Folic Acid, Folinic Acid, 5 Methyl TetraHydroFolate Supplementation for Mutations That Affect Epigenesis through the Folate and One-Carbon Cycles

Abstract

Methylation is an essential biochemical mechanism that is central to the transmission of life, and crucially responsible for regulating gametogenesis and continued embryo development. The methylation of DNA and histones drives cell division and regulation of gene expression through epigenesis and imprinting. Brain development and its maturation also depend on correct lipid methylation, and continued neuronal function depends on biogenic amines that require methylation for their synthesis. All methylation processes are carried out via a methyltransferase enzyme and its unique co-factor S-adenosylmethionine (SAM); the transfer of a methyl group to a target molecule results in the release of SAH (SA homocysteine), and then homocysteine (Hcy). Both of these molecules are toxic, inhibiting methylation in a variety of ways, and Hcy recycling to methionine is imperative; this is achieved via the one carbon cycle, supported by the folates cycle. Folate deficiency causes hyperhomocysteinaemia, with several associated diseases; during early pregnancy, deficiency interferes with closure of the neural tube at the fourth week of gestation, and nutraceutical supplementation has been routinely prescribed to prevent neural tube defects, mainly involving B vitamins, Zn and folates. The two metabolic pathways are subject to single nucleotide polymorphisms that alter their activity/capacity, often severely, impairing specific physiological functions including fertility, brain and cardiac function. The impact of three types of nutraceutical supplements, folic acid (FA), folinic acid (FLA) and 5 Methyl THF (MTHF), will be discussed here, with their positive effects alongside potentially hazardous secondary effects. The issue surrounding FA and its association with UMFA (unmetabolized folic acid) syndrome is now a matter of concern, as UMFA is currently found in the umbilical cord of the fetus, and even in infants’ blood. We will discuss its putative role in influencing the acquisition of epigenetic marks in the germline, acquired during embryogenesis, as well as the role of FA in the management of cancerous disease.

Comparison of differential metabolites in brain tissue of aged marmosets and serum of elderly patients after prolonged anesthesia

“…This hypothesis is supported by the upregulation of lactate levels in the brain tissues of anesthetized aged marmosets and postoperative serum of humans. An important active substance in folate metabolism is 5-methyl THF, which provides the active methyl group that drives the methionine cycle (Menezo et al, 2022). Some studies have suggested that folate metabolism could be a potential alternative source of NADPH (Chen et al, 2019).…”

MTHFR SNPs (Methyl Tetrahydrofolate Reductase, Single Nucleotide Polymorphisms) C677T and A1298C Prevalence and Serum Homocysteine Levels in >2100 Hypofertile Caucasian Male Patients

“…In considering therapeutic options, it has been clearly demonstrated that high doses of folic acid are not a reasonable option [ 13 , 14 ]. Supplementation with 5-methyl tetrahydrofolate (5MTHF), the compound immediately downstream from the MTHFR bottleneck, has shown real efficacy [ 18 , 32 , 37 , 42 ]. After the first preliminary publications [ 18 , 37 ], more than 300 pregnancies, mostly spontaneous, were followed by deliveries in the treated couples, with not a single report of NTD or adverse obstetrical problems.…”

Cloning of a novel tetrahydrofolate-dependent dicamba demethylase gene from dicamba-degrading consortium and characterization of the gene product

“…Compared with DMO, the advantage of the THF-dependent demethylases Dmt and Dmt50 is that they do not need reducing force NADH, so it is more energy-saving. In addition, the 5-methyl-THF generated during dicamba demethylation can be used for the synthesis of purine, pyrimidine, glycine and methionine, as well as the methylation of DNA, fatty acids and enzymes ( Sullivan et al, 2021 ; Menezo et al, 2022 ). However, the disadvantage of Dmt and Dmt50 is that their activities were lower than that of DMO, which greatly limits their abilities to detoxify dicamba.…”