Impaired regeneration of monoglutamyl tetrahydrofolate leads to cellular folate depletion in mothers affected by a spina bifida pregnancy.
Periconceptional folate prevents neural tube defects (NTD) by a mechanism which is unclear. The present study found significant changes in the equilibrium of the homocysteine remethylation cycle in NTD affected mothers, possibly involving B12-dependent methionine synthase or 5,10-methylenetetrahydrofolate reductase. Data were consistent with impaired Hcy remethylation leading to poor regeneration of H4PteGlu1, the main intracellular precursor of all folates. This lesion leads to cellular folate deficiency indicated by a significantly lower radioassay RBC folate and 5CH3H4PteGlu4 in affected mothers. The drop in this tetraglutamate is associated with an increase in the abundance of longer chain oligo-gamma-glutamyl folate, again reflecting the underlying folate deficiency. This effect may compromise purine, DNA-thymine, and methionine production, particularly during embryogenesis when folate demand is high. At this time serine hydroxymethyltransferase may play a critical role in conserving H4PteGlu1 for purine synthesis. Many of these depletion effects were corrected with folate supplementation for 1 month.
Lucock
M D
MD
Research School of Medicine, Centre for Reproduction, Growth and Development, Division of Paediatrics and Child Health, D Floor, Clarendon Wing, Leeds General Infirmary, University of Leeds, Leeds, West Yorkshire, LS2 9NS, United Kingdom.
Daskalakis
I
I
Lumb
C H
CH
Schorah
C J
CJ
Levene
M I
MI
D005260:Female; D005492:Folic Acid / Q000008:administration & dosage / Q000096:biosynthesis / Q000097:blood; D005494:Folic Acid Deficiency / Q000150:complications / Q000235:genetics*; D006801:Humans; D011247:Pregnancy; D011248:Pregnancy Complications; D016135:Spinal Dysraphism / Q000150:complications / Q000378:metabolism*; D013763:Tetrahydrofolates / Q000096:biosynthesis* / Q000235:genetics; D014805:Vitamin B 12 / Q000097:blood
D013763:Tetrahydrofolates; C030371:5,6,7,8-tetrahydrofolic acid; D005492:Folic Acid; D014805:Vitamin B 12