Levomefolic acid

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Levomefolic acid
5-Methyltetrahydrofolate.png
Names
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
(L-5-Me-THFA, L-5-Me-H4FA),
anion: L-5-methyltetrahydrofolate (L-5-Me-THF, L-5-Me-H4F), L-methylfolate
Metafolin
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
KEGG
MeSH 5-methyltetrahydrofolate
PubChem CID
UNII
  • 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
    Key: ZNOVTXRBGFNYRX-STQMWFEESA-N
  • 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-/m0/s1
    Key: ZNOVTXRBGFNYRX-STQMWFEEBP
  • CN1c2c([nH]c(nc2=O)N)NC[C@@H]1CNc3ccc(cc3)C(=O)N[C@@H](CCC(=O)O)C(=O)O
Properties
C20H25N7O6
Molar mass 459.463 g·mol−1
Pharmacology
B03BB51 ( WHO )
oral, transdermal, subcutaneous
Legal status
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

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. [1]

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). [2]

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). [3]

Metabolism

MTHFR metabolism: folate cycle, methionine cycle, trans-sulfuration and hyperhomocysteinemia. 5-MTHF: 5-methyltetrahydrofolate; 5,10-methyltetrahydrofolate; BAX: Bcl-2-associated X protein; BHMT: betaine-homocysteine S-methyltransferase; CBS: cystathionine beta synthase; CGL: cystathionine gamma-lyase; DHF: dihydrofolate (vitamin B9); DMG: dimethylglycine; dTMP: thymidine monophosphate; dUMP: deoxyuridine monophosphate; FAD flavine adenine dicucleotide; FTHF: 10-formyltetrahydrofolate; MS: methionine synthase; MTHFR: methylenetetrahydrofolate reductase; SAH: S-adenosyl-L-homocysteine; SAME: S-adenosyl-L-methionine; THF: tetrahydrofolate. MTHFR metabolism.svg
MTHFR metabolism: folate cycle, methionine cycle, trans-sulfuration and hyperhomocysteinemia. 5-MTHF: 5-methyltetrahydrofolate; 5,10-methyltetrahydrofolate; BAX: Bcl-2-associated X protein; BHMT: betaine-homocysteine S-methyltransferase; CBS: cystathionine beta synthase; CGL: cystathionine gamma-lyase; DHF: dihydrofolate (vitamin B9); DMG: dimethylglycine; dTMP: thymidine monophosphate; dUMP: deoxyuridine monophosphate; FAD flavine adenine dicucleotide; FTHF: 10-formyltetrahydrofolate; MS: methionine synthase; MTHFR: methylenetetrahydrofolate reductase; SAH: S-adenosyl-L-homocysteine; SAME: S-adenosyl-L-methionine; THF: tetrahydrofolate.

Medical uses

Major depressive disorder

Research suggests that levomefolic acid (L-methylfolate) taken with a first-line antidepressant [4] provides a modest adjunctive antidepressant effect for individuals who do not respond or have only a partial therapeutic response to SSRI or SNRI medication, [5] [6] and might be a more cost-effective adjunctive agent than second-generation antipsychotics. [7]

Cardiovascular disease and cancer

Levomefolic acid (and folic acid in turn) has been proposed for treatment of cardiovascular disease [8] [9] and advanced cancers such as breast and colorectal cancers. [10] It bypasses several metabolic steps in the body and better binds thymidylate synthase with FdUMP, a metabolite of the drug fluorouracil.

Patent issues

In March 2012, Merck & Cie of Switzerland, Pamlab LLC (maker of Metanx and Cerefolin, Neevo DHA, and Deplin), and South Alabama Medical Science Foundation (SAMSF) (the plaintiffs) filed a complaint in the United States District Court for the Eastern District of Texas against four defendants: Macoven Pharmaceuticals (owned by Pernix Therapeutics), Gnosis SpA of Italy, Gnosis U.S.A and Gnosis Bioresearch Switzerland. The plaintiffs alleged that the defendants infringed on several of the plaintiffs' patents. [11] The Macoven products named in the suit are: "Vitaciric-B", "ALZ-NAC", "PNV DHA", and l-methylfolate calcium (levomefolate calcium). [12]

In September 2012, the same three plaintiffs filed a complaint requesting that the International Trade Commission begin a 19 U.S.C.   § 1337 investigation of the same four defendants. The complaint states that Gnosis' "Extrafolic-S" and products which are made from it, infringe upon three of their patents: US 5997915  , US 6673381  , and US 7172778  . [13]

Formulations

Levomefolate calcium, a calcium salt of levomefolic acid is sold under the brand name Metafolin [14] and incorporated in Deplin. [15] Levomefolate magnesium is a magnesium salt of levomefolic acid, manufactured as DeltaFolate, a primary ingredient in EnLyte. [16]

See also

Related Research Articles

<span class="mw-page-title-main">Folate</span> Vitamin B9; nutrient essential for DNA synthesis

Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and storage. Folate is required for the body to make DNA and RNA and metabolise amino acids necessary for cell division. As the human body cannot make folate, it is required in the diet, making it an essential nutrient. It occurs naturally in many foods. The recommended adult daily intake of folate in the U.S. is 400 micrograms from foods or dietary supplements.

<span class="mw-page-title-main">Homocysteine</span> Chemical compound

Homocysteine or Hcy: is a non-proteinogenic α-amino acid. It is a homologue of the amino acid cysteine, differing by an additional methylene bridge (-CH2-). It is biosynthesized from methionine by the removal of its terminal Cε methyl group. In the body, homocysteine can be recycled into methionine or converted into cysteine with the aid of vitamin B6, B9, and B12.

<i>S</i>-Adenosyl methionine Chemical compound found in all domains of life with largely unexplored effects

S-Adenosyl methionine (SAM), also known under the commercial names of SAMe, SAM-e, or AdoMet, is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic reactions occur throughout the body, most SAM is produced and consumed in the liver. More than 40 methyl transfers from SAM are known, to various substrates such as nucleic acids, proteins, lipids and secondary metabolites. It is made from adenosine triphosphate (ATP) and methionine by methionine adenosyltransferase. SAM was first discovered by Giulio Cantoni in 1952.

<span class="mw-page-title-main">Homocystinuria</span> Medical condition

Homocystinuria or HCU is an inherited disorder of the metabolism of the amino acid methionine due to a deficiency of cystathionine beta synthase or methionine synthase. It is an inherited autosomal recessive trait, which means a child needs to inherit a copy of the defective gene from both parents to be affected. Symptoms of homocystinuria can also be caused by a deficiency of vitamins B6, B12, or folate.

<span class="mw-page-title-main">Folinic acid</span> Derivative of folic acid used in cancer treatment

Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of methotrexate and pyrimethamine. It is also used in combination with 5-fluorouracil to treat colorectal cancer and pancreatic cancer, may be used to treat folate deficiency that results in anemia, and methanol poisoning. It is taken by mouth, injection into a muscle, or injection into a vein.

<span class="mw-page-title-main">Methylenetetrahydrofolate reductase</span> Rate-limiting enzyme in the methyl cycle

Methylenetetrahydrofolate reductase (MTHFR) is the rate-limiting enzyme in the methyl cycle, and it is encoded by the MTHFR gene. Methylenetetrahydrofolate reductase catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine. Natural variation in this gene is common in otherwise healthy people. Although some variants have been reported to influence susceptibility to occlusive vascular disease, neural tube defects, Alzheimer's disease and other forms of dementia, colon cancer, and acute leukemia, findings from small early studies have not been reproduced. Some mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency. Complex I deficiency with recessive spastic paraparesis has also been linked to MTHFR variants. In addition, the aberrant promoter hypermethylation of this gene is associated with male infertility and recurrent spontaneous abortion.

<span class="mw-page-title-main">Trimethylglycine</span> Chemical compound

Trimethylglycine is an amino acid derivative that occurs in plants. Trimethylglycine was the first betaine discovered; originally it was simply called betaine because, in the 19th century, it was discovered in sugar beets.

<span class="mw-page-title-main">Methionine synthase</span> Mammalian protein found in Homo sapiens

Methionine synthase (MS, MeSe, MTR) is responsible for the regeneration of methionine from homocysteine. In humans it is encoded by the MTR gene (5-methyltetrahydrofolate-homocysteine methyltransferase). Methionine synthase forms part of the S-adenosylmethionine (SAMe) biosynthesis and regeneration cycle, and is the enzyme responsible for linking the cycle to one-carbon metabolism via the folate cycle. There are two primary forms of this enzyme, the Vitamin B12 (cobalamin)-dependent (MetH) and independent (MetE) forms, although minimal core methionine synthases that do not fit cleanly into either category have also been described in some anaerobic bacteria. The two dominant forms of the enzymes appear to be evolutionary independent and rely on considerably different chemical mechanisms. Mammals and other higher eukaryotes express only the cobalamin-dependent form. In contrast, the distribution of the two forms in Archaeplastida (plants and algae) is more complex. Plants exclusively possess the cobalamin-independent form, while algae have either one of the two, depending on species. Many different microorganisms express both the cobalamin-dependent and cobalamin-independent forms.

<span class="mw-page-title-main">Hyperhomocysteinemia</span> Medical condition

Hyperhomocysteinemia is a medical condition characterized by an abnormally high level of total homocysteine in the blood, conventionally described as above 15 μmol/L.

<span class="mw-page-title-main">Folate deficiency</span> Abnormally low level of folate (vitamin B9) in the body

Folate deficiency, also known as vitamin B9 deficiency, is a low level of folate and derivatives in the body. This may result in a type of anemia in which red blood cells become abnormally large and is a late finding in folate deficiency and folate deficiency anemia is the term given for this medical condition. Signs of folate deficiency are often subtle. Symptoms may include feeling tired, heart palpitations, shortness of breath, feeling faint, open sores on the tongue, loss of appetite, changes in the color of the skin or hair, irritability, and behavioral changes. Temporary reversible infertility may occur. Folate deficiency anemia during pregnancy may give rise to the birth of low weight birth premature infants and infants with neural tube defects.

<span class="mw-page-title-main">Tetrahydrofolic acid</span> Chemical compound

Tetrahydrofolic acid (THFA), or tetrahydrofolate, is a folic acid derivative.

<span class="mw-page-title-main">5,10-Methylenetetrahydrofolate</span> Chemical compound

5,10-Methylenetetrahydrofolate (N5,N10-Methylenetetrahydrofolate; 5,10-CH2-THF) is cofactor in several biochemical reactions. It exists in nature as the diastereoisomer [6R]-5,10-methylene-THF.

In enzymology, a methylenetetrahydrofolate reductase (ferredoxin) (EC 1.5.7.1) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Antifolate</span> Class of antimetabolite medications

Antifolates are a class of antimetabolite medications that antagonise (that is, block) the actions of folic acid (vitamin B9). Folic acid's primary function in the body is as a cofactor to various methyltransferases involved in serine, methionine, thymidine and purine biosynthesis. Consequently, antifolates inhibit cell division, DNA/RNA synthesis and repair and protein synthesis. Some such as proguanil, pyrimethamine and trimethoprim selectively inhibit folate's actions in microbial organisms such as bacteria, protozoa and fungi. The majority of antifolates work by inhibiting dihydrofolate reductase (DHFR).

<span class="mw-page-title-main">MTRR (gene)</span> Protein-coding gene in the species Homo sapiens

Methionine synthase reductase, also known as MSR, is an enzyme that in humans is encoded by the MTRR gene.

<span class="mw-page-title-main">Prenatal vitamin</span> Vitamin and mineral supplements

Prenatal vitamins, also known as prenatal supplements, are vitamin and mineral supplements intended to be taken before and during pregnancy and during postnatal lactation. Although not intended to replace a healthy diet, prenatal vitamins provide women of childbearing age with nutrients recognized by the various health organizations including the American Dietetic Association as helpful for a healthy pregnancy outcome. It may be appropriate to start taking prenatal vitamins once the woman enters childbearing age, however if a person is not pregnant or planning to become pregnant the Mayo Clinic does not recommend taking these supplements. Prenatal vitamins are similar to other multivitamins but do contain different amounts of specific nutrients to better suit the needs of an expecting mother.

<span class="mw-page-title-main">Drospirenone/ethinylestradiol/levomefolic acid</span> Pharmaceutical combination

Drospirenone/ethinylestradiol/levomefolic acid (EE/DRSP/LMF), sold under the brand name Beyaz among others, is a combination of ethinylestradiol (EE), an estrogen, drospirenone (DRSP), a progestogen, antimineralocorticoid, and antiandrogen, and levomefolic acid (LMF), a form of vitamin B9, which is used as a birth control pill to prevent pregnancy in women. The formulation contains folate as the calcium salt of levomefolic acid to lower the risk of complications such as fetal neural tube defects should the medication fail as a form of birth control. EE/DRSP/LMF was approved for use by the US Food and Drug Administration (FDA) in September 2010.

Rowena Green Matthews, born in 1938, is the G. Robert Greenberg Distinguished University professor emeritus at the University of Michigan, Ann Arbor. Her research focuses on the role of organic cofactors as partners of enzymes catalyzing difficult biochemical reactions, especially folic acid and cobalamin. Among other honors, she was elected to the National Academy of Sciences in 2002 and the Institute of Medicine in 2004.

Methylenetetrahydrofolate reductase deficiency is the most common genetic cause of elevated serum levels of homocysteine (hyperhomocysteinemia). It is caused by genetic defects in MTHFR, which is an important enzyme in the methyl cycle.

Riboflavin-responsive exercise intolerance is a rare disorder caused by mutations of the SLC25A32 gene that encodes the mitochondrial folate transporter. Patients suffer from exercise intolerance and may have disrupted motor function.

References

  1. Pietrzik K, Bailey L, Shane B (August 2010). "Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics". Clinical Pharmacokinetics. 49 (8): 535–48. doi:10.2165/11532990-000000000-00000. PMID   20608755. S2CID   12876272.
  2. "5-methyltetrahydrofolate – Compound Summary", PubChem, NCBI, retrieved 25 September 2012
  3. "CerefolinNAC Caplets Package Insert" (PDF).
  4. Sussman, Norman (1 March 2009). "Selecting a First-line Antidepressant: New Analysis". Primary Psychiatry. 16: 19–22.
  5. Maruf, Abdullah Al; Poweleit, Ethan A.; Brown, Lisa C.; Strawn, Jeffrey R.; Bousman, Chad A. (2022). "Systematic Review and Meta-Analysis of L-Methylfolate Augmentation in Depressive Disorders". Pharmacopsychiatry. 55 (3): 139–147. doi:10.1055/a-1681-2047. ISSN   1439-0795. PMID   34794190.
  6. Lam, Nelson Siu Kei; Long, Xin Xin; Li, Xuegang; Saad, Mirette; Lim, Florence; Doery, James CG; Griffin, Robert C.; Galletly, Cherrie (2022). "The potential use of folate and its derivatives in treating psychiatric disorders: A systematic review". Biomedicine & Pharmacotherapy. 146: 112541. doi: 10.1016/j.biopha.2021.112541 . PMID   34953391. S2CID   245436052.
  7. Wade RL, Kindermann SL, Hou Q, Thase ME (January 2014). "Comparative assessment of adherence measures and resource use in SSRI/SNRI-treated patients with depression using second-generation antipsychotics or L-methylfolate as adjunctive therapy". Journal of Managed Care Pharmacy. 20 (1): 76–85. doi: 10.18553/jmcp.2014.20.1.76 . PMC   10438233 . PMID   24372461.
  8. Willems FF, Boers GH, Blom HJ, Aengevaeren WR, Verheugt FW (March 2004). "Pharmacokinetic study on the utilisation of 5-methyltetrahydrofolate and folic acid in patients with coronary artery disease". British Journal of Pharmacology. Nature Publishing Group. 141 (5): 825–30. doi:10.1038/sj.bjp.0705446. PMC   1574248 . PMID   14769778.
  9. Fohr IP, Prinz-Langenohl R, Brönstrup A, Bohlmann AM, Nau H, Berthold HK, Pietrzik K (February 2002). "5,10-Methylenetetrahydrofolate reductase genotype determines the plasma homocysteine-lowering effect of supplementation with 5-methyltetrahydrofolate or folic acid in healthy young women" (PDF). The American Journal of Clinical Nutrition. American Society for Clinical Nutrition. 75 (2): 275–82. doi: 10.1093/ajcn/75.2.275 . PMID   11815318.[ dead link ]
  10. Ströhle A, Wolters M, Hahn A (June 2005). "Folic acid and colorectal cancer prevention: molecular mechanisms and epidemiological evidence (Review)". International Journal of Oncology. 26 (6): 1449–64. doi:10.3892/ijo.26.6.1449. PMID   15870856.
  11. The six patents named were US 5997915 , US 6011040 , US 6254904 , US 6673381 , US 7674490 and US 7172778 .
  12. "Pernix Therapeutics' Subsidiary Macoven Pharmaceuticals, LLC Named in Suit by Merck, Pamlab, L.L.C. and Others for Alleged". Bloomberg. 6 March 2012. Retrieved 1 October 2012.
  13. Schweibenz EW (10 September 2012). "SAMSF, Merck, and Pamlab File New 337 Complaint Regarding Certain Reduced Folate Nutraceutical Products and L-methylfolate Raw Ingredients Used Therein". Oblon, Spivak, McClelland, Maier & Neustadt, L.L.P. Archived from the original on 1 October 2012.
  14. "Metafolin". MilliporeSigma. Retrieved 28 November 2022. Metafolin® is our manufactured calcium salt of L-5-methyltetrahydrofolic or L-methylfolate. ... The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the US and Canada.
  15. "DEPLIN®". For Healthcare Professionals. Retrieved 28 November 2022.
  16. "EnLyte with DeltaFolate". dailymed.nlm.nih.gov. Retrieved 28 November 2022.