Elevation of 2-methylcitric acid I and II levels in serum, urine, and cerebrospinal fluid of patients with cobalamin deficiency.
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.
Allen
R H
RH
Department of Medicine, University of Colorado Health Sciences Center, Denver 80262.
Stabler
S P
SP
Savage
D G
DG
Lindenbaum
J
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D002950:Citrate (si)-Synthase / Q000502:physiology; D002951:Citrates / Q000097:blood / Q000134:cerebrospinal fluid / Q000652:urine; D005260:Female; D005494:Folic Acid Deficiency / Q000097:blood / Q000134:cerebrospinal fluid / Q000652:urine; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007674:Kidney Diseases / Q000097:blood / Q000134:cerebrospinal fluid / Q000652:urine; D008297:Male; D008875:Middle Aged; D013237:Stereoisomerism; D014806:Vitamin B 12 Deficiency / Q000097:blood / Q000134:cerebrospinal fluid / Q000652:urine
D002951:Citrates; C031605:2-methylcitric acid; D002950:Citrate (si)-Synthase