5,10-Methylenetetrahydrofolate

5-MTHF is the methyl donor for remethylation of Hcy by cobalamin-dependent methionine synthase yielding methionine, which is converted to SAMe by methionine adenosyltransferase.

From: Epigenetics of Aging and Longevity , 2018

Hemostasis and Thrombosis

Antonio Capurso , Cristiano Capurso , in Principles of Nutrigenetics and Nutrigenomics, 2020

Polymorphisms of Genes Involved in Homocysteine-Methionine Metabolism: Example of Gene–Environment Interaction

Elevated levels of homocysteine in the blood represent a potential risk factor for cerebrovascular diseases such as stroke and a predisposition to thrombosis and other pathological conditions. The reason for an elevated homocysteine level in the blood may be inadequate nutrition or genetic variants that reduce the activity of enzymes necessary to remove homocysteine efficiently from the blood. A diet containing vitamins B12 and B6 and folic acid helps lower homocysteine level in the blood.

Several polymorphisms have been described in 5,10-methylene tetrahydrofolate reductase (MTHFR) and methionine synthase (MS) genes. Some of these polymorphisms were found to have a crucial role in the thrombotic risk associated with homocysteine blood level and nutritional status.

MTHFR is an enzyme involved in converting the amino acid homocysteine to another amino acid, methionine, providing the folate derivative for converting homocysteine to methionine. Another enzyme, MS, is responsible for regenerating methionine from homocysteine. Two polymorphisms of these genes hare crucial for thrombotic risk:

1

.The C677T polymorphism in exon 4 of the MTHFR gene, which leads to the amino acid substitution of alanine by valine at codon 222 (A222V), causing a thermolabile enzyme with lower activity; and

2

.2756 A   →   G of MS, which leads to amino acid substitution of aspartate by glycine.

These two polymorphisms are associated with (i) decreased activity of the enzyme MTHFR; (ii) a relative deficiency in the remethylation process of homocysteine into methionine; and (iii) mild t -moderate hyperhomocysteinemia, a condition recognized as an independent risk factor for atherosclerosis and thrombosis. In studies on the interaction between these polymorphisms and B vitamin nutritional status in individuals affected by thromboembolic events, the genetic influence of the MTHFR polymorphism on homocysteine levels was not significant in individuals at high risk for thrombotic events who exhibited serum levels of folate and/or vitamin B12 above the 50th percentile of distribution in the general population.

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Biosynthesis of Vitamins in Plants Part B

Stéphane Ravanel , ... Fabrice Rébeillé , in Advances in Botanical Research, 2011

B Interconversion of C1-Substituted Folates

5,10-Methylene-THF, 5,10-methenyl-THF and 10-formyl-THF can be interconverted by the enzymes MTHFD and MTHFC. These activities are reversible and are associated with the cytosol, mitochondria and plastids (Hanson and Roje, 2001). Thus, the combination of SHMT, MTHFD and MTHFC activities can supply each cell compartment with C1-substituted folates required for nucleotides, formylmethionyl-tRNA or pantothenate synthesis (Fig. 2).

Methyl-THF has no other known metabolic fate than methionine synthesis. Methylene-THF reductase (MTHFR) serves a key role in C1 metabolism by converting 5,10-methylene-THF to 5-methyl-THF. The NADPH-dependent MTHFR from yeast and animals irreversibly directs the methyl group of 5-methyl-THF to methylation of homocysteine (Roje et al., 2002a). Because this reaction has the potential to deplete the cytosolic 5,10-methylene-THF pool, the regulation of MTHFR is crucial for C1 metabolism. In yeast and animal cells, methyl-group biogenesis is regulated in vivo by a feedback-loop in which S-adenosylmethionine (AdoMet), a derivative of methionine that is used for methylation reactions, inhibits MTHFR (Roje et al., 2002a). Plant MTHFRs are cytosolic enzymes that differ from their yeast and mammalian counterparts because they are NADH-dependent, reversible and not regulated by AdoMet (Fig. 2; Roje et al., 1999). The reversibility of the reaction is sufficient to control C1-fluxes into methyl-group biogenesis and does not need a feedback inhibition by AdoMet.

5-formyl-THF is a ubiquitous member of biological folates but is the only derivative that does not serve as a C1-unit donor. It is considered that 5-formyl-THF is a potential regulator of C1 metabolism because it is a potent inhibitor of SHMT and several other folate-utilizing enzymes (Stover and Schirch, 1993). 5-formyl-THF is formed during the irreversible hydrolysis of 5,10-methenyl-THF catalysed by a side reaction of SHMT in the presence of glycine. 5-formyl-THF cycloligase (FCL, also referred to as 5,10-methenyl-THF synthetase) is the only enzyme that uses 5-formyl-THF by catalysing an ATP-dependent conversion to the metabolically active form 5,10-methenyl-THF (Stover and Schirch, 1993). FCL is a cytosolic enzyme in yeast and animals, whereas in plants, it is located in mitochondria (Fig. 2), a compartment where the 5-CHO derivatives represent up to 50–70% of the folate pool (Chan and Cossins, 2003; Orsomando et al., 2005; Roje et al., 2002b).

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Molecular Diagnostics for Coagulopathies

M.B. Smolkin , P.L. Perrotta , in Diagnostic Molecular Pathology, 2017

Methylenetetrahydrofolate Reductase Mutations

The conversion of 5,10-methylenetetrahydrofolate to folate, a cosubstrate for homocysteine remethylation to methionine, is catalyzed by the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR). Methionine is then converted to S-adenosylmethionine, which functions as an essential methyl donor. A thermolabile variant C665T (p.Ala222Val, more commonly referred to as C677T) and the A1286C (p.Glu429Ala) variant are two common polymorphic genetic variants that encode for forms of this enzyme with decreased enzymatic activity [17,18]. Approximately 25% of Hispanics and 10–15% of North American Caucasians are homozygous for the thermolabile variant [19]. C665T and C1286A are in linkage disequilibrium with each other. Therefore, a combination of both variants is usually seen only in individuals who are compound heterozygotes in the trans position. Combined homozygosity for one variant and heterozygosity for the other variant is not uncommon [20]. It was originally thought that reduced MTHFR activity led to hyperhomocysteinemia, which may lead to an increased risk for coronary heart disease, venous thromboembolism, and recurrent pregnancy loss [21–23]. A recent meta-analysis challenged the hypothesis that long-term moderately elevated homocysteine levels have any effect on cardiovascular disease [24]. As a result of these and other studies, the American College of Medical Genetics (ACMG) has issued a practice guideline that does not recommend MTHFR testing as part of the routine evaluation of patients with thrombophilia testing because of the lack of clinical utility [25].

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Epigenetics and migraine

S.H. Gan , M.M. Shaik , in Neuropsychiatric Disorders and Epigenetics, 2017

11.3 Homocysteine and Migraine

The MTHFR enzyme catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. The MTHFR C677T allele results in an amino acid change and a reduction in MTHFR activity leading to mild hyperhomocysteinemia [35]. Therefore, it is hypothesized that homocysteine-related endothelial dysfunction may be involved in the initiation and maintenance of migraine attacks. During a migraine attack, the concentration of oxygen present in the brain is reduced as a result of vasodilatation or a temporary thrombosis of cerebral blood vessels, primarily caused by the excitatory amino acid homocysteine [36]. Elevated levels of homocysteine in neurons can damage DNA, alter DNA repair functions, and/or disturb DNA methylation, all of which may lead to oxidative stress.

Folate plays an important role in the transfer of a one-carbon moiety and is an essential cofactor for the de novo biosynthesis of purines and thymidylate (Fig. 11.1) [37]. MTHFR, an intracellular coenzymatic form of folate, is pivotal for the conversion of deoxyuridylate to thymidylate and can be oxidized to 10-formyltetrahydrofolate for de novo purine synthesis [37]. Healthy subjects with the MTHFR 677TT genotype have been reported as having hypomethylated DNA when compared to subjects bearing the wild-type genotype, indicating an association between plasma homocysteine levels, folate levels and DNA methylation status [38]. However, subjects with the MTHFR 1298AC polymorphism displayed lower DNA methylation status when compared to subjects with the 677TT genotype [39]. The difference between these polymorphisms is significant with regard to the absence of the 677CT mutation when compared with the double wild-type genotype 677CC/1298AA [38,40].

Figure 11.1. Homocysteine Metabolism and Role of Methionine and Vitamins in DNA Methylation

CBS, Cystathionine beta synthase; DHFR, dihydrofolate reductase; dTMP, deoxy-thymidylate mono phosphate; dUMP, deoxy-uridine mono phosphate; MS, methionine synthase; MTHFR, methylenetetrahydrofolate reductase; SAM, S-adenosyl methionine; SAH, S-adenosyl-l-homocysteine; THF, tetrahydrofolate.

The 1298AA/677TT genotype exhibited decreased genomic DNA methylation in the presence of low plasma folate levels. The MTHFR 1298AC polymorphism does not impair enzyme function, and thus does not significantly affect the pathway of homocysteine remethylation or biological methylation functions, indicating that the 1298AC mutation has a minor effect on one-carbon metabolism resulting from reduced MTHFR enzyme function [41]. The 677CT polymorphism lies at the base of the binding site of flavin adenine dinucleotide, a MTHFR cofactor, and has been shown to affect MTHFR enzyme activity more significantly than the 1298AC variant [42,43]. Therefore, it appears that vitamin B12 plays an important role in MTHFR methylation [44].

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Antimetabolites

Carmen Avendaño , J. Carlos Menéndez , in Medicinal Chemistry of Anticancer Drugs, 2008

4.4.2 Enhancement of the inhibition of TS by 5-FU

The action of TS requires the presence of 5,10-methylene-THF, and for this reason the coadministration of precursors of this cofactor increases the cytotoxicity of 5-FU in many cancer cell lines. For instance, the combination of 5-FU or ftorafur with leucovorin (LV, 5-formyl-THF) gave superior response rates than the single agents, and particularly the use of leucovorin to modulate UFT leads to a three-component combination called orzel that has been proposed as first-line chemotherapy of colorectal cancer. 27 Leucovorin enters the cell via the reduced folate carrier (RFC) and is metabolized to 5,10-methylene-THF, without requiring the participation of DHFR, by cyclization to 5,10-methynyl-THF followed by NADP-mediated reduction of the iminium function (Fig. 2.24).

Figure 2.24. Biotransformation of leucovorin into 5,10-methylene-THF.

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Water-Soluble Vitamins and Nonnutrients

Martin Kohlmeier , in Nutrient Metabolism (Second Edition), 2015

Metabolism

Polyglutamyl side chains: At least five folate metabolites have direct functional importance, including THF, dihydrofolate, 5,10-methylene-THF 5-methyl-THF, 5-formyl-THF, 10-formyl-dihydrofolate, and 10-formyl-THF. Additional forms are crucial intermediates of folate metabolism. All of these vitamers require polyglutamyl side chains of specific length to be fully active. The removal and addition of glutamyl groups as described previously is an integral part of folate metabolism that controls both retention and function.

Folate activation: Dihydrofolate reductase (EC1.5.1.3) catalyzes the NADP-dependent reduction of folate to 7,8-dihydrofolate and then to 5,6,7,8-THF. This folate-activating enzyme is inhibited by the anticancer agent methotrexate (Figure 10.30).

Figure 10.30. Dihydrofolate reductase activates folate.

Folate reactivation: The reactions of folate metabolites are numerous and complex. Reactions that use one active form often generate another functionally important form. On the other hand, such reactions are essential to unload one-carbon groups and regenerate free folate for other reactions. The picture is further complicated by the fact that some of these activities are bundled into multifunctional proteins.

5,10-methylene-THF : The conversion of serine to glycine by glycine hydroxymethyltransferase (EC2.1.2.1) generates large quantities of 5,10-methylene-THF. Catabolism of glycine through the mitochondrial glycine cleavage system (aminomethyltransferase, EC2.1.2.10) also eliminates a carbon with 5,10-methylene-THF. NADPH-dependent reduction of 5,10-methenyl-THF by methylenetetrahydrofolate dehydrogenase (MTHFD1, EC1.5.1.5), an activity of the C1-THF synthase, also generates 5,10-methylene-THF. The trifunctional C1-THF synthase protein combines in humans the activities of MTHFD1, formate-THF ligase (EC6.3.4.3), and methenyl-THF cyclohydrolase (EC3.5.4.9). In addition, 5,10-methylene-THF can be generated from 10-formyl-THF by the methenyl-THF cyclohydrolase (EC3.5.4.9) activity of C1-THF synthase, and it is the cofactor for deoxythymidine monophosphate (dTMP) synthesis by thymidylate synthase (EC2.1.1.45). This reaction releases dihydrofolate, which can be reduced to THF again. Alternatively, both the NADPH-dependent methylenetetrahydrofolate reductase (EC1.5.1.20) and the FADH-dependent 5,10-methylenetetrahydrofolate reductase (EC1.7.99.5) can convert 5,10-methylene-THF into 5-methyl-THF, which then must be disposed of in turn. Both enzymes contain FAD as a prosthetic group ( Figure 10.31).

Figure 10.31. Folate interconversions.

5,10-methenyl-THF: The PLP-dependent glutamate formimidoyltransferase (EC2.1.2.5) is a key enzyme of histidine metabolism, which moves a formidoyl group to THF. The resulting 5-formimino-THF is converted to 5,10-methenyl-THF by formiminotetrahydrofolate cyclodeaminase (EC4.3.1.4), the second activity of the bifunctional protein formiminotransferase-cyclodeaminase.

5-methyl-THF: The methylcobalamin-containing 5-methyltetrahydrofolate-homocysteine S-meth-yltransferase (EC2.1.1.13) and betaine:homocysteine methyltransferase (EC2.1.1.5) are the only enzymes that utilize 5-methyl-THF in significant quantities. A reduction of their activities (particularly due to vitamin B12 deficiency) decreases the availability of THF for other reactions.

10-formyl-THF: Phosphoribosylglycinamide formyltransferase (EC2.1.2.2) and phosphoribosyl aminoimidazole carboxamide formyltransferase (AICAR transformylase, EC2.1.2.3) use 10-formyl-THF in purine synthesis. Both reactions release THF. Alternatively, formyltetrahydrofolate dehydrogenase (EC1.5.1.6) can regenerate THF from 10-formyl-THF by splitting off carbon dioxide in an NADPH-generating reaction.

5-formyl-THF: This is a minor folate metabolite, which may come from food or from the reaction of N-formyl-l-glutamate with THF, catalyzed by glutamate formimidoyltransferase (EC2.1.2.5, PLP). The ATP-driven enzyme 5-formyltetrahydrofolate cyclo-ligase (EC6.3.3.2, requires PLP) converts 5-formyl-THF to 5,10-methenyl-THF (Baggott et al., 2001).

10-formyl dihydrofolate: This metabolite arises from the reaction of formate with dihydrofolate, catalyzed by formate-dihydrofolate ligase (EC6.3.4.17) as detailed next. Here, 10-formyl dihydrofolate can serve as a cofactor for the penultimate step of inosine-5′-monophosphate (IMP; purine) synthesis catalyzed by phosphoribosylaminoimidazole carboxamide formyltransferase (AICAR transformylase, EC2.1.2.3). Spontaneous oxidation is also possible, which generates the metabolically inert metabolite 10-formyl folate (Baggott et al., 2001).

Folate catabolism: Dihydrofolate and 10-formyl-THF are particularly sensitive to oxidative degradation with the release of para-aminobenzoic acid (pABA). It has been proposed that ferritin specifically facilitates the oxidative cleavage of 10-formyl-THF and that the degradation of this metabolite is an important modulator of intracellular folate concentration (Suh et al., 2001). Acetylation of pAPG by arylamine N-acetyltransferases (EC2.3.1.5) facilitates the removal of inactive folate catabolites from cells.

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Ovarian Cycle

Stefania Ferrari , ... Maria Paola Costi , in Vitamins and Hormones, 2018

2.1 TS Catalytic Function

The catalytic activity is performed by TS in its homodimeric active state, through the catalytic Cys195 residue and assisted by the cofactor 5,10-methylene-tetrahydrofolate (mTHF) (Carreras & Santi, 1995). The active-site cysteine residue gives Michael addition to the 6-position of dUMP to give an enolate, which attacks mTHF, thus forming a ternary complex (Fig. 4). The enzyme-catalyzed removal of the C5 proton leads to the beta-elimination of THF. Oxidation of the latter gives dihydrofolate (DHF) and the enzyme-bound thymidylate enolate. Finally, the reverse of the first step releases the active-site cysteine residue and produces dTMP (Carreras & Santi, 1995). A great amount of mutagenesis, enzymatic kinetic, and crystallographic studies have been addressed to clarify the TS catalytic mechanism. Finer-Moore, Santi, and Stroud (2003) reviewed all these studies and proposed that, in addition to Cys195, other few conserved residues were essential in the catalysis. Arg215, adjacent to the active-site cysteine, was postulated to activate the cysteine through electrostatic interactions. Although its role has not been proven, the variant Arg215Lys, among all the tested ones, is the only one with a value of k cat close to that of the wild-type enzyme. This is likely due to the fact that lysine has electrostatic properties similar to those of arginine. His196 and Asn226 are proposed to modulate the orientation and pK a of ordered water molecules acting as a general acid during nucleophilic attack of the catalytic cysteine at the C6 atom of dUMP. Asp218 has been proposed to be the acid that catalyzes protonation of N5 of the cofactor, while Tyr135 favors removal of a proton from the C5 atom of dUMP thus catalyzing the breakdown of the covalent ternary complex. Glu87 catalyzes hydrogen transfers to and from the nucleotide pyrimidine ring during different chemical steps. Asn226 has also a critical role in substrate selectivity. Most of the other highly conserved residues in the enzyme, Arg50, Trp109, Arg175, Gln214, Ser216, His256, Tyr258, contribute to catalysis mainly driving conformational changes in the enzyme and helping the different actors of the reactions to assume the optimal orientations to react (Ferrari et al., 2008; Finer-Moore et al., 2003). Inhibitors able to interact with them or to affect their contribution to the reaction, e.g., by binding in an allosteric site, may force and stabilize the enzyme in a conformational state, such as the inactive one, that cannot afford catalysis. TS is describe as a half-of-the-sites activity enzyme under physiological conditions, i.e., the two active sites of a protein dimer can work for a catalytic event one at a time (Anderson, O'Neil, DeLano, & Stroud, 1999; Weichsel, Montfort, Cieśla, & Maley, 1995). Some residues are believed to be involved in monomer–monomer communications responsible for a negative cooperativity between the substrate bindings at the two active pockets in a dimer. These are Gnl214, Arg215, and Ser216 that interact with dUMP and influence Tyr213 (Fig. 2). The latter residue interacts with its counterpart in the opposite monomer. However, crystallographic studies can rarely reproduce such structural details because of the experimental conditions required to obtain the crystallographic structures.

Fig. 4

Fig. 4. Thymidylate synthase catalysis. The –SH group from Cys195 in human thymidylate synthase reacts with 2′-deoxyuridine-5′-monophosphate (dUMP) and 5,10-methylentetrahydrofolate (CH2-H4FOLATE) to produce 2′-deoxythymidine-5′-monophosphate (dTMP) and dihydrofolate (H2FOLATE). PABA-GLU state for para-aminobenzoic acid and glutamic acid moieties of the folate cofactor.

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Wilson Disease

Valentina Medici , Karl-Heinz Weiss , in Handbook of Clinical Neurology, 2017

MTHFR gene

A key enzyme in folate and methionine metabolism is 5,10-methylenetetrahydrofolate reductase (MTHFR), which catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Mutations of MTHFR are associated with increased homocysteine levels, which may contribute to greater severity of WD or to its phenotypic variability. Two-hundred and forty-five patients with WD were genotyped for the two MTHFR polymorphisms, C677T and A1298C, and genotype–phenotype correlations were studied. The C667T genotype was more frequent than expected according to Hardy–Weinberg equilibrium. The C677T allele was associated more frequently with hepatic onset. The A1298C allele was associated with younger age at presentation. MTHFR polymorphisms were not associated with any difference in copper metabolism (Gromadzka et al., 2011). Even though these initial observations were not explored in other populations and hyperhomocysteinemia has not been described in WD, the possibility that homocysteine or aberrant methionine metabolism can affect the phenotype is interesting, as homocysteine can pass the blood–brain barrier and can also have neurotoxic effects by interacting with copper (White et al., 2001; Linnebank et al., 2006). In addition, methionine metabolism is closely related to mechanisms of DNA and histone methylation with potential consequences for gene expression regulation.

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Amino Acid Metabolism

Raymond Y. Wang , ... Stephen D. Cederbaum , in Emery and Rimoin's Principles and Practice of Medical Genetics (Sixth Edition), 2013

92.4.2 N 5,10-methylenetetrahydrofolate Reductase Deficiency

The active cofactor necessary for the conversion of homocysteine to l-methionine is N 5-methyltetrahydrofolate. This cofactor is resynthesized from N 5,10-methylenetetrahydrofolate by the enzyme N 5,10-methylenetetrahydrofolate reductase (MTHFR). A small number of children have been reported with a deficiency of this enzyme (OMIM 236250). Patients deficient in the synthesis of N 5,10-methylenetetrahydrofolate accumulate homocysteine and have low or low-normal plasma methionine levels (135).

Affected patients show a spectrum of clinical symptoms. Young infants have been identified with severe neurological symptoms of hypotonia, poor feeding, failure to thrive, seizures, lack of neurocognitive development, and severe apnea. Most have died at younger than 1   year of age due to central respiratory failure. Several infants have responded well to high-protein intake, with or without supplementation with methyl-donor medications such as folinic acid and betaine. Older children have been identified with MTHFR deficiency after presenting to medical attention for mental retardation, acute psychosis, muscle weakness, ataxia, marfanoid habitus, spastic paraparesis, or thromboembolic events (136). Adults have presented with gait disturbance. Some have shown improvement in symptoms when supplemented with pharmacologic doses of folate.

The disorder is inherited as an autosomal recessive condition. There is evidence that obligate heterozygotes can be distinguished by measurement of the enzymatic activity. Prenatal diagnosis has been accomplished. A number of mutations have been identified in these cases, and there is reasonable correlation between residual enzyme activity and clinical severity (135). However, there can be substantial variability within families, with one asymptomatic adult sibling of an affected patient having been reported (137).

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Amino Acids and Nitrogen Compounds

Martin Kohlmeier , in Nutrient Metabolism (Second Edition), 2015

Metabolism

Conversion to serine : The glycine-cleavage system (glycine hydroxymethyltransferase, EC2.1.2.1) converts Gly into serine by one-carbon transfer from 5,10-methylenetetrahydrofolate ( Figure 8.18). Under some circumstances, this reaction runs in the reverse direction.

Figure 8.18. Glycine metabolism.

The glycine cleavage system: Glycine is decarboxylated in mitochondria by a large PHP-dependent glycine dehydrogenase (EC1.4.4.2) complex composed of multiple subunits (namely, P, T, L, and H); the H subunit contains lipoamide. In a fashion similar to the three lipoate-dependent alpha-keto acid dehydrogenases, the lipoamide arm acts as an acceptor for a methylene group from glycine, transfers it to folate, and the group is reduced in the process. The T subunit then transfers the hydrogen via FAD to NAD.

Minor pathways: Alanine-glyoxylate aminotransferase (EC2.6.1.44) in liver peroxisomes normally generates Gly by transferring the amino group from alanine to glyoxylate. Since this reaction is reversible, a small percentage (0.1%) of Gly is converted to glyoxylate and then to oxalate. Glyoxylate is also the product of the reaction of oxidative Gly deamination by the FAD-containing d-amino acid oxidase (EC1.4.3.3) in peroxisomes, and of several PLP-dependent transamination reactions (glycine aminotransferase, EC2.6.1.4; alanine-glyoxylate aminotransferase, EC2.6.1.44; aromatic amino acid-glyoxylate aminotransferase, EC2.6.1.60; and kynurenine-glyoxylate aminotransferase, EC2.6.1.63).

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