In this blog, we will elaborate on the significance of the Folate cycle, Methionine cycle, and Transsulfuration Pathway, exploring their roles in detail and introducing the key genes that govern them.
Author: Lynn Nader
- To broaden the understanding on multiple gene interactions in the Methylation metabolism
- To provide a deeper insight into the different cycles
- To establish an overview of the interconnectivity between each cycle.
Methylation is a biochemical process that involves the addition of a methyl group (CH3) to various molecules within cells in the human body (Moore et al., 2013). These methyl groups play a role in gene regulation and metabolic processes, acting as crucial molecular switches that can turn genes on or off and govern metabolic pathways (Barchi & Strain, 2023; He et al., 2017). When methylation occurs at optimal levels, it has a positive effect on many reactions in the body that are involved in cardiovascular, neurological, reproductive, and detoxification systems, including those relating to DNA production, neurotransmitter production, liver health, histamine metabolism and other (Z. Jin & Liu, 2018; Kandi & Vadakedath, 2015; Moore et al., 2013).
Interestingly, methylation is not a static process, but a dynamic and ongoing cascade of reactions (Bannister et al., 2002), comprising several interconnected pathways (Menezo et al., 2020), namely: (1) the folate cycle, essential for DNA maintenance; (2) the methionine cycle, necessary for the production of methyl donors like S-Adenosyl Methionine (SAMe); and (3) the transsulfuration pathway, crucial for metabolising homocysteine (Clare et al., 2019). Each of these pathways brings its own unique components to play, orchestrating the flow of methylation, and thus, contributing to overall well-being. Understanding these processes is pivotal as it unveils how genetic variations can impact methylation and, in turn, influence our overall health and well-being.
The Folate Cycle
The folate cycle is a series of enzymatic reactions that interconvert different forms of folate, with the primary goal of generating methyl groups for various cellular reactions such as DNA synthesis and repair, methylation reactions, homocysteine metabolism and other (Zheng & Cantley, 2019). This cycle includes a variety of genes requiring various key nutrients for optimal function (Coppedè et al., 2019; Ducker & Rabinowitz, 2017; Hiraoka & Kagawa, 2017; Lee et al., 2009; Salbaum & Kappen, 2012):
- SHMT (Serine Hydroxymethyltransferase) is an enzyme that catalyses the conversion of serine to glycine while transferring a one-carbon unit to tetrahydrofolate (THF), generating 5,10-methylene-THF (Ducker & Rabinowitz, 2017). This intermediate is essential for the synthesis of thymidine, a component of DNA (Bury-Moné, 2014; Tjong et al., 2023). SHMT’s activity connects the serine-glycine pathway to the folate cycle, ensuring the availability of one-carbon units necessary for nucleotide biosynthesis and overall cellular function (Ducker et al., 2016; Ducker & Rabinowitz, 2017; Herbig et al., 2002). Additionally, SHMT uses vitamin B6 as a cofactor (Perry et al., 2007; Pilesi et al., 2023) and is involved in homocysteine metabolism (Cuskelly et al., 2001; Heil et al., 2001). Variations in this gene can reduce the availability of substrate needed for the next step of the cycle (Herbig et al., 2002), potentially leading to mood disorders (Hashimoto et al., 2016; Reynolds et al., 1984) and the accumulation of homocysteine (Cuskelly et al., 2001; MacFarlane et al., 2006; Martinez et al., 2000; Wernimont et al., 2012), which could result in an increased cardiovascular risk (Ganguly & Alam, 2015; Peng et al., 2015), as well as neurodevelopmental conditions (Heil et al., 2001).
- MTHFD1 (Methylenetetrahydrofolate Dehydrogenase 1) is a key enzyme in the folate cycle and has three functions: (1) the ATP-dependent conversion of formate and THF to 10-formyl-THF (synthase); (2) the interconversion of 10-formyl-THF and 5,10-methenyl-THF (cyclohydrolase); and (3) the NADP-dependent reduction of 5,10-methenyl-THF to 5,10-methylene-THF (dehydrogenase) (Burda et al., 2015; Fox & Stover, 2008; Hum et al., 1988; National Library of Medicine, 2023b). This process provides one carbon units for purine nucleotide synthesis, essential for DNA and RNA production (Field et al., 2016), thus supporting fundamental processes in cell growth and maintenance. Rather than alter one of MTHFD1’s three enzyme activities, variations in this gene are thought to lead to reduced enzyme stability, meaning it is degraded more rapidly (Christensen et al., 2009). As a result, a diet lacking in folate combined with a variation in this gene is associated with developmental defects (Carroll et al., 2009; J. Jiang et al., 2014).
- MTHFR (Methylenetetrahydrofolate Reductase) is a crucial enzyme in the folate cycle that converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate (5-MTHF) (Coppedè et al., 2019), the active form of folate used in methylation reactions (Carboni, 2022). Variations in the MTHFR gene can lead to the production of a heat-sensitive MTHFR (Leclerc et al., 2013; Raghubeer & Matsha, 2021) that binds less strongly with its cofactor (vitamin B2) (Hustad et al., 2013), thus showing a reduced activity and function (Raghubeer & Matsha, 2021). This reduced activity can lead to elevated homocysteine levels, which are associated with an increased risk of cardiovascular disease (Dean, 2012; Den Heijer et al., 2005; Holmes et al., 2011; H. Jin et al., 2018; Kelly et al., 2002; Khandanpour et al., 2009; Leclerc et al., 2013; Mehlig et al., 2013; Wald et al., 2002), neural tube defects in infants (Leclerc et al., 2013; Soleimani-Jadidi et al., 2022; Tsang et al., 2015; van der Put et al., 1995; X. W. Wang et al., 2012; Yan et al., 2012) and other health issues.
The Methionine Cycle
The methionine cycle is closely interconnected with the folate cycle and primarily focuses on the recycling of methionine and the production of SAMe (Klein Geltink & Pearce, 2019). SAMe serves as the primary methyl donor in a multitude of cellular methylation reactions, including DNA, RNA, protein and lipid methylation (Klein Geltink & Pearce, 2019; Neidhart, 2016; Parkhitko et al., 2019; Shaw, 2019). The methionine cycle also plays a role in regulating homocysteine levels by converting it back to methionine (Antonio et al., 1997). This cycle includes a variety of genes requiring various key nutrients for optimal function (Parkhitko et al., 2019):
- PEMT (Phosphatidylethanolamine N-methyltransferase) is an enzyme that plays a critical role in the synthesis of phosphatidylcholine (PC) (National Library of Medicine, 2023c), a component of cell membranes that surrounds cells and plays a role in shutting fats out of cells in the liver to be trafficked around the body or excreted (J. Li et al., 2023; Song et al., 2005). PEMT transfers three methyl groups from SAMe to phosphatidylethanolamine, converting it to PC (Obeid, 2013). This reaction consumes SAMe and contributes to lipid metabolism (J. Li et al., 2023; Obeid, 2013). As part of its activity, PEMT also produces homocysteine (J. Li et al., 2023). Variations in PEMT can reduce its activity which could lead to a deficiency in the production of PC and SAMe consumption (Ivanov et al., 2009). This altered activity may have implications for cell membrane composition (i.e. potential accumulation of fat within liver cells) and methylation reactions (Buchman et al., 1995; da Costa et al., 2014; Song et al., 2005).
- BHMT (Betaine-Homocysteine Methyltransferase) is an enzyme that catalyses the remethylation of homocysteine to methionine using betaine as a methyl donor (Feng et al., 2011). It provides an alternative route for homocysteine metabolism and methionine production (Barra et al., 2006), particularly when variants in other genes involved are present (i.e. MTHFR, MTR/MTRR). Betaine, which is required for BHMT function (Ou et al., 2007), can be derived from dietary sources, such as choline (Zeisel et al., 2003). Variations in the BHMT can affect the efficiency of homocysteine remethylation and methionine production, thus potentially leading to increased homocysteine levels in the blood and lower methionine levels (Clifford et al., 2012; D. Li et al., 2019; F. Li et al., 2008).
- MTR (Methionine Synthase or MS) is an essential enzyme that converts homocysteine to methionine by utilising 5-MTHF as a donor for a methyl group (Froese et al., 2019; Suh et al., 2016). The methyl group is transferred to vitamin B12, which then gives it to homocysteine, forming methionine (Allen, 2012). As 5-MTHF loses its methyl group, THF is formed which re-enters the folate cycle (Colman & Herbert, 1980). Variations in the MTR gene may reduce or increase its activity, depending on which variant is carried. A reduction in the enzyme’s activity can lead to elevated homocysteine levels and may be associated with cardiovascular (Chen et al., 2001; O’Leary et al., 2005) and neurological disorders (Bhatia & Singh, 2015). Whereas an enhancement in its activity may increase levels of DNA methylation (Weiner et al., 2014), which is not always favourable (Ehrlich, 2019) despite being a process fundamental to life (B. Jin et al., 2011).
- MTRR (5-Methyltetrahydrofolate-Homocysteine Methyltransferase Reductase or Methionine Synthase Reductase) is another enzyme in the methionine cycle with the primary function to support and maintain the activity of MTR (Yadav et al., 2021). MS relies on vitamin B12 as a crucial cofactor (Brody, 1999). However, over time, this vitamin B12 can become inactive (Leal et al., 2004). MTRR plays a key role in disassociating MS from the inactive vitamin B12, making way for a functional vitamin B12 molecule to bind (Olteanu et al., 2002). This process ensures the ongoing production of methionine. Variations in MTRR have been shown to interact less strongly with MS, resulting in a reduction in its activity and eventually a buildup of homocysteine (García-Minguillán et al., 2014; Gaughan et al., 2001) which is strongly associated with cardiovascular (Chrysant & Chrysant, 2018; Ganguly & Alam, 2015) and neurological outcomes (Jamerson et al., 2013; Y. Wang et al., 2015).
- Other Genetic Variations: Genes within the folate cycle can exert an influence on the function of interconnected cycles, such as the methionine cycle. Therefore, genetic variations in the folate cycle-related genes possess the capacity to impact methionine metabolism. For example, reduced MTHFR activity can lead to elevated homocysteine levels, affecting methionine recycling.
While the MTR and MTRR genes are primarily associated with the methionine cycle, they are functionally interconnected with the folate cycle to ensure the proper synthesis of methionine and regulation of homocysteine levels in the body (Brody, 1999; Yadav et al., 2021).
The Transsulfuration Pathway
The transsulfuration pathway is a critical biochemical pathway closely interlinked with the methionine cycle (Parkhitko et al., 2019; Sbodio et al., 2019). It converts homocysteine, a potentially toxic amino acid, into cysteine (Sbodio et al., 2019), a key amino acid necessary for the synthesis of proteins, glutathione, and other essential molecules (Clemente Plaza et al., 2018). Additionally, this pathway generates alpha-ketobutyrate (Lesner et al., 2020) and ultimately taurine and sulphate (Stipanuk & Ueki, 2011). The cycle includes a variety of genes requiring various key nutrients for optimal function (Berry et al., 2020; Sbodio et al., 2019):
- CBS (Cystathionine Beta-Synthase) is an enzyme that irreversibly converts homocysteine to cystathionine, the first step of the transsulfuration pathway (National Library of Medicine, 2023a). It requires two cofactors to function: vitamin B6 and heme (Dimster-Denk et al., 2013). There are about 200 known variations of the CBS gene (Samarasinghe et al., 2022; The Human Gene Mutation Database, 2022), some of which increase (Aras et al., 2000) or decrease its activity (Lievers et al., 2003; López-Quesada et al., 2003). This has been associated with higher levels of ammonia (Stipanuk & Ueki, 2011), or higher levels of homocysteine respectively (Kluijtmans et al., 1996; Majtan et al., 2023; Sacharow et al., 1993).
- CTH (Cystathionine Gamma-Lyase or Cystathionase) is an enzyme involved in the second step of the transsulfuration pathway, which converts cystathionine into cysteine (Boukaba et al., 2016; Sbodio et al., 2019). It also requires vitamin B6 as a cofactor to function (Ishii et al., 2010). While there are several variants of interest, there is a limited number of studies highlighting that they are associated with higher homocysteine levels (Y. Li et al., 2008). However, no clear cause nor mechanism were provided, although a reduced activity seems to be the most probable cause.
- SUOX (Sulfite Oxidase) is an enzyme responsible for the conversion of sulphite to sulphate (Du et al., 2021) which is essential for various biological processes, including the synthesis of sulphur-containing molecules (Dawson, 2013; Király et al., 2012; Kopriva & Rennenberg, 2004; Leustek, 2002). It utilises molybdenum as a cofactor in order to function (Oliphant et al., 2022). A limited number of studies has been conducted on SUOX variants involving its mechanism, but it is believed that they can result in sulfite oxidase deficiency, leading to the accumulation of sulphite in the body (Du et al., 2021). Coupled with a diet lacking in its cofactor, it may cause neurological symptoms, developmental delays, and other health issues (National Library of Medicine, 2023d).
Pathway interactions and shared components
The folate cycle, methionine cycle, and transsulfuration pathway are interconnected metabolic pathways in the body that share certain intermediates and interact in several ways. Here's how these pathways overlap:
- Homocysteine as a Common Intermediate:
Homocysteine is a central molecule that links these three pathways.
The folate cycle provides the necessary methyl groups to convert homocysteine into methionine. It is also produced in the methionine cycle as an intermediate during the conversion of methionine to SAM. Homocysteine is also a precursor for cysteine, which is synthesised in the transsulfuration pathway.
- Folate Cycle and Methionine Cycle Interaction:
- Folate, in the form of tetrahydrofolate (THF), is involved in the methionine cycle as it donates methyl groups (from 5-MTHF) to facilitate the conversion of homocysteine to methionine.
- Methionine, in turn, serves as a precursor for SAM, a critical methyl donor in various cellular methylation reactions, including DNA methylation and neurotransmitter synthesis.
- Folate Cycle and Transsulfuration Pathway Interaction:
- Folate indirectly affects the transsulfuration pathway by influencing homocysteine levels. Variations in some genes coupled with environmental factors can lead to the accumulation of homocysteine, which will then be directed towards the transsulfuration pathway.
- In the transsulfuration pathway, homocysteine is converted to cysteine, which is important for synthesising proteins, glutathione, and other sulphur-containing molecules.
- Methionine Cycle and Transsulfuration Pathway Interaction:
- The methionine cycle and transsulfuration pathway intersect at the level of homocysteine. Depending on the metabolic needs of the body, homocysteine can be directed either towards the remethylation pathway, within the methionine cycle or the transsulfuration pathway.
- Remethylation of homocysteine within the methionine cycle regenerates methionine, which is critical for protein synthesis and SAM production.
- In the transsulfuration pathway, homocysteine is irreversibly converted to cysteine, which is important for synthesising proteins, glutathione, and other sulphur-containing molecules.
Over And Under Methylation
Proper methylation is essential for a wide range of physiological functions. However, both undermethylation and overmethylation can have clinical implications.
It's important to note that individual responses to methylation status can vary widely, and the clinical implications may differ from person to person as methylation status is influenced by genetic factors, diet, lifestyle, and environmental factors. Therefore, it is essential to approach methylation-related issues with comprehensive evaluations in order to provide lifestyle modifications and/or nutritional supplements.
Importance of testing
In the context of the folate cycle, methionine cycle, and transsulfuration pathway, a wellness DNA test can identify single nucleotide polymorphisms (SNPs) or genetic variations that may impact key genes within these pathways (P. Y. Kwok, 2001; P.-Y. Kwok & Chen, 2003; Shastry, 2009). Understanding these genetic variations allows individuals and healthcare providers to gain insights into potential susceptibilities or needs related to methylation.
While wellness genetic testing provides valuable information, it's important to emphasise that having a specific genetic variation doesn't necessarily equate to a predetermined health outcome (S. Jiang et al., 2023). Genetic variations often interact with lifestyle factors, diet and environmental influences, making the picture complex (Q. Jin & Shi, 2019; Picardi et al., 2020). This is where counselling and support come into play. Experts in the field can interpret test results and provide guidance on how genetic variations might impact an individual’s health, as well as help make informed decisions about lifestyle changes, preventive measures or therapeutic interventions.
In summary, methylation represents a dynamic cascade of reactions, forming a network of interconnected pathways. The folate cycle supplies methyl groups that are vital for DNA synthesis, methylation reactions, and homocysteine regulation, with genes like SHMT, MTHFD1 and MTHFR influencing its function. Similarly, the methionine cycle is essential for SAMe production, a key methyl donor, and homocysteine regulation with genes like MTR/MTRR, PEMT and BHMT contributing to its dynamics. The transsulfuration pathway, involving genes such as CBS, CTH, and SUOX, converts homocysteine to cysteine and other sulphur-containing compounds. These pathways, interconnected through homocysteine production/utilisation, methyl group transfer, and amino acid metabolism, are pivotal for various cellular processes. Variations in genes involved may cause disturbances that can impact DNA synthesis, detoxification, and other outcomes affecting overall health; this underlines the significance of testing coupled with tailored nutritional and metabolic support when addressing genetic variations within these pathways.
Contrary to the persisting knowledge that often focuses solely on the MTHFR gene when it comes to methylation, it is essential to recognise that there are more factors at play (genes and environment), all of which play a crucial role in methylation and should be taken into consideration.
Allen, L. H. (2012). Vitamin B-121. Advances in Nutrition, 3(1), 54–55. https://doi.org/10.3945/an.111.001370
Antonio, C. M., Nunes, M. C., Refsum, H., & Abraham, A. K. (1997). A novel pathway for the conversion of homocysteine to methionine in eukaryotes. Biochemical Journal, 328(Pt 1), 165–170.
Aras, O., Hanson, N. Q., Yang, F., & Tsai, M. Y. (2000). Influence of 699C-->T and 1080C-->T polymorphisms of the cystathionine beta-synthase gene on plasma homocysteine levels. Clinical Genetics, 58(6), 455–459. https://doi.org/10.1034/j.1399-0004.2000.580605.x
Bannister, A. J., Schneider, R., & Kouzarides, T. (2002). Histone Methylation: Dynamic or Static? Cell, 109(7), 801–806. https://doi.org/10.1016/S0092-8674(02)00798-5
Barchi, J. J., & Strain, C. N. (2023). The effect of a methyl group on structure and function: Serine vs. threonine glycosylation and phosphorylation. Frontiers in Molecular Biosciences, 10. https://www.frontiersin.org/articles/10.3389/fmolb.2023.1117850
Barra, L., Fontenelle, C., Ermel, G., Trautwetter, A., Walker, G. C., & Blanco, C. (2006). Interrelations between Glycine Betaine Catabolism and Methionine Biosynthesis in Sinorhizobium meliloti Strain 102F34. Journal of Bacteriology, 188(20), 7195–7204. https://doi.org/10.1128/JB.00208-06
Berry, T., Abohamza, E., & Moustafa, A. A. (2020). Treatment-resistant schizophrenia: Focus on the transsulfuration pathway. Reviews in the Neurosciences, 31(2), 219–232. https://doi.org/10.1515/revneuro-2019-0057
Bhatia, P., & Singh, N. (2015). Homocysteine excess: Delineating the possible mechanism of neurotoxicity and depression. Fundamental & Clinical Pharmacology, 29(6), 522–528. https://doi.org/10.1111/fcp.12145
Boukaba, A., Sanchis-Gomar, F., & García-Giménez, J. L. (2016). Chapter 3 - Epigenetic Mechanisms as Key Regulators in Disease: Clinical Implications. In J. L. García-Giménez (Ed.), Epigenetic Biomarkers and Diagnostics (pp. 37–66). Academic Press. https://doi.org/10.1016/B978-0-12-801899-6.00003-6
Brody, T. (1999). 9—VITAMINS. In T. Brody (Ed.), Nutritional Biochemistry (Second Edition) (pp. 491–692). Academic Press. https://doi.org/10.1016/B978-012134836-6/50012-3
Buchman, A. L., Dubin, M. D., Moukarzel, A. A., Jenden, D. J., Roch, M., Rice, K. M., Gornbein, J., & Ament, M. E. (1995). Choline deficiency: A cause of hepatic steatosis during parenteral nutrition that can be reversed with intravenous choline supplementation. Hepatology (Baltimore, Md.), 22(5), 1399–1403.
Burda, P., Kuster, A., Hjalmarson, O., Suormala, T., Bürer, C., Lutz, S., Roussey, G., Christa, L., Asin-Cayuela, J., Kollberg, G., Andersson, B. A., Watkins, D., Rosenblatt, D. S., Fowler, B., Holme, E., Froese, D. S., & Baumgartner, M. R. (2015). Characterization and review of MTHFD1 deficiency: Four new patients, cellular delineation and response to folic and folinic acid treatment. Journal of Inherited Metabolic Disease, 38(5), 863–872. https://doi.org/10.1007/s10545-015-9810-3
Bury-Moné, S. (2014). Antibacterial Therapeutic Agents: Antibiotics and Bacteriophages. In Reference Module in Biomedical Sciences. Elsevier. https://doi.org/10.1016/B978-0-12-801238-3.00244-0
Carboni, L. (2022). Active Folate Versus Folic Acid: The Role of 5-MTHF (Methylfolate) in Human Health. Integrative Medicine: A Clinician’s Journal, 21(3), 36–41.
Carroll, N., Pangilinan, F., Molloy, A. M., Troendle, J., Mills, J. L., Kirke, P. N., Brody, L. C., Scott, J. M., & Parle-McDermott, A. (2009). Analysis of the MTHFD1 promoter and risk of neural tube defects. Human Genetics, 125(3), 247–256. https://doi.org/10.1007/s00439-008-0616-3
Chen, J., Stampfer, M. J., Ma, J., Selhub, J., Malinow, M. R., Hennekens, C. H., & Hunter, D. J. (2001). Influence of a methionine synthase (D919G) polymorphism on plasma homocysteine and folate levels and relation to risk of myocardial infarction. Atherosclerosis, 154(3), 667–672. https://doi.org/10.1016/s0021-9150(00)00469-x
Christensen, K. E., Rohlicek, C. V., Andelfinger, G. U., Michaud, J., Bigras, J.-L., Richter, A., Mackenzie, R. E., & Rozen, R. (2009). The MTHFD1 p.Arg653Gln variant alters enzyme function and increases risk for congenital heart defects. Human Mutation, 30(2), 212–220. https://doi.org/10.1002/humu.20830
Chrysant, S. G., & Chrysant, G. S. (2018). The current status of homocysteine as a risk factor for cardiovascular disease: A mini review. Expert Review of Cardiovascular Therapy, 16(8), 559–565. https://doi.org/10.1080/14779072.2018.1497974
Clare, C. E., Brassington, A. H., Kwong, W. Y., & Sinclair, K. D. (2019). One-Carbon Metabolism: Linking Nutritional Biochemistry to Epigenetic Programming of Long-Term Development. Annual Review of Animal Biosciences, 7, 263–287. https://doi.org/10.1146/annurev-animal-020518-115206
Clemente Plaza, N., Reig García-Galbis, M., & Martínez-Espinosa, R. M. (2018). Effects of the Usage of l-Cysteine (l-Cys) on Human Health. Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry, 23(3), 575. https://doi.org/10.3390/molecules23030575
Clifford, A. J., Chen, K., McWade, L., Rincon, G., Kim, S.-H., Holstege, D. M., Owens, J. E., Liu, B., Müller, H.-G., Medrano, J. F., Fadel, J. G., Moshfegh, A. J., Baer, D. J., & Novotny, J. A. (2012). Gender and Single Nucleotide Polymorphisms in MTHFR, BHMT, SPTLC1, CRBP2, CETP, and SCARB1 Are Significant Predictors of Plasma Homocysteine Normalized by RBC Folate in Healthy Adults123. The Journal of Nutrition, 142(9), 1764–1771. https://doi.org/10.3945/jn.112.160333
Colman, N., & Herbert, V. (1980). FOLATE METABOLISM IN BRAIN. In S. Kumar (Ed.), Biochemistry of Brain (pp. 103–125). Pergamon. https://doi.org/10.1016/B978-0-08-021345-3.50008-3
Coppedè, F., Stoccoro, A., Tannorella, P., Gallo, R., Nicolì, V., & Migliore, L. (2019). Association of Polymorphisms in Genes Involved in One-Carbon Metabolism with MTHFR Methylation Levels. International Journal of Molecular Sciences, 20(15), 3754. https://doi.org/10.3390/ijms20153754
Cuskelly, G. J., Stacpoole, P. W., Williamson, J., Baumgartner, T. G., & Gregory, J. F. (2001). Deficiencies of folate and vitamin B6 exert distinct effects on homocysteine, serine, and methionine kinetics. American Journal of Physiology-Endocrinology and Metabolism, 281(6), E1182–E1190. https://doi.org/10.1152/ajpendo.2001.281.6.E1182
da Costa, K.-A., Corbin, K. D., Niculescu, M. D., Galanko, J. A., & Zeisel, S. H. (2014). Identification of new genetic polymorphisms that alter the dietary requirement for choline and vary in their distribution across ethnic and racial groups. The FASEB Journal, 28(7), 2970–2978. https://doi.org/10.1096/fj.14-249557
Dawson, P. A. (2013). Role of sulphate in development. Reproduction (Cambridge, England), 146(3), R81-89. https://doi.org/10.1530/REP-13-0056
Dean, L. (2012). Methylenetetrahydrofolate Reductase Deficiency. In V. M. Pratt, S. A. Scott, M. Pirmohamed, B. Esquivel, B. L. Kattman, & A. J. Malheiro (Eds.), Medical Genetics Summaries. National Center for Biotechnology Information (US). http://www.ncbi.nlm.nih.gov/books/NBK66131/
Den Heijer, M., Lewington, S., & Clarke, R. (2005). Homocysteine, MTHFR and risk of venous thrombosis: A meta-analysis of published epidemiological studies. Journal of Thrombosis and Haemostasis: JTH, 3(2), 292–299. https://doi.org/10.1111/j.1538-7836.2005.01141.x
Dimster-Denk, D., Tripp, K. W., Marini, N. J., Marqusee, S., & Rine, J. (2013). Mono and Dual Cofactor Dependence of Human Cystathionine β-Synthase Enzyme Variants In Vivo and In Vitro. G3: Genes|Genomes|Genetics, 3(10), 1619–1628. https://doi.org/10.1534/g3.113.006916
Du, P., Hassan, R. N., Luo, H., Xie, J., Zhu, Y., Hu, Q., Yan, J., & Jiang, W. (2021). Identification of a novel SUOX pathogenic variants as the cause of isolated sulfite oxidase deficiency in a Chinese pedigree. Molecular Genetics & Genomic Medicine, 9(2), e1590. https://doi.org/10.1002/mgg3.1590
Ducker, G. S., Chen, L., Morscher, R. J., Ghergurovich, J. M., Esposito, M., Teng, X., Kang, Y., & Rabinowitz, J. D. (2016). Reversal of cytosolic one-carbon flux compensates for loss of mitochondrial folate pathway. Cell Metabolism, 23(6), 1140–1153. https://doi.org/10.1016/j.cmet.2016.04.016
Ducker, G. S., & Rabinowitz, J. D. (2017). One-Carbon Metabolism in Health and Disease. Cell Metabolism, 25(1), 27–42. https://doi.org/10.1016/j.cmet.2016.08.009
Ehrlich, M. (2019). DNA hypermethylation in disease: Mechanisms and clinical relevance. Epigenetics, 14(12), 1141–1163. https://doi.org/10.1080/15592294.2019.1638701
Feng, Q., Kalari, K., Fridley, B. L., Jenkins, G., Ji, Y., Abo, R., Hebbring, S., Zhang, J., Nye, M. D., Leeder, J. S., & Weinshilboum, Richard. M. (2011). Betaine-homocysteine methyltransferase: Human liver genotype-phenotype correlation. Molecular Genetics and Metabolism, 102(2), 126–133. https://doi.org/10.1016/j.ymgme.2010.10.010
Field, M. S., Kamynina, E., & Stover, P. J. (2016). MTHFD1 Regulates Nuclear de novo Thymidylate Biosynthesis and Genome Stability. Biochimie, 126, 27–30. https://doi.org/10.1016/j.biochi.2016.02.001
Fox, J. T., & Stover, P. J. (2008). Chapter 1 Folate‐Mediated One‐Carbon Metabolism. In Vitamins & Hormones (Vol. 79, pp. 1–44). Academic Press. https://doi.org/10.1016/S0083-6729(08)00401-9
Froese, D. S., Fowler, B., & Baumgartner, M. R. (2019). Vitamin B12 , folate, and the methionine remethylation cycle-biochemistry, pathways, and regulation. Journal of Inherited Metabolic Disease, 42(4), 673–685. https://doi.org/10.1002/jimd.12009
Ganguly, P., & Alam, S. F. (2015). Role of homocysteine in the development of cardiovascular disease. Nutrition Journal, 14, 6. https://doi.org/10.1186/1475-2891-14-6
García-Minguillán, C. J., Fernandez-Ballart, J. D., Ceruelo, S., Ríos, L., Bueno, O., Berrocal-Zaragoza, M. I., Molloy, A. M., Ueland, P. M., Meyer, K., & Murphy, M. M. (2014). Riboflavin status modifies the effects of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) polymorphisms on homocysteine. Genes & Nutrition, 9(6), 435. https://doi.org/10.1007/s12263-014-0435-1
Gaughan, D. J., Kluijtmans, L. A. J., Barbaux, S., McMaster, D., Young, I. S., Yarnell, J. W. G., Evans, A., & Whitehead, A. S. (2001). The methionine synthase reductase (MTRR) A66G polymorphism is a novel genetic determinant of plasma homocysteine concentrations. Atherosclerosis, 157(2), 451–456. https://doi.org/10.1016/S0021-9150(00)00739-5
Hashimoto, K., Yoshida, T., Ishikawa, M., Fujita, Y., Niitsu, T., Nakazato, M., Watanabe, H., Sasaki, T., Shiina, A., Hashimoto, T., Kanahara, N., Hasegawa, T., Enohara, M., Kimura, A., & Iyo, M. (2016). Increased serum levels of serine enantiomers in patients with depression. Acta Neuropsychiatrica, 28(3), 173–178. https://doi.org/10.1017/neu.2015.59
He, L., Steinocher, H., Shelar, A., Cohen, E. B., Heim, E. N., Kragelund, B. B., Grigoryan, G., & DiMaio, D. (2017). Single methyl groups can act as toggle switches to specify transmembrane Protein-protein interactions. eLife, 6, e27701. https://doi.org/10.7554/eLife.27701
Heil, S. G., Van der Put, N. M., Waas, E. T., den Heijer, M., Trijbels, F. J., & Blom, H. J. (2001). Is mutated serine hydroxymethyltransferase (SHMT) involved in the etiology of neural tube defects? Molecular Genetics and Metabolism, 73(2), 164–172. https://doi.org/10.1006/mgme.2001.3175
Herbig, K., Chiang, E.-P., Lee, L.-R., Hills, J., Shane, B., & Stover, P. J. (2002). Cytoplasmic serine hydroxymethyltransferase mediates competition between folate-dependent deoxyribonucleotide and S-adenosylmethionine biosyntheses. The Journal of Biological Chemistry, 277(41), 38381–38389. https://doi.org/10.1074/jbc.M205000200
Hiraoka, M., & Kagawa, Y. (2017). Genetic polymorphisms and folate status. Congenital Anomalies, 57(5), 142–149. https://doi.org/10.1111/cga.12232
Holmes, M. V., Newcombe, P., Hubacek, J. A., Sofat, R., Ricketts, S. L., Cooper, J., Breteler, M. M. B., Bautista, L. E., Sharma, P., Whittaker, J. C., Smeeth, L., Fowkes, F. G. R., Algra, A., Shmeleva, V., Szolnoki, Z., Roest, M., Linnebank, M., Zacho, J., Nalls, M. A., … Casas, J. P. (2011). Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: A meta-analysis of genetic studies and randomised trials. Lancet (London, England), 378(9791), 584–594. https://doi.org/10.1016/S0140-6736(11)60872-6
Hum, D. W., Bell, A. W., Rozen, R., & MacKenzie, R. E. (1988). Primary structure of a human trifunctional enzyme. Isolation of a cDNA encoding methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase. The Journal of Biological Chemistry, 263(31), 15946–15950.
Hustad, S., Schneede, J., & Ueland, P. M. (2013). Riboflavin and Methylenetetrahydrofolate Reductase. In Madame Curie Bioscience Database [Internet]. Landes Bioscience. https://www.ncbi.nlm.nih.gov/books/NBK6145/
Ishii, I., Akahoshi, N., Yamada, H., Nakano, S., Izumi, T., & Suematsu, M. (2010). Cystathionine γ-Lyase-deficient Mice Require Dietary Cysteine to Protect against Acute Lethal Myopathy and Oxidative Injury. The Journal of Biological Chemistry, 285(34), 26358–26368. https://doi.org/10.1074/jbc.M110.147439
Ivanov, A., Nash-Barboza, S., Hinkis, S., & Caudill, M. A. (2009). Genetic variants in phosphatidylethanolamine N-methyltransferase (PEMT) and methylenetetrahydrofolate dehydrogenase (MTHFD1) influence biomarkers of choline metabolism when folate intake is restricted. Journal of the American Dietetic Association, 109(2), 313–318. https://doi.org/10.1016/j.jada.2008.10.046
Jamerson, B. D., Payne, M. E., Garrett, M. E., Ashley-Koch, A. E., Speer, M. C., & Steffens, D. C. (2013). Folate Metabolism Genes, Dietary Folate and Response to Antidepressant Medications in Late-Life Depression. International Journal of Geriatric Psychiatry, 28(9), 925–932. https://doi.org/10.1002/gps.3899
Jiang, J., Zhang, Y., Wei, L., Sun, Z., & Liu, Z. (2014). Association between MTHFD1 G1958A polymorphism and neural tube defects susceptibility: A meta-analysis. PloS One, 9(6), e101169. https://doi.org/10.1371/journal.pone.0101169
Jiang, S., Liberti, L., & Lebo, D. (2023). Direct-to-Consumer Genetic Testing: A Comprehensive Review. Therapeutic Innovation & Regulatory Science. https://doi.org/10.1007/s43441-023-00567-5
Jin, B., Li, Y., & Robertson, K. D. (2011). DNA Methylation. Genes & Cancer, 2(6), 607–617. https://doi.org/10.1177/1947601910393957
Jin, H., Cheng, H., Chen, W., Sheng, X., Levy, M. A., Brown, M. J., & Tian, J. (2018). An evidence-based approach to globally assess the covariate-dependent effect of the MTHFR single nucleotide polymorphism rs1801133 on blood homocysteine: A systematic review and meta-analysis. The American Journal of Clinical Nutrition, 107(5), 817–825. https://doi.org/10.1093/ajcn/nqy035
Jin, Q., & Shi, G. (2019). Meta-Analysis of SNP-Environment Interaction with Heterogeneity. Human Heredity, 84(3), 117–126. https://doi.org/10.1159/000504170
Jin, Z., & Liu, Y. (2018). DNA methylation in human diseases. Genes & Diseases, 5(1), 1–8. https://doi.org/10.1016/j.gendis.2018.01.002
Kandi, V., & Vadakedath, S. (2015). Effect of DNA Methylation in Various Diseases and the Probable Protective Role of Nutrition: A Mini-Review. Cureus, 7(8), e309. https://doi.org/10.7759/cureus.309
Kelly, P. J., Rosand, J., Kistler, J. P., Shih, V. E., Silveira, S., Plomaritoglou, A., & Furie, K. L. (2002). Homocysteine, MTHFR 677C-->T polymorphism, and risk of ischemic stroke: Results of a meta-analysis. Neurology, 59(4), 529–536. https://doi.org/10.1212/wnl.59.4.529
Khandanpour, N., Willis, G., Meyer, F. J., Armon, M. P., Loke, Y. K., Wright, A. J. A., Finglas, P. M., & Jennings, B. A. (2009). Peripheral arterial disease and methylenetetrahydrofolate reductase (MTHFR) C677T mutations: A case-control study and meta-analysis. Journal of Vascular Surgery, 49(3), 711–718. https://doi.org/10.1016/j.jvs.2008.10.004
Király, L., Künstler, A., Höller, K., Fattinger, M., Juhász, C., Müller, M., Gullner, G., & Zechmann, B. (2012). Sulfate supply influences compartment specific glutathione metabolism and confers enhanced resistance to Tobacco mosaic virus during a hypersensitive response. Plant Physiology and Biochemistry, 59, 44–54. https://doi.org/10.1016/j.plaphy.2011.10.020
Klein Geltink, R. I., & Pearce, E. L. (2019). The importance of methionine metabolism. eLife, 8, e47221. https://doi.org/10.7554/eLife.47221
Kluijtmans, L. A., Boers, G. H., Stevens, E. M., Renier, W. O., Kraus, J. P., Trijbels, F. J., van den Heuvel, L. P., & Blom, H. J. (1996). Defective cystathionine beta-synthase regulation by S-adenosylmethionine in a partially pyridoxine responsive homocystinuria patient. Journal of Clinical Investigation, 98(2), 285–289.
Kopriva, S., & Rennenberg, H. (2004). Control of sulphate assimilation and glutathione synthesis: Interaction with N and C metabolism. Journal of Experimental Botany, 55(404), 1831–1842. https://doi.org/10.1093/jxb/erh203
Kwok, P. Y. (2001). Methods for genotyping single nucleotide polymorphisms. Annual Review of Genomics and Human Genetics, 2, 235–258. https://doi.org/10.1146/annurev.genom.2.1.235
Kwok, P.-Y., & Chen, X. (2003). Detection of single nucleotide polymorphisms. Current Issues in Molecular Biology, 5(2), 43–60.
Leal, N. A., Olteanu, H., Banerjee, R., & Bobik, T. A. (2004). Human ATP:Cob(I)alamin adenosyltransferase and its interaction with methionine synthase reductase. The Journal of Biological Chemistry, 279(46), 47536–47542. https://doi.org/10.1074/jbc.M405449200
Leclerc, D., Sibani, S., & Rozen, R. (2013). Molecular Biology of Methylenetetrahydrofolate Reductase (MTHFR) and Overview of Mutations/Polymorphisms. In Madame Curie Bioscience Database [Internet]. Landes Bioscience. https://www.ncbi.nlm.nih.gov/books/NBK6561/
Lee, Y. L., Xu, X., Wallenstein, S., & Chen, J. (2009). Gene Expression Profiles of the One-carbon Metabolism Pathway. Journal of Genetics and Genomics = Yi Chuan Xue Bao, 36(5), 277–282. https://doi.org/10.1016/S1673-8527(08)60115-0
Lesner, N. P., Gokhale, A. S., Kota, K., DeBerardinis, R. J., & Mishra, P. (2020). α-ketobutyrate links alterations in cystine metabolism to glucose oxidation in mtDNA mutant cells. Metabolic Engineering, 60, 157–167. https://doi.org/10.1016/j.ymben.2020.03.010
Leustek, T. (2002). Sulfate Metabolism. The Arabidopsis Book / American Society of Plant Biologists, 1, e0017. https://doi.org/10.1199/tab.0017
Li, D., Yang, J., Zhao, Q., Zhang, C., Ren, B., Yue, L., Du, B., Godfrey, O., Huang, X., & Zhang, W. (2019). Genetic and epigenetic regulation of BHMT is associated with folate therapy efficacy in hyperhomocysteinaemia. Asia Pacific Journal of Clinical Nutrition, 28(4), 879–887. https://doi.org/10.6133/apjcn.201912_28(4).0025
Li, F., Feng, Q., Lee, C., Wang, S., Pelleymounter, L. L., Moon, I., Eckloff, B. W., Wieben, E. D., Schaid, D. J., Yee, V., & Weinshilboum, R. M. (2008). Human Betaine-Homocysteine Methyltransferase (BHMT) and BHMT2: Common Gene Sequence Variation and Functional Characterization. Molecular Genetics and Metabolism, 94(3), 326–335. https://doi.org/10.1016/j.ymgme.2008.03.013
Li, J., Xin, Y., Li, J., Chen, H., & Li, H. (2023). Phosphatidylethanolamine N-methyltransferase: From Functions to Diseases. Aging and Disease, 14(3), 879–891. https://doi.org/10.14336/AD.2022.1025
Li, Y., Zhao, Q., Liu, X.-L., Wang, L.-Y., Lu, X.-F., Li, H.-F., Chen, S.-F., Huang, J.-F., & Gu, D.-F. (2008). Relationship between cystathionine gamma-lyase gene polymorphism and essential hypertension in Northern Chinese Han population. Chinese Medical Journal, 121(8), 716–720.
Lievers, K. J. A., Kluijtmans, L. A. J., Heil, S. G., Boers, G. H. J., Verhoef, P., Den Heijer, M., Trijbels, F. J. M., & Blom, H. J. (2003). Cystathionine beta-synthase polymorphisms and hyperhomocysteinaemia: An association study. European Journal of Human Genetics: EJHG, 11(1), 23–29. https://doi.org/10.1038/sj.ejhg.5200899
López-Quesada, E., Vilaseca, M. A., & Lailla, J. M. (2003). Plasma total homocysteine in uncomplicated pregnancy and in preeclampsia. European Journal of Obstetrics, Gynecology, and Reproductive Biology, 108(1), 45–49. https://doi.org/10.1016/s0301-2115(02)00367-6
MacFarlane, A. J., Liu, X., Perry, C. A., Allen, S., & Stover, P. J. (2006). Regulation of Homocysteine Remethylation by Cytoplasmic Serine Hydroxymethyltransferase. The FASEB Journal, 20(5), A958–A958. https://doi.org/10.1096/fasebj.20.5.A958-a
Majtan, T., Kožich, V., & Kruger, W. D. (2023). Recent therapeutic approaches to cystathionine beta-synthase-deficient homocystinuria. British Journal of Pharmacology, 180(3), 264–278. https://doi.org/10.1111/bph.15991
Martinez, M., Cuskelly, G. J., Williamson, J., Toth, J. P., & Gregory, J. F. (2000). Vitamin B-6 Deficiency in Rats Reduces Hepatic Serine Hydroxymethyltransferase and Cystathionine β-Synthase Activities and Rates of In Vivo Protein Turnover, Homocysteine Remethylation and Transsulfuration. The Journal of Nutrition, 130(5), 1115–1123. https://doi.org/10.1093/jn/130.5.1115
Mehlig, K., Leander, K., de Faire, U., Nyberg, F., Berg, C., Rosengren, A., Björck, L., Zetterberg, H., Blennow, K., Tognon, G., Torén, K., Strandhagen, E., Lissner, L., & Thelle, D. (2013). The association between plasma homocysteine and coronary heart disease is modified by the MTHFR 677C>T polymorphism. Heart (British Cardiac Society), 99(23), 1761–1765. https://doi.org/10.1136/heartjnl-2013-304460
Menezo, Y., Clement, P., Clement, A., & Elder, K. (2020). Methylation: An Ineluctable Biochemical and Physiological Process Essential to the Transmission of Life. International Journal of Molecular Sciences, 21(23), 9311. https://doi.org/10.3390/ijms21239311
Moore, L. D., Le, T., & Fan, G. (2013). DNA Methylation and Its Basic Function. Neuropsychopharmacology, 38(1), 23–38. https://doi.org/10.1038/npp.2012.112
National Library of Medicine. (2023a). CBS cystathionine beta-synthase [Homo sapiens (human)]—Gene—NCBI [United States government]. National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/gene/875
National Library of Medicine. (2023b). MTHFD1 methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1 [Homo sapiens (human)]—Gene—NCBI [Official website of the United States government]. National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/gene/4522
National Library of Medicine. (2023c). PEMT phosphatidylethanolamine N-methyltransferase [Homo sapiens (human)]—Gene—NCBI. National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/gene/10400
National Library of Medicine. (2023d). SUOX sulfite oxidase [Homo sapiens (human)]—Gene—NCBI. https://www.ncbi.nlm.nih.gov/gene/6821
Neidhart, M. (2016). Chapter 27—Methyl Donors. In M. Neidhart (Ed.), DNA Methylation and Complex Human Disease (pp. 429–439). Academic Press. https://doi.org/10.1016/B978-0-12-420194-1.00027-0
Obeid, R. (2013). The Metabolic Burden of Methyl Donor Deficiency with Focus on the Betaine Homocysteine Methyltransferase Pathway. Nutrients, 5(9), 3481–3495. https://doi.org/10.3390/nu5093481
O’Leary, V. B., Mills, J. L., Pangilinan, F., Kirke, P. N., Cox, C., Conley, M., Weiler, A., Peng, K., Shane, B., Scott, J. M., Parle-McDermott, A., Molloy, A. M., Brody, L. C., & Members of the Birth Defects Research Group. (2005). Analysis of methionine synthase reductase polymorphisms for neural tube defects risk association. Molecular Genetics and Metabolism, 85(3), 220–227. https://doi.org/10.1016/j.ymgme.2005.02.003
Oliphant, K. D., Fettig, R. R., Snoozy, J., Mendel, R. R., & Warnhoff, K. (2022). Obtaining the necessary molybdenum cofactor for sulfite oxidase activity in the nematode Caenorhabditis elegans surprisingly involves a dietary source. The Journal of Biological Chemistry, 299(1), 102736. https://doi.org/10.1016/j.jbc.2022.102736
Olteanu, H., Munson, T., & Banerjee, R. (2002). Differences in the efficiency of reductive activation of methionine synthase and exogenous electron acceptors between the common polymorphic variants of human methionine synthase reductase. Biochemistry, 41(45), 13378–13385. https://doi.org/10.1021/bi020536s
Ou, X., Yang, H., Ramani, K., Ara, A. I., Chen, H., Mato, J. M., & Lu, S. C. (2007). Inhibition of human betaine–homocysteine methyltransferase expression by S-adenosylmethionine and methylthioadenosine. Biochemical Journal, 401(Pt 1), 87–96. https://doi.org/10.1042/BJ20061119
Parkhitko, A. A., Jouandin, P., Mohr, S. E., & Perrimon, N. (2019). Methionine metabolism and methyltransferases in the regulation of aging and lifespan extension across species. Aging Cell, 18(6). https://doi.org/10.1111/acel.13034
Peng, H., Man, C., Xu, J., & Fan, Y. (2015). Elevated homocysteine levels and risk of cardiovascular and all-cause mortality: A meta-analysis of prospective studies. Journal of Zhejiang University. Science. B, 16(1), 78–86. https://doi.org/10.1631/jzus.B1400183
Perry, C., Yu, S., Chen, J., Matharu, K. S., & Stover, P. J. (2007). Effect of Vitamin B6 Availability on Serine Hydroxymethyltransferase in MCF-7 Cells. Archives of Biochemistry and Biophysics, 462(1), 21–27. https://doi.org/10.1016/j.abb.2007.04.005
Picardi, A., Giuliani, E., & Gigantesco, A. (2020). Genes and environment in attachment. Neuroscience and Biobehavioral Reviews, 112, 254–269. https://doi.org/10.1016/j.neubiorev.2020.01.038
Pilesi, E., Angioli, C., Graziani, C., Parroni, A., Contestabile, R., Tramonti, A., & Vernì, F. (2023). A gene-nutrient interaction between vitamin B6 and serine hydroxymethyltransferase (SHMT) affects genome integrity in Drosophila. Journal of Cellular Physiology, 238(7), 1558–1566. https://doi.org/10.1002/jcp.31033
Raghubeer, S., & Matsha, T. E. (2021). Methylenetetrahydrofolate (MTHFR), the One-Carbon Cycle, and Cardiovascular Risks. Nutrients, 13(12). https://doi.org/10.3390/nu13124562
Reynolds, E. H., Carney, M. W., & Toone, B. K. (1984). Methylation and mood. Lancet (London, England), 2(8396), 196–198. https://doi.org/10.1016/s0140-6736(84)90482-3
Sacharow, S. J., Picker, J. D., & Levy, H. L. (1993). Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency. In M. P. Adam, G. M. Mirzaa, R. A. Pagon, S. E. Wallace, L. J. Bean, K. W. Gripp, & A. Amemiya (Eds.), GeneReviews®. University of Washington, Seattle. http://www.ncbi.nlm.nih.gov/books/NBK1524/
Salbaum, J. M., & Kappen, C. (2012). Genetic and Epigenomic Footprints of Folate. Progress in Molecular Biology and Translational Science, 108, 129–158. https://doi.org/10.1016/B978-0-12-398397-8.00006-X
Samarasinghe, N., Mahaliyanage, D., De Silva, S., Jasinge, E., Punyasiri, N., & Dilanthi, H. W. (2022). Association of selected genetic variants in CBS and MTHFR genes in a cohort of children with homocystinuria in Sri Lanka. Journal of Genetic Engineering & Biotechnology, 20, 164. https://doi.org/10.1186/s43141-022-00449-7
Sbodio, J. I., Snyder, S. H., & Paul, B. D. (2019). Regulators of the transsulfuration pathway. British Journal of Pharmacology, 176(4), 583–593. https://doi.org/10.1111/bph.14446
Shastry, B. S. (2009). SNPs: Impact on gene function and phenotype. Methods in Molecular Biology (Clifton, N.J.), 578, 3–22. https://doi.org/10.1007/978-1-60327-411-1_1
Shaw, S. (2019). Chapter 2.1—S-Adenosylmethionine (SAMe). In S. M. Nabavi & A. S. Silva (Eds.), Nonvitamin and Nonmineral Nutritional Supplements (pp. 11–17). Academic Press. https://doi.org/10.1016/B978-0-12-812491-8.00002-3
Soleimani-Jadidi, S., Meibodi, B., Javaheri, A., Tabatabaei, R. S., Hadadan, A., Zanbagh, L., Abbasi, H., Bahrami, R., Mirjalili, S. R., Karimi-Zarchi, M., & Neamatzadeh, H. (2022). Association between Fetal MTHFR A1298C (rs1801131) Polymorphism and Neural Tube Defects Risk: A Systematic Review and Meta-Analysis. Fetal and Pediatric Pathology, 41(1), 116–133. https://doi.org/10.1080/15513815.2020.1764682
Song, J., Costa, K. A. da, Fischer, L. M., Kohlmeier, M., Kwock, L., Wang, S., & Zeisel, S. H. (2005). Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD). The FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 19(10), 1266–1271. https://doi.org/10.1096/fj.04-3580com
Stipanuk, M. H., & Ueki, I. (2011). Dealing with methionine/homocysteine sulfur: Cysteine metabolism to taurine and inorganic sulfur. Journal of Inherited Metabolic Disease, 34(1), 17–32. https://doi.org/10.1007/s10545-009-9006-9
Suh, E., Choi, S.-W., & Friso, S. (2016). Chapter 36 - One-Carbon Metabolism: An Unsung Hero for Healthy Aging. In M. Malavolta & E. Mocchegiani (Eds.), Molecular Basis of Nutrition and Aging (pp. 513–522). Academic Press. https://doi.org/10.1016/B978-0-12-801816-3.00036-4
The Human Gene Mutation Database. (2022). HGMD® mutation result. The Human Gene Mutation Database. https://www.hgmd.cf.ac.uk/ac/all.php
Tjong, E., Dimri, M., & Mohiuddin, S. S. (2023). Biochemistry, Tetrahydrofolate. In StatPearls. StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK539712/
Tsang, B. L., Devine, O. J., Cordero, A. M., Marchetta, C. M., Mulinare, J., Mersereau, P., Guo, J., Qi, Y. P., Berry, R. J., Rosenthal, J., Crider, K. S., & Hamner, H. C. (2015). Assessing the association between the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and blood folate concentrations: A systematic review and meta-analysis of trials and observational studies. The American Journal of Clinical Nutrition, 101(6), 1286–1294. https://doi.org/10.3945/ajcn.114.099994
van der Put, N. M., Steegers-Theunissen, R. P., Frosst, P., Trijbels, F. J., Eskes, T. K., van den Heuvel, L. P., Mariman, E. C., den Heyer, M., Rozen, R., & Blom, H. J. (1995). Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet (London, England), 346(8982), 1070–1071. https://doi.org/10.1016/s0140-6736(95)91743-8
Wald, D. S., Law, M., & Morris, J. K. (2002). Homocysteine and cardiovascular disease: Evidence on causality from a meta-analysis. BMJ (Clinical Research Ed.), 325(7374), 1202. https://doi.org/10.1136/bmj.325.7374.1202
Wang, X. W., Luo, Y. L., Wang, W., Zhang, Y., Chen, Q., & Cheng, Y. L. (2012). Association between MTHFR A1298C polymorphism and neural tube defect susceptibility: A metaanalysis. American Journal of Obstetrics and Gynecology, 206(3), 251.e1-7. https://doi.org/10.1016/j.ajog.2011.12.021
Wang, Y., Liu, Y., Ji, W., Qin, H., Wu, H., Xu, D., Tukebai, T., & Wang, Z. (2015). Analysis of MTR and MTRR Polymorphisms for Neural Tube Defects Risk Association. Medicine, 94(35), e1367. https://doi.org/10.1097/MD.0000000000001367
Weiner, A. S., Boyarskikh, U. A., Voronina, E. N., Mishukova, O. V., & Filipenko, M. L. (2014). Methylenetetrahydrofolate reductase C677T and methionine synthase A2756G polymorphisms influence on leukocyte genomic DNA methylation level. Gene, 533(1), 168–172. https://doi.org/10.1016/j.gene.2013.09.098
Wernimont, S. M., Clark, A. G., Stover, P. J., Wells, M. T., Litonjua, A. A., Weiss, S. T., Gaziano, J. M., Vokonas, P. S., Tucker, K. L., & Cassano, P. A. (2012). Folate network genetic variation predicts cardiovascular disease risk in non-Hispanic white males. The Journal of Nutrition, 142(7), 1272–1279. https://doi.org/10.3945/jn.111.157180
Yadav, U., Kumar, P., & Rai, V. (2021). Distribution of Methionine Synthase Reductase (MTRR) Gene A66G Polymorphism in Indian Population. Indian Journal of Clinical Biochemistry, 36(1), 23–32. https://doi.org/10.1007/s12291-019-00862-9
Yan, L., Zhao, L., Long, Y., Zou, P., Ji, G., Gu, A., & Zhao, P. (2012). Association of the maternal MTHFR C677T polymorphism with susceptibility to neural tube defects in offsprings: Evidence from 25 case-control studies. PloS One, 7(10), e41689. https://doi.org/10.1371/journal.pone.0041689
Zeisel, S. H., Mar, M.-H., Howe, J. C., & Holden, J. M. (2003). Concentrations of Choline-Containing Compounds and Betaine in Common Foods. The Journal of Nutrition, 133(5), 1302–1307. https://doi.org/10.1093/jn/133.5.1302
Zheng, Y., & Cantley, L. C. (2019). Toward a better understanding of folate metabolism in health and disease. The Journal of Experimental Medicine, 216(2), 253–266. https://doi.org/10.1084/jem.20181965