VOMIT Pathway – Propionyl CoA Intermediate

Propionyl CoA is a common intermediate in catabolism of essential amino acids and odd chain fatty acids. It is also called VOMIT pathway which stands for:

• Valine
• Odd chain fatty acids
• Methionine
• Isoleucine
• Threonine

They enter TCA cycle – using PMS pathway:

1. Propionyl CoA
2. Methylmalonyl CoA
3. Succinyl CoA

Defects in VOMIT Pathway

Defect in Branched Chain Ketoacid Dehydrogenase (BCKD) – Maple Syrup Urine Disease (MSUD)

Defect in enzyme Branched Chain Ketoacid Dehydrogenase:

• Enzyme similar to pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase – requires thiamine, lipoic acid, CoA, FAD, NAD+
• Defect in BCKD leads to elevation of plasma concentrations of the branched-chain amino acids and corresponding keto acids
• Present in Inner mitochondrial membrane

Features:

1. Infantile onset – normal for first week; progressive symptoms
2. Leucine accumulation – Neurological symptoms
   • Impair regulation of cell volume – resulting in decreased serum sodium concentration and increased intracellular water, leading to cerebral edema.
   • Another mechanism of neurotoxicity may be increased production of glutamate, glutamine, and gamma-aminobutyric acid (GABA) caused by the rapid transport of leucine across the blood-brain barrier.
   • Features: Mental retardation, Abnormal muscle tone
3. Isoleucine accumulation – Maple syrup odor of urine
4. Caramel colored urine
5. Ketosis, Coma and Death

Treatment: Restriction of dietary valine, leucine and isoleucine

Defect in Propionyl-CoA Carboxylase and Methylmalonyl-CoA Mutase

Inability to handle all 5 components of VOMIT

Propionyl-CoA carboxylase requires Biotin (Vit.B7) and Methylmalonyl-CoA Mutase requires Cobalamin (Vit. B12)

Pathophysiology:

• Accumulated organic acids inhibit gluconeogenesis: hypoglycemia
• Fatty acids are transported into mitochondria as carnitine conjugates where they are b-oxidized to ketones: ketosis.
• Organic acid inhibits the urea cycle: hyperammonemia
• Organic acid inhibits glycine degradation: hyperglycinemia
• Organic acid inhibits hematopoeisis: neutropenia

Features:

• Ketoacidosis – due to failure to metabolize ketoacids produced from 4 amino acids
• Propionyl-CoA carboxylase deficiency (Propionic acidemia): Accumulation of –
  • Propionic acid
  • Methyl citrate
  • Hydroxypropionic acid
• Methylmalonyl-CoA mutase deficiency: Accumulation of-
  • Methylmalnate leading to Methylmalonic aciduria

Treatment: Diet low in valine, methionine, isoleucine and threonine

Homocystinemia/Homocystinuria

Causes:

1. Cystathione synthase deficiency (requires vitamin B6)
2. Decreased affinity of cystathione synthase for Pyridoxal Phosphate (B6)
3. Homocysteine methyl transferase deficiency (requires vitamin B12)
4. Deficiency of Folate, Vitamin B6 or B12

Defect:

1. Inability to re-methylate homocysteine to methionine (Vit B12, folate and homocysteine methyl transferase deficiency)
2. Inability to make cystathione to go into propionic acid pathway (Cystathione synthase and Vit. B6 deficiency)

Pathophysiology:

Homocysteines have “-SH” groups which are reducing agents.

Atherosclerosis:

Marfan-like syndrome:

• Fibrillin-1 contains ∼13% cysteine residues and can be modified by homocysteine.

Presentation:

1. DVT, Stroke, Myocardial infarction
2. Marfan-like: Mental retardation, Lens dislocation (downward as opposed to Marfan’s syndrome in which dislocation is outward and upward), tall habitus with long extremities