CBS Gene and its Influence on the Methylation Cycle
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CBS Gene and its Influence on the Methylation Cycle
Date of Content: May 20, 2024
Written by: Avanthika Nityanand
Reviewed by: Maarit Tiirikainen, PhD
Disclaimer: This article does not include all possible risk variants for the CBS gene and is for informational purposes only. This article is not intended for diagnosis. Please talk to a healthcare professional if you have symptoms associated with these variants.
What is the CBS Gene?
The CBS geneis a crucial gene encoding the enzyme Cystathionine Beta-Synthase. This enzyme plays a pivotal role in the metabolic pathway known as the transsulfuration pathway, which converts homocysteine to cystathionine. This conversion is a crucial step in metabolizing sulfur-containing amino acids. It is critical for maintaining proper levels of homocysteine and methionine in the blood.
The CBS gene is on chromosome 21. The functional pathways of the encoded enzyme, Systathionine Beta-Synthase (CBS), involves several vital biochemical processes, including cysteine, glutathione, taurine, and hydrogen sulfide synthesis. These molecules are essential for detoxification, antioxidant defense, and modulation of neurotransmission. Genetic variations in the CBS gene can lead to dysregulation of these pathways and result in elevated homocysteine levels, a condition known as hyperhomocysteinemia. This condition is associated with various health issues, including vascular diseases, neurological disorders, and congenital flaws.
The importance of the CBS enzyme extends beyond merely maintaining amino acid levels; it also impacts overall cellular health and function. Research into the role of CBS has provided insights into the complex interactions between genetics, diet, and disease. It is also a target for therapeutic interventions in diseases with sulfur metabolism disruption. For example, dietary adjustments and supplementation can help manage CBS gene mutations and their systemic effects.
Understanding the function and regulation of the CBS is crucial for comprehending broader aspects of human health and disease, particularly those related to amino acid metabolism and cardiovascular health. Ongoing research continues to reveal the intricate balance required in sulfur metabolism and the potential consequences when there is a disruption in this balance.
Overview of the Methylation Cycle
The central theme of the methylation cycle is the conversion of homocysteine to methionine, an essential amino acid. The methylation cycle helps keep your homocysteine levels in check. As discussed in the earlier section, high homocysteine levels can lead to several health issues.
Here are the steps in the methylation cycle involving key enzymes and intermediates:
[1] Conversion of Serine to Glycine
- Enzyme: Serine Hydroxymethyltransferase (SHMT)
- Reaction: Serine + Tetrahydrofolate (THF) → Glycine + 5,10-Methylenetetrahydrofolate (5,10-MTHF)
[2] Conversion of 5,10-MTHF to 5-MTHF
- Enzyme: Methylenetetrahydrofolate Reductase (MTHFR)
- Reaction: 5,10-Methylenetetrahydrofolate (5,10-MTHF) → 5-Methyltetrahydrofolate (5-MTHF)
[3] Conversion of Homocysteine to Methionine
- Enzyme: Methionine Synthase (MTR)
- Reaction: Homocysteine + 5-Methyltetrahydrofolate (5-MTHF) → Methionine + Tetrahydrofolate (THF)
- Coenzyme: Methionine Synthase Reductase (MTRR) keeps MTR active
[4] Alternative Pathway for Homocysteine to Methionine
- Enzyme: Betaine-Homocysteine Methyltransferase (BHMT)
- Reaction: Homocysteine + Betaine → Methionine + Dimethylglycine
[5] Conversion of Methionine to SAM
- Enzyme: Methionine Adenosyltransferase (MAT)
- Reaction: Methionine + ATP → S-Adenosylmethionine (SAM)
[6] Methylation Reactions
- SAM as Methyl Donor: SAM donates a methyl group to various substrates (DNA, RNA, proteins, lipids) and becomes S-Adenosylhomocysteine (SAH).
[7] Conversion of SAH to Homocysteine
- Enzyme: S-Adenosylhomocysteine Hydrolase (SAHH)
- Reaction: S-Adenosylhomocysteine (SAH) → Homocysteine + Adenosine
[8] Transsulfuration Pathway (Alternative route for homocysteine) [we are here]
- Enzyme: Cystathionine Beta-Synthase (CBS)
- Reaction: Homocysteine + Serine → Cystathionine
- Subsequent Reaction: Cystathionine converts to cysteine and other metabolites.
The CBS gene produces the enzyme cystathionine beta-synthase. This enzyme uses Vitamin B6 (pyridoxine) to convert homocysteine and serine into cystathionine.
Additionally, through the transsulfuration process, cystathionine can be converted into taurine or glutathione. This process is crucial for making cysteine-containing amino acids, which are vital for protein structure, antioxidant activity, detoxification, and metabolic functions.
Importance of Healthy Homocysteine Levels
Appropriate homocysteine levels are essential because elevated levels of homocysteine, a sulfur-containing amino acid, are associated with an increased risk of cardiovascular diseases, including coronary artery disease, stroke, and peripheral arterial disease. High homocysteine levels can damage the lining of arteries, promote blood clot formation, and increase oxidative stress, all of which contribute to the development and progression of atherosclerosis.Â
Additionally, elevated homocysteine is linked to other health issues such as cognitive decline, dementia, and certain birth flaws. Monitoring and managing homocysteine levels through diet, lifestyle changes, and, in some cases, medication, can be crucial for maintaining cardiovascular health and preventing related complications.
How Does the CBS Gene Affect the Methylation Cycle?
Genetic variation in the CBS gene can influence the methylation cycle significantly due to its role in processing homocysteine, a sulfur-containing amino acid crucial for methylation reactions.Â
Methylation is a biochemical process involving transferring a methyl group (one carbon atom and three hydrogen atoms) onto amino acids, proteins, enzymes, and DNA, which can affect their function and activity. The methylation cycle is vital for numerous cellular processes, including DNA repair, gene expression, and the synthesis of neurotransmitters.
Here are important functions of the CBS enzyme:
Reducing Homocysteine Levels
The enzyme encoded by the CBS gene, cystathionine beta-synthase, catalyzes the first step in the transsulfuration pathway, where homocysteine is converted into cystathionine. This conversion is crucial because it helps regulate the homocysteine level in the body. Elevated homocysteine levels can lead to a variety of health issues, including cardiovascular diseases and neurological conditions. By converting homocysteine into cystathionine, the CBS enzyme indirectly supports the recycling of homocysteine into methionine or its conversion into other sulfur-containing compounds.
Making Glutathione
Furthermore, the transsulfuration pathway facilitated by the CBS enzyme produces essential raw material for glutathione synthesis. Glutathione is a major antioxidant that protects cells from oxidative stress and helps maintain the redox balance within cells, which is crucial for normal cellular function and disease prevention.
Variations in the CBS gene can lead to altered enzyme activity, potentially causing a buildup of homocysteine and a subsequent imbalance in methylation-dependent processes. This dysregulation can impair DNA synthesis and repair, disrupt gene expression, and alter neurotransmitter synthesis, manifesting in various diseases and conditions.
Implications of the CBS Gene Variations
Several studies have looked into the role of the CBS gene variation and their effects on homocysteine levels and other health aspects.
A 2013 meta-analysis of genome-wide association studies (GWAS) involving 44,147 individuals of European descent investigated the CBS gene and 12 other loci for their association with total homocysteine (tHcy) concentrations and coronary artery disease (CAD) risk. This study aimed to determine if genetic polymorphisms linked to tHcy levels correlate with CAD. The results identified 13 loci, including six novel ones, that explained 5.9% of the variation in tHcy levels. However, a genotype risk score (GRS) based on these variants showed no significant association with CAD risk. This suggests that common genetic variants affecting tHcy levels do not influence CAD risk in white populations, thereby challenging the causal relevance of elevated tHcy levels for CAD.
A study from 2010 looked into genetic variation in the CBS gene and how this might influence susceptibility to arsenic-induced disease by affecting arsenic metabolism. In an arsenic-exposed population in Cordoba Province, Argentina, individuals with variant genotypes for CBS SNPs rs234709 and rs4920037 exhibited a 24% and 26% increase, respectively, in the proportion of arsenic excreted as the more toxic monomethylarsonic acid (%MMA) compared to wild-type homozygotes. This variation is comparable to differences observed between individuals with and without arsenic-related diseases in other studies. These findings suggest that CBS polymorphisms play a role in arsenic metabolism and potentially in the risk of arsenic-related diseases.
Get your LifeDNA Methylation Genes report to understand your methylation gene polymorphisms in detail.Â
Optimize Your Homocysteine Levels Naturally
To optimize homocysteine levels through diet, focus on the following strategies:
- Increase Folate (Vitamin B9) Intake: Leafy greens (spinach, kale), legumes (beans, lentils), fruits (oranges, bananas), fortified cereals. Folate helps convert homocysteine into methionine, reducing its levels.
- Boost Vitamin B12 (Cobalamin) Intake: Meat (beef, chicken), fish (salmon, tuna), dairy products (milk, cheese), fortified plant-based milk or cereals. Vitamin B12 is crucial for converting homocysteine into methionine, helping to lower homocysteine levels.
- Consume More Vitamin B6 (Pyridoxine): Poultry (chicken, turkey), fish (salmon, tuna), potatoes, bananas, and fortified cereals. Vitamin B6 helps convert homocysteine to cysteine, another amino acid, lowering homocysteine levels.
- Increase Riboflavin (Vitamin B2) Intake: Dairy products (milk, yogurt), eggs, lean meats, green leafy vegetables, and fortified cereals. Riboflavin supports the activity of enzymes involved in homocysteine metabolism.
- Ensure Adequate Choline Intake: Eggs, beef liver, chicken, shrimp, and soybeans. Choline helps produce betaine, which aids in converting homocysteine to methionine.
- Limit Alcohol Consumption: Alcohol can impair the function of enzymes involved in homocysteine metabolism and exacerbate high homocysteine levels.
- Include Antioxidant-Rich Foods: Fruits (berries, oranges), vegetables (broccoli, bell peppers), nuts, and seeds. Antioxidants can help protect against oxidative stress, which may be high with elevated homocysteine.
- Consider Omega-3 Fatty Acids: Fatty fish (salmon, mackerel), flaxseeds, chia seeds, and walnuts. Omega-3 fatty acids have been associated with lower homocysteine levels and improved heart health.
Incorporating these nutrient-rich foods into your diet can help maintain healthy homocysteine levels and support overall cardiovascular health. Always consult with a healthcare professional before making significant changes to your diet or starting new supplements.
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