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Methylation: More than the MTHFR gene. Genes in the Folate cycle, Methionine cycle, and Transsulfuration Pathway

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  


Learning objectives:

  1. To broaden the understanding on multiple gene interactions in the Methylation metabolism
  2. To provide a deeper insight into the different cycles
  3. To establish an overview of the interconnectivity between each cycle.

Related tests:

Omnos DNA

Doctor's Data Methylation plasma

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.



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