5,10-methylenetetrahydrofolate

5,10-Methylenetetrahydrofolate

5,10-Methylenetetrahydrofolate

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.

Quick Facts Names, Identifiers ...

As an intermediate in one-carbon metabolism, 5,10-CH2-THF converts to 5-methyltetrahydrofolate, 5-formyltetrahydrofolate, and methenyltetrahydrofolate. It is substrate for the enzyme methylenetetrahydrofolate reductase (MTHFR)[1][2] It is mainly produced by the reaction of tetrahydrofolate with serine, catalyzed by the enzyme serine hydroxymethyltransferase.

Selected functions

Formaldehyde equivalent

Methylenetetrahydrofolate is a source of the equivalent of formaldehyde or CH22+ in biosyntheses.

Methylenetetrahydrofolate is also an intermediate in the detoxification of formaldehyde.[3]

Pyrimidine biosynthesis

It is the one-carbon donor for thymidylate synthase, for methylation of 2-deoxy-uridine-5-monophosphate (dUMP) to 2-deoxy-thymidine-5-monophosphate (dTMP). The coenzyme is necessary for the biosynthesis of thymidine and is the C1-donor in the reactions catalyzed by TS and thymidylate synthase (FAD).

Biomodulator

[6R]-5,10-methylene-THF is a biomodulator that has proven to enhance the desired cytotoxic antitumor effect of Fluorouracil (5-FU) and can bypass the metabolic pathway required by other folates (such as leucovorin) to achieve necessary activation.[4] The active metabolite is being evaluated in clinical trials for patients with colorectal cancer in combination with 5-FU.

MTHFR metabolism: folate cycle, methionine cycle, trans-sulfuration and hyperhomocysteinemia. 5-MTHF: 5-methyltetrahydrofolate; 5,10-methylenetetrahydrofolate; 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.

See also

References

  1. [1]
    "Entrez Gene: MTHFR methylenetetrahydrofolate reductase (NAD(P)H)".
  2. [2]
    Födinger M, Hörl WH, Sunder-Plassmann G (2000). "Molecular biology of 5,10-methylenetetrahydrofolate reductase". J Nephrol. 13 (1): 20–33. PMID 10720211.
  3. [3]
    Marx, C. J.; Chistoserdova, L.; Lidstrom, M. E. (2003). "Formaldehyde-detoxifying role of the tetrahydromethanopterin-linked pathway in Methylobacterium extorquens AM1". J. Bacteriol. 185 (24): 7160–8. doi:10.1128/jb.185.23.7160-7168.2003. PMC 296243. PMID 14645276.
  4. [4]
    Danenberg, Peter V.; Gustavsson, Bengt; Johnston, Patrick; Lindberg, Per; Moser, Rudolf; Odin, Elisabeth; Peters, Godefridus J.; Petrelli, Nicholas (2016-10-01). "Folates as adjuvants to anticancer agents: Chemical rationale and mechanism of action". Critical Reviews in Oncology/Hematology. 106: 118–131. doi:10.1016/j.critrevonc.2016.08.001. ISSN 1879-0461. PMID 27637357.
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