose of the Study:

  • To review current understanding of PA pathophysiology and treatment limitations.
  • To explore emerging therapeutic strategies, including gene-based and small-molecule approaches.
  • To propose a novel combination therapy targeting short-chain fatty acid metabolism and CoA homeostasis.

Main Methods:

  • Literature review of PA pathophysiology, current management, and novel therapeutic strategies.
  • Analysis of metabolic pathways affected by propionyl-CoA accumulation.
  • Conceptualization of a precision metabolic therapy combining multiple interventions.

Main Results:

  • Propionyl-CoA accumulation disrupts TCA cycle flux, ammonia detoxification, and promotes oxidative stress.
  • Existing treatments face challenges with tolerability, efficacy, and extrahepatic disease.
  • Gene therapy and small molecules show promise but require further development.
  • Emerging strategies focus on metabolic reprogramming and restoring CoA pools.

Conclusions:

  • Rational combination therapy targeting multiple metabolic nodes is proposed as a superior strategy for PA.
  • This approach aims to restore metabolic balance by addressing propionyl-CoA burden and CoA homeostasis.
  • Precision metabolic therapy holds potential for improved long-term outcomes in PA patients.