Low Folate Status and Relationship with Betaine and Homocysteine

  • Jose M. Colomina
  • Michelle M. Murphy
Living reference work entry


Folate and betaine participate in homocysteine metabolism through the methionine synthase (MS) and betaine-homocysteine methyltransferase (BMHT) pathways, respectively. The ubiquitous MS pathway depends on 5-methyltetrahydrofolate and cobalamin as cofactors in the remethylation of homocysteine to methionine. When folate and cobalamin supply are adequate, homocysteine remethylation to methionine is predominantly by the MS pathway. The BHMT pathway appears to play an important role in very early embryogenesis and fetal development (in animal studies) but is then limited mainly to the kidney and liver in human adults.

Low or suboptimal folate status still affects non-supplement users and low consumers of voluntarily fortified foods in populations where mandatory fortification with folic acid is absent.

Limited dietary folate and/or cobalamin intake impairs homocysteine remethylation via the MS pathway thus leading to increased blood homocysteine and reduced methionine synthesis. Evidence from in vitro and animal studies shows that the BHMT pathway is upregulated when folate status is low. Preliminary evidence supports the hypothesis that homocysteine remethylation by BHMT is enhanced when the MS pathway is impaired due to low folate status in human adults and during pregnancy. Further research is required to demonstrate that BHMT activity increases in response to low folate status and to determine the extent to which the BHMT pathway can compensate for MS pathway impairment.


Folate Betaine Cobalamin Homocysteine Methionine synthase Betaine-homocysteine methyltransferase Methionine 

List of Abbreviations


One carbon


One carbon metabolism






Betaine-homocysteine methyltransferase




Choline dehydrogenase




Dimethylglycine dehydrogenase


Flavin adenine dinucleotide


Methionine synthase


Methylenetetrahydrofolate reductase


Neural tube defects


Post-methionine load


Pune Maternal Nutrition Study


S-adenosyl methionine


Sarcosine dehydrogenase


Single nucleotide polymorphisms


Fasting total plasma homocysteine




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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Unit of Preventive Medicine and Public Health, Department of Basic Medical Sciences, Faculty of Medicine and Health SciencesIISPV, Universitat Rovira i VirgiliReus, TarragonaSpain
  2. 2.Biomedical Research Networking Center for the Pathophysiology of ObesityCarlos III Institute of HealthMadridSpain

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