Levomefolic acid

Levomefolic acid
IUPAC name (2S)-2-[ [4-[(2-Amino-5-methyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl) methylamino]benzoyl]amino]pentanedioic acid
Other names 5-methyltetrahydrofolic acid (5-Me-THFA, 5-Me-H4FA), anion: 5-methyltetrahydrofolate (5-Me-THF, 5-Me-H4F), L-methylfolate
Identifiers
CAS number	134-35-0
PubChem	444412
ChemSpider	388371
UNII	8S95DH25XC Y
KEGG	D09353
MeSH	5-methyltetrahydrofolate
Jmol-3D images	Image 1
SMILES O=C(O)[C@H](NC(=O)c1ccc(cc1)NCC3N(/C2=C(/N/C(=N\C2=O)N)NC3)C)CCC(=O)O
InChI InChI=1/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-/m1/s1 Key: ZNOVTXRBGFNYRX-ZGTCLIOFBZ
Properties
Molecular formula	C20H25N7O6
Molar mass	459.46 g/mol
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Levomefolic acid (INN) or metafolin (5-methyltetrahydrofolic acid) is the natural, active form of folic acid used at the cellular level for DNA reproduction, the cysteine cycle and the regulation of homocysteine among other functions. The un-methylated form, folic acid (vitamin B₉), is a synthetic form of folate found in nutritional supplements. Synthetic folic acid is metabolized in the body into levomefolic acid. Approximately 10% of the general population (homozygous TT) lack the enzymes needed to receive any benefit from folic acid.^{[citation needed]} Another 40% of the population (heterozygous CT) appear to convert only a limited amount of folic acid into levomefolic acid. They cannot fully process supplemental folic acid at RDA or higher dose levels.^{[citation needed]} The remaining population do not have a known MTHFR polymorphism and can therefore metabolize folic acid more efficiently.

It is synthesized in the absorptive cells of the small intestine from polyglutamylated dietary folate. It is a methylated derivate of tetrahydrofolate (THF, H₄F). Levomefolic acid is generated by methylenetetrahydrofolate reductase (MTHFR) from 5,10-methylenetetrahydrofolate (5,10-CH₂-THF, MTHF) and used to recycle homocysteine back to methionine by 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) also known as methionine synthase (MS).

Levomefolic acid has been proposed for treatment of cardiovascular disease^[1][2] and advanced cancers such as breast and colorectal cancers. It bypasses several metabolic steps in the body and better binds thymidylate synthase with fDump, a metabolite of the drug fluorouracil.

Commercial use

Commercial use of levomefolic acid in pharmaceutical products began in Europe in the early part of this decade^{[clarification needed]} and have now^[when?] appeared in the U.S. This approach to folate supplementation has potential to impact prenatal care, homocysteine management, and the treatment of depression, dementia and cardiovascular concerns.

• Prenatal care: low folate status has been linked to neural tube defects, recurrent pregnancy loss, low birth weight and a variety of age-related high risk complications of pregnancy.

• Homocysteine management: elevated homocysteine is frequently linked to the presence of the MTHFR polymorphism.

• Depression: folate status has been linked to the performance of SSRI drugs. Many patients have required folate supplementation in order to adequately respond to standard treatment protocol.

• Dementia: folate status has been linked to the efficacy of neural transmitters and cognitive performance. Only active, levomefolic acid can cross the blood brain barrier.

• Diabetic neuropathy: folate status has been shown to have a substantial impact upon wound care.

Brands

Oral doses of levomefolic acid have been developed in Germany and are marketed under the brand name Metafolin.

• Cerefolin NAC (5.6 mg) – Nutritional requirements of individuals under a physician's treatment for neurovascular oxidative stress or hyperhomocysteinemia, with particular emphasis for those individuals diagnosed with or at risk for mild to moderate cognitive impairment, vascular dementia, Alzheimer's disease or recurrent or ischemic.

• Deplin (7.5 mg or 15 mg) – Dietary management of suboptimal folate levels in depressed patients.

• Metanx (2.8 mg) – Dietary management of endothelial dysfunction in patients with diabetic peripheral neuropathy.

• Néevo and NeevoDHA (1 mg) – Dietary management of those women under a physician's treatment for vitamin deficiency throughout pregnancy, postnatal and the lactating periods. Néevo is specifically indicated for: patients with high risk pregnancies, older OB patients, and patients unable to fully metabolize folic acid.

• Zervalx (1 mg) – Dietary management of the following patient conditions: preconception hyperhomocysteinemia; intermediate to higher-risk pregnancies that require an increased dietary folate intake; hemolytic, megaloblastic or sickle cell anemia complicated by folate deficiency; and methotrexate induced plasma hyperhomocysteinemia.

See also

• 5-Methyltetrahydrofolate-homocysteine methyltransferase (MTR)
• S-Adenosylmethionine (SAMe)
• Methylenetetrahydrofolate reductase (MTHFR)
• 5,10-Methylenetetrahydrofolate (5,10-CH₂-THF, MTHF)

References

• CALCIUM L-5-METHYLTETRAHYDROFOLATE (L-5-MTHF-Ca)
• Localized depletion: the key to colorectal cancer risk mediated by MTHFR genotype and folate?

1. ^ Willems, Frank F; Boers GHJ, Blom HJ, Aengevaeren WRM, Verheugt FWA (2004 March). "Pharmacokinetic study on the utilisation of 5-methyltetrahydrofolate and folic acid in patients with coronary artery disease". Br J Pharmacol (Nature Publishing Group) 145 (5): 825–830. doi:10.1038/sj.bjp.0705446. PMC 1574248. PMID 14769778. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1574248. >
2. ^ Iris P Fohr, Reinhild Prinz-Langenohl, Anja Brönstrup, Anja M Bohlmann, Heinz Nau, Heiner K Berthold, and Klaus Pietrzik, IP; Prinz-Langenohl, R; Brönstrup, A; Bohlmann, AM; Nau, H; Berthold, HK; Pietrzik, K (2002). "5,10-Methylenetetrahydrofolate reductase genotype determines the plasma homocysteine-lowering effect of supplementation with 5-methyltetrahydrofolate or folic acid in healthy young women". Am J Clin Nutr (American Society for Clinical Nutrition) 75 (2): 275–282. PMID 11815318. http://webcache.googleusercontent.com/search?q=cache:NriMrILGOoIJ:www.geno-type.com/ts/GenoType/pdf/Fohr.pdf&cd=6&hl=en&ct=clnk. 

External links

• Stahl, SM (October 2007). "Novel Therapeutics for Depression: L-methylfolate as a Trimonoamine Modulator and Antidepressant-Augmenting Agent". CNS Spectrums 12 (10): 739–744. PMID 17934378. http://www.cnsspectrums.com/aspx/article_pf.aspx?articleid=1267.