(6S)-5-methyltetrahydrofolic acid (CHEBI:136009)

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CHEBI:136009 - (6S)-5-methyltetrahydrofolic acid

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ChEBI Name	(6S)-5-methyltetrahydrofolic acid

ChEBI ID	CHEBI:136009

ChEBI ASCII Name	(6S)-5-methyltetrahydrofolic acid

Definition	A 5-methyltetrahydrofolic acid that has 6S-configuration.

Stars	This entity has been manually annotated by the ChEBI Team.

Secondary ChEBI IDs	CHEBI:41381

Supplier Information	ChemicalBook:CB41236097, ZINC000100028278

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C2F - Ideal conformer

Mrv1927 02082210183D

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Mrv1927 02082210183D

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reading 58 atoms

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Wikipedia	License
Levomefolic acid (INN, also known as L-5-MTHF, L-methylfolate and L-5-methyltetrahydrofolate and (6S)-5-methyltetrahydrofolate, and (6S)-5-MTHF) is the primary biologically active form of folate used at the cellular level for DNA reproduction, the cysteine cycle and the regulation of homocysteine. It is also the form found in circulation and transported across membranes into tissues and across the blood–brain barrier. In the cell, L-methylfolate is used in the methylation of homocysteine to form methionine and tetrahydrofolate (THF). THF is the immediate acceptor of one carbon unit for the synthesis of thymidine-DNA, purines (RNA and DNA) and methionine. The un-methylated form, folic acid (vitamin B9), is a synthetic form of folate, and must undergo enzymatic reduction by dihydrofolate reductase (DHFR) to become biologically active. It is synthesized in the absorptive cells of the small intestine from polyglutamylated dietary folate. It is a methylated derivative of tetrahydrofolate. Levomefolic acid is generated by methylenetetrahydrofolate reductase (MTHFR) from 5,10-methylenetetrahydrofolate (MTHF) and used to recycle homocysteine back to methionine by methionine synthase (MS). L-Methylfolate is water-soluble and primarily excreted via the kidneys. In a study of 21 subjects with coronary artery disease, peak plasma levels were reached in one to three hours following oral or parenteral administration. Peak concentrations were found to be more than seven times higher than folic acid (129 ng/ml vs. 14.1 ng/ml). Patients at risk for vitamin B12 deficiency should consult with their medical provider prior to taking L-Methylfolate. The interrelationship between these two vitamins (L-Methylfolate and B12) is best explained by the methyl trap hypothesis.
Read full article at Wikipedia

Formula

C20H25N7O6

Net Charge

Average Mass

459.463

Monoisotopic Mass

459.18663

InChI

InChI=1S/C20H25N7O6/c1-27-12(9-23-16-15(27)18(31)26-20(21)25-16)8-22-11-4-2-10(3-5-11)17(30)24-13(19(32)33)6-7-14(28)29/h2-5,12-13,22H,6-9H2,1H3,(H,24,30)(H,28,29)(H,32,33)(H4,21,23,25,26,31)/t12-,13-/m0/s1

InChIKey

ZNOVTXRBGFNYRX-STQMWFEESA-N

SMILES

CN1[C@@H](CNC2=CC=C(C=C2)C(=O)N[C@@H](CCC(O)=O)C(O)=O)CNC2=C1C(=O)NC(N)=N2

Roles Classification
Biological Role(s):	human metabolite Any mammalian metabolite produced during a metabolic reaction in humans (Homo sapiens). (via 5-methyltetrahydrofolic acid ) water-soluble vitamin (role) Any vitamin that dissolves in water and readily absorbed into tissues for immediate use. Unlike the fat-soluble vitamins, they are not stored in the body and need to be replenished regularly in the diet and will rarely accumulate to toxic levels since they are quickly excreted from the body via urine. (via B vitamin )

Application(s):	nutraceutical A product in capsule, tablet or liquid form that provide essential nutrients, such as a vitamin, an essential mineral, a protein, an herb, or similar nutritional substance. (via B vitamin )

View more via ChEBI Ontology

ChEBI Ontology
Outgoing	(6S)-5-methyltetrahydrofolic acid (CHEBI:136009) is a 5-methyltetrahydrofolic acid (CHEBI:15641) (6S)-5-methyltetrahydrofolic acid (CHEBI:136009) is conjugate acid of (6S)-5-methyltetrahydrofolate(2−) (CHEBI:18608)

Incoming	(6S)-5-methyltetrahydrofolate(2−) (CHEBI:18608) is conjugate base of (6S)-5-methyltetrahydrofolic acid (CHEBI:136009)

IUPAC Name

N-[4-({[(6S)-2-amino-5-methyl-4-oxo-3,4,5,6,7,8-hexahydropteridin-6-yl]methyl}amino)benzoyl]-L-glutamic acid

INNs	Sources
acide lévoméfolique	WHO MedNet
ácido levomefólico	WHO MedNet
acidum levomefolicum	WHO MedNet
levomefolic acid	WHO MedNet

Synonyms	Sources
(6S)-5-methyl-5,6,7,8-tetrahydrofolic acid	ChEBI
(6S)-5-methyl-THF	ChEBI
(6S)-5-methylTHFA	ChEBI
L-5-methyltetrahydrofolate	ChemIDplus
L-5-methyltetrahydrofolic acid	KEGG DRUG

Manual Xrefs	Databases
392351	ChemSpider
4621	DrugCentral
C2F	PDBeChem
D09353	KEGG DRUG
HMDB0254053	HMDB
Levomefolic_acid	Wikipedia
US2007190596	Patent
US2010151533	Patent
View more database links

Registry Number	Type	Source
31690-09-2	CAS Registry Number	ChemIDplus

Citations

Lam NSK, Long XX, Li X, Saad M, Lim F, Doery JC, Griffin RC, Galletly C (2022)
The potential use of folate and its derivatives in treating psychiatric disorders: A systematic review.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 146, 112541 [PubMed:34953391]
[show Abstract]

Objectives

To examine the strengths and limitations of existing data to provide guidance for the use of folate supplements as treatment, with or without other psychotropic medications, in various psychiatric disorders. To identify area for further research in terms of the biosynthesis of mechanism of folate and genetic variants in metabolic pathway in human.

Methods

A systematic review of published literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, to assess whether folate supplements are beneficial in certain psychiatric disorders (depression, bipolar disorder, schizophrenia, autism spectrum disorder, and attention deficit hyperactivity disorder). Methodology of this review is registered with Prospero (Registration number CRD 42021266605).

Data sources

Eligible studies were identified using a systematic search of four electronic databases: Embase, Pubmed, PsycINFO, and Cochrane. The search strategy covered the time period from 1974 to August 16th, 2021. Therefore, this review examines randomized control trials or open-label trials completed during this period.

Results

We identified 23 studies of folate supplements in various psychiatric disorders for critical review. Of these, 9 studies investigated the efficacy of folate supplements in major depressive disorders, 5 studies in schizophrenia, 6 studies in autism spectrum disorder, 2 studies in bipolar affective disorder and 1 study in attention deficit hyperactive disorder. The most consistent finding association of oral levomefolic acid or 5-methylfolate with improvement in clinical outcomes in mental health conditions as mentioned above, especially in major depressive disorder (including postpartum and post-menopausal depression), schizophrenia, autism spectrum disorder, attention deficit hyperactivity disorder and bipolar affective disorder. Folate supplements were well tolerated.

Limitation

Our results are not representative of all types of studies such as case reports or case series studies, nor are they representative of the studies conducted in languages that are not in English or not translated in English.

Conclusion

Increasing evidence from clinical trials consistently demonstrate folate supplements, especially levomefolic acid or 5-methylfolate, may improve clinical outcomes for certain psychiatric diseases, especially as an adjunct pharmacotherapy with minimal side effects.

Pannia E, Hammoud R, Kubant R, Sa JY, Simonian R, Wasek B, Ashcraft P, Bottiglieri T, Pausova Z, Anderson GH (2021)
High Intakes of [6S]-5-Methyltetrahydrofolic Acid Compared with Folic Acid during Pregnancy Programs Central and Peripheral Mechanisms Favouring Increased Food Intake and Body Weight of Mature Female Offspring.
Nutrients 13, 1477 [PubMed:33925570]
[show Abstract]

Pannia E, Hammoud R, Simonian R, Arning E, Ashcraft P, Wasek B, Bottiglieri T, Pausova Z, Kubant R, Anderson GH (2020)
[6S]-5-Methyltetrahydrofolic Acid and Folic Acid Pregnancy Diets Differentially Program Metabolic Phenotype and Hypothalamic Gene Expression of Wistar Rat Dams Post-Birth.
Nutrients 13, E48 [PubMed:33375730]
[show Abstract]

Obeid R, Schön C, Pietrzik K, Menzel D, Wilhelm M, Smulders Y, Knapp JP, Böhni R (2020)
Pharmacokinetics of Sodium and Calcium Salts of (6S)-5-Methyltetrahydrofolic Acid Compared to Folic Acid and Indirect Comparison of the Two Salts.
Nutrients 12, E3623 [PubMed:33255787]
[show Abstract]

Cochrane KM, Mayer C, Devlin AM, Elango R, Hutcheon JA, Karakochuk CD (2020)
Is natural (6S)-5-methyltetrahydrofolic acid as effective as synthetic folic acid in increasing serum and red blood cell folate concentrations during pregnancy? A proof-of-concept pilot study.
Trials 21, 380 [PubMed:32370802]
[show Abstract]

Background

North American health authorities recommend 0.4 mg/day folic acid before conception and throughout pregnancy to reduce the risk of neural tube defects. Folic acid is a synthetic form of folate that must be reduced by dihydrofolate reductase and then further metabolized. Recent evidence suggests that the maximal capacity for this process is limited and unmetabolized folic acid has been detected in the circulation. The biological effects of unmetabolized folic acid are unknown. A natural form of folate, (6S)-5-methyltetrahydrofolic acid (Metafolin®), may be a superior alternative because it does not need to be reduced in the small intestine. Metafolin® is currently used in some prenatal multivitamins; however, it has yet to be evaluated during pregnancy.

Methods/design

This double-blind, randomized trial will recruit 60 pregnant women aged 19-42 years. The women will receive either 0.6 mg/day folic acid or an equimolar dose (0.625 mg/day) of (6S)-5-methyltetrahydrofolic acid for 16 weeks. The trial will be initiated at 8-21 weeks' gestation (after neural tube closure) to reduce the risk of harm should (6S)-5-methyltetrahydrofolic acid prove less effective. All women will also receive a prenatal multivitamin (not containing folate) to ensure adequacy of other nutrients. Baseline and endline blood samples will be collected to assess primary outcome measures, including serum folate, red blood cell folate and unmetabolized folic acid. The extent to which the change in primary outcomes from baseline to endline differs between treatment groups, controlling for baseline level, will be estimated using linear regression. Participants will have the option to continue supplementing until 1 week postpartum to provide a breastmilk and blood sample. Exploratory analyses will be completed to evaluate breastmilk and postpartum blood folate concentrations.

Discussion

This proof-of-concept trial is needed to obtain estimates of the effect of (6S)-5-methyltetrahydrofolic acid compared to folic acid on circulating biomarkers of folate status during pregnancy. These estimates will inform the design of a definitive trial which will be powered to assess whether (6S)-5-methyltetrahydrofolic acid is as effective as folic acid in raising blood folate concentrations during pregnancy. Ultimately, these findings will inform folate supplementation policies for pregnant women.

Trial registration

ClinicalTrials.gov, ID: NCT04022135. Registered on 14 July 2019.

Verlinde PH, Oey I, Lemmens L, Deborggraeve WM, Hendrickx ME, Van Loey AM (2010)
Influence of reducing carbohydrates on (6S)-5-methyltetrahydrofolic acid degradation during thermal treatments.
Journal of agricultural and food chemistry 58, 6190-6199 [PubMed:20423084]
[show Abstract]

Verlinde PH, Oey I, Hendrickx ME, Van Loey AM, Temme EH (2008)
L-ascorbic acid improves the serum folate response to an oral dose of [6S]-5-methyltetrahydrofolic acid in healthy men.
European journal of clinical nutrition 62, 1224-1230 [PubMed:17622258]
[show Abstract]

Indrawati I, Verlinde P, Ottoy F, Van Loey A, Hendrickx M (2004)
Implications of beta-mercaptoethanol in relation to folate stability and to determination of folate degradation kinetics during processing: a case study on [6S]-5-methyltetrahydrofolic acid.
Journal of agricultural and food chemistry 52, 8247-8254 [PubMed:15612825]
[show Abstract]

Last Modified

14 February 2022

ChEBI

CHEBI:136009 - (6S)-5-methyltetrahydrofolic acid

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