Elevation of 2-methylcitric acid I and II levels in serum, urine, and cerebrospinal fluid of patients with cobalamin deficiency

Metabolism. 1993 Aug;42(8):978-88. doi: 10.1016/0026-0495(93)90010-l.


Citrate synthase catalyzes the condensation of acetyl-coenzyme A (CoA) and oxaloacetic acid to form citric acid. The enzyme also catalyzes the condensation of propionyl-CoA and oxaloacetic acid with a maximal reaction velocity (Vmax) approximately 10(-4) times that of acetyl-CoA to form 2-methylcitric acid, which contains two asymmetric carbon atoms and exists as two pairs of related enantiomers designated as 2-methylcitric acid I and II. Cobalamin (Cbl) deficiency can lead to increases in intracellular levels of propionyl-CoA. To assess the magnitude of increased synthesis of 2-methylcitric acid in Cbl deficiency, we developed a new capillary gas chromatographic-mass spectrometric assay and measured 2-methylcitric acid levels in serum and cerebrospinal fluid (CSF) of normal subjects and patients with clinically confirmed Cbl deficiency. The normal range for 2-methylcitric acid level was 60 to 228 nmol/L for serum in 50 normal blood donors and 323 to 1,070 nmol/L for CSF in 19 normal subjects. In 50 patients with clinically confirmed Cbl deficiency, values for 2-methylcitric acid in serum ranged from 93 to 13,500 nmol/L; 44 (88%) had values above the normal range. In five patients with clinically confirmed Cbl deficiency, levels of the sum of 2-methylcitric acid I and II ranged from 1,370 to 16,300 nmol/L in CSF, and all five (100%) patients had levels above the normal range. We conclude that levels of 2-methylcitric acid are elevated in serum and CSF of most patients with Cbl deficiency.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Citrate (si)-Synthase / physiology
  • Citrates* / blood
  • Citrates* / cerebrospinal fluid
  • Citrates* / urine
  • Female
  • Folic Acid Deficiency / blood
  • Folic Acid Deficiency / cerebrospinal fluid
  • Folic Acid Deficiency / urine
  • Gas Chromatography-Mass Spectrometry
  • Humans
  • Kidney Diseases / blood
  • Kidney Diseases / cerebrospinal fluid
  • Kidney Diseases / urine
  • Male
  • Middle Aged
  • Stereoisomerism
  • Vitamin B 12 Deficiency* / blood
  • Vitamin B 12 Deficiency* / cerebrospinal fluid
  • Vitamin B 12 Deficiency* / urine


  • Citrates
  • 2-methylcitric acid
  • Citrate (si)-Synthase