The Implication of a Polymorphism in the Methylenetetrahydrofolate Reductase Gene in Homocysteine Metabolism and Related Civilisation Diseases

Abstract

Methylenetetrahydrofolate reductase (MTHFR) is a key regulatory enzyme in the one-carbon cycle. This enzyme is essential for the metabolism of methionine, folate, and RNA, as well as for the production of proteins, DNA, and RNA. MTHFR catalyses the irreversible conversion of 5,10-methylenetetrahydrofolate to its active form, 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Numerous variants of the MTHFR gene have been recognised, among which the C677T variant is the most extensively studied. The C677T polymorphism, which results in the conversion of valine to alanine at codon 222, is associated with reduced activity and an increased thermolability of the enzyme. Impaired MTHFR efficiency is associated with increased levels of homocysteine, which can contribute to increased production of reactive oxygen species and the development of oxidative stress. Homocysteine is acknowledged as an independent risk factor for cardiovascular disease, while chronic inflammation serves as the common underlying factor among these issues. Many studies have been conducted to determine whether there is an association between the C677T polymorphism and an increased risk of cardiovascular disease, hypertension, diabetes, and overweight/obesity. There is substantial evidence supporting this association, although several studies have concluded that the polymorphism cannot be reliably used for prediction. This review examines the latest research on MTHFR polymorphisms and their correlation with cardiovascular disease, obesity, and epigenetic regulation.

Keywords: MTHFR; folate; gene variants.

Figure 1

The balance between the folate cycle and the methionine cycle is affected by vitamin B₁₂. FPG, Folate polyglutamates; FMG, Folate monoglutamates; GCPII, glutamate carboxypeptidase II; PCFT1, proton-coupled folate transporter; DHF, dihydrofolate; DHRF, dihydrofolate reductase; THF, tetrahydrofolate; MTHFD, methylenetetrahydrofolate dehydrogenase; SHMT, serinehydroxymethyl transferase; Ser, Serine; Gly, Glycine; MTHFR, methylenetetrahydrofolate reductase; NADPH, nicotinamide adenine dinucleotide phosphate; FADH₂, dihydroflavine-adeninedinucleotide; MS, methionine synthase; Met, Methionine; MAT, methionine adenosyltransferase; SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine; SAHH, S-adenosylhomocysteine hydrolase; BHMT, Betaine-homocysteine methyltransferase; CBS, Cystathionine-β-synthase; CTH, Cystathionine gamma lyase; GCL, glutamate cysteine ligase; GSS, Glutathione synthetase; Glu, Glutamic acid; B₂, vitamin B₂ (riboflavin); B₆, vitamin B₆ (pyridoxine); B₁₂, vitamin B₁₂ (cobalamin).

Figure 2

Schematic representation of MTHFR protein. The numbers given represent amino acids in human MTHFR.

Figure 3

Forms of homocysteine (Hcy) with a special focus on blood oxidation. PROT-SH, Plasma protein containing thiol, mainly albumin; R-SH, Hcy, Cys, glutathione, glutamylcysteine, cysteinylglycine; PROT-SS-Hcy, Protein-bound Hcy; R, thiol or disulphide group, R-SS-Hcy, free, oxidised Hcy; HS-Hcy, free, reduced Hcy.

Figure 4

Formation of homocysteine (Hcy) and albumin-bound Hcy in circulation. 1—Transport of free reduced homocysteine (Hcy-SH) from cells to the circulation. 2—Hepatic secretion of albumin thiolate anion (Alb-Cys34-S⁻) into the circulation. 3—Auto-oxidation of free reduced cysteine (Cys-SH) to cystine (Cys-S-S-Cys) by ceruloplasmin. 4—Reaction of the albumin thiolate anion (Alb-Cys34-S⁻) with cystine (Cys-S-S-Cys) to form the Alb-Cys34-S-S-Cys and cysteine thiolate anion. 5—Reaction of free reduced homocysteine (Hcy-SH) with cysteine-bound albumin (Alb-Cys34-S-S-Cys) to form mixed homocysteine–cysteine disulphide (Hcy-S-S-Cys) and albumin thiolate anion (Alb-Cys34-S⁻) 6—Reaction of albumin thiolate anion with Hcy-S-S-Cys and with homocystine (Hcy-S-S-Hcy). 7—Auto-oxidation of Hcy to homocystine (Hcy-S-S-Hcy) through reaction with copper-His3 of albumin; O₂*⁻, superoxide anion; *, free radicals form.

Figure 5

Processes leading to endothelial dysfunction induced by homocysteine and asymmetric dimethylarginine (ADMA). O₂*⁻, superoxide anion; OONO⁻, peroxynitrite anion.