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Methylation

By Joan Verdick

Lesson on Methylation

This is long, but to really understand methylation you need to understand some basics. I am going to make this as simple as I can. It is so much more complicated. I will give the definition of methylation and genetics towards the end but mention it throughout. By understanding the basics first, it will help you understand what methylation is and why it is so important for you to support it.

1. Atoms : There are many different kinds of atoms. Everything on earth, including your body, is made up of atoms and atoms bind to make up molecules.

2. Molecules: Molecules store concentrated energy for the biological processes. Molecules bind to make chemicals.

3. Chemicals: Chemicals are a combination of atoms and molecules bound together. In the body, different chemicals are needed for different biological processes and functions.

4. Biological processes: A biological process is a process in a living organism. Biological processes are made up of any number of chemical reactions or other events that result in a transformation.

5. Chemical reactions: A chemical reaction is when molecules are changed when adding, combining or getting rid of (binding and unbinding) different kinds of atoms. One type of chemical reaction is called methylation (more on that later). Chemical reactions are critical to keeping cells alive.

6. Cells: Cells are called the building blocks of life. There are living organisms on earth that are made up of only one cell. Human bodies are made up of many different kinds of cells that make up different body parts and organs. For example, the largest organ in the body is our skin. A whole bunch of special cells that we call skin cells are bound together and make up our skin. Our skin cells are different from the cells that make up our other organs like our colon cells that make up our colon.

Each cell in our body is somewhat self-contained and self-maintaining. The cell can take in nutrients, convert nutrient molecules into energy, carry out specialized functions, and reproduce. We don’t have to think about it. Our cells can do their jobs on their own because each cell in our body stores its own set of instructions (genetic material/DNA) for carrying out each of its own activities. To function, each specific cell depends upon its own ability to extract/take out and use, the chemical energy stored in the specific molecules that is needs. Different cells need different molecules. The energy from the molecules that the cell needs is derived from what is called metabolic pathways.

7. Metabolic pathways: Metabolic pathways are a series of chemical reactions breaking down, changing the initial substance to shape it into the product with the exact chemical structure that is needed. Example: we eat a hamburger. To change the hamburger into the nutrients the body needs many things have to happen and there are terms that describe them. The whole process of eating the hamburger and breaking it down from start to finish is called the biological process. The sum total of all the chemical reactions involved is called metabolism. Chemical reactions must follow a specific order to break down (metabolize) a specific substance and that is called the metabolic pathway. Some metabolic pathways lead to changing the molecule so it can pass though the cell membrane and give the specific cell what it needs like in some cases of methylation (more on that later).

8. Cell membrane: Cells have an outer coating called the membrane. The membrane is permeable; meaning it allows certain molecules and chemicals to come in and go out of the cell to “feed” it and to allow it to eliminate its waste. When the cell is supplied with the chemicals it needs, it uses those chemicals for a specific function and that is called cell-metabolism.

9. Cell Metabolism: Cell metabolism is a term that means all the chemical processes that happen in a cell so the cell can maintain a living state. Just like the body needing to metabolize its food into nutrients, the cells in the body need to metabolize the nutrients into useable molecules and chemicals. One of the chemical processes in cell metabolism is methylation (more on that later).

Enzymes are crucial in the cell metabolism The genetic material/DNA within the cell gives the cell it’s instructions on how it is to use the enzymes to metabolize the nutrients.

10. Enzymes: Enzymes are special proteins that catalyze (accelerate/cause) specific chemical reactions. In these chemical reactions, the first molecules at the beginning of the process are called substrates, and the enzyme changes them into different kinds of molecules. Enzymes are known to catalyze about 4,000 different biochemical reactions. Some enzymes are produced by enzyme-genes like the MTHFR gene that produces an enzyme (more on that later).

Almost all processes in the cell need enzymes in order to occur at significant rates. Enzymes can catalyze up to several million chemical reactions per second. Since enzymes are extremely selective for their substrates (meaning that there is a specific enzyme activity for a specific molecule), and speed up only a few reactions from among many possibilities, the set of enzymes made in a cell determines which metabolic pathways occur in that cell.

There are also a group of enzymes called coenzymes. They carry chemical groups between enzymes. Vitamins can be coenzymes.

11. Vitamins: Vitamins are nutrients required in very small amounts for essential metabolic reactions (metabolism) in the body. The term vitamin does not include other essential nutrients such as dietary minerals, essential fatty acids, or essential amino acids, nor does it encompass the large number of other nutrients that promote health but that are not strictly essential. Vitamins are biomolecules (chemical compounds that are bound molecules) that act both as catalysts and substrates in chemical reactions. When acting as a catalyst, vitamins are bound to enzymes and are called cofactors. Vitamins also act as coenzymes to carry chemical groups between enzymes. For example, the vitamin B9/folic acid carries various forms of carbon groups–methyl, formyl or methylene within the cell.

12. Proteins: Protein is the material that carries out the functions of the cell. A protein is made up of specific amino acids. Protein also forms the structure of certain cells. A sound body depends on the continuous interplay of thousands of different proteins, acting together in just the right amounts and in just the right places – and each properly functioning protein is the product of an intact, properly functioning gene. Protein is also a necessary component in our diet, since we cannot synthesize (make) all the amino acids we need and must obtain essential amino acids from food. Through the process of digestion, our body breaks down protein into free amino acids that can be used for protein synthesis (creating new and different protein).

13. Amino Acids: Amino Acid is a name for a group of special molecules that are bound together in a chain by what is called a peptide bond. A peptide bond is a special bond that is formed between two molecules. Amino Acids are the basic structural units that make up protein. Amino acids play a role in methylation (more on that later).

14. DNA: DNA (deoxyribonucleic acid) DNA is found in our cells. The main role of DNA is the long term storage of information and instructions. DNA is often compared to a blueprint, since it contains the instructions for our cells on how to construct other components of that cell, such as proteins and other molecules. It is the material that codes for amino acids to form proteins, which in turn carry out functions of the cell. We hear a lot about DNA now days used in identifying people. The long chains of DNA molecules are calls strands. The strands are wrapped in a protective protein. The strands also wrap around another specific kind of protein. Some strands of DNA can be up to seven feet long. DNA strands curl up into balls. You have probably seen pictures of a part of a DNA strand. It looks like a colorful spiral staircase. Along the strands of DNA in your cells, are long sections/segments called genes. The biological information contained in your body is encoded in your genes along your DNA strands.

There 23 very long, special stands of DNA in your cells are called chromosomes. The genes on these chromosomes determine what you look like, if you are male of female, etc. Here is a great site that has a visual presentation of what DNA is if you are interested. (just keep clicking next on the tiny red arrows in the lower right corner) http://www.rockefeller.edu/interactive/allis/allis_histone_11.swf

Here is another great site on DNA methylation

http://whsc.emory.edu/_pubs/momentum/2004spring/big.htm

Which molecules and chemicals are on the strand on DNA and how they function is very complicated. Just remember that the DNA in the cell holds the instructions on how a cell should function to stay alive and keep you alive.

15. Genes: Genes are sections/segments of the DNA strands that hold our genetic information. Genes are found on the strand in pairs. There are many different kinds of genes. Genes interact with each other to influence physical development and behavior. Many genes exist on a DNA strand. The “Human Genome Project” estimates that there are 20,000 to 25,000 different kinds of genes in our body. (4) Some genes enable cells to make proteins needed for basic functions; called housekeeping genes, they are active in many types of cells. Other genes are inactive most of the time. Some genes are enzyme-genes that produce specific kinds of enzymes, like the MTHFR gene (more on that later). Some genes play a role in early development of the embryo and are then shut down forever. Many genes encode (transform) proteins that are unique to a particular kind of cell and that give the cell its character like the making of a brain cell, say, different from a skin cell. A normal cell activates just the genes it needs at the moment and actively suppresses the rest.

The proper functioning of genes is really important. Genes, through the proteins they encode, determine all body processes, including how the body responds to challenges from the environment, how efficiently we process foods, how effectively we detoxify poisons, and how vigorously we respond to infections. More than 4,000 diseases are thought to stem from mutated genes inherited from one’s mother and/or father.

16. Promoters: Promoters are what their name implies. They are special protein molecules that are located on the DNA strand at the beginning (upstream) of a gene. They enhance/promote the genes functions. They signal specific enzymes to activate and then works as a booster to help the enzyme to start its process. Sometimes that process is methylation (more on that later).

17. Mutated Gene: A mutation is a change in a gene that should not have changed. Since genes are found in pairs, one side or the other or both sides can mutate. Genes can be mutated in many ways. When a gene contains a mutation, the protein encoded by that gene will be abnormal. Some protein changes are insignificant, others are disabling.

Mutations occur all the time in every cell in the body. Each cell, however, has the remarkable ability to recognize mistakes and fix them before it passes them along to its descendants. But a cell’s DNA repair mechanisms can fail, or be overwhelmed, or become less efficient with age. Over time, mistakes can accumulate.

Gene mutations can be either inherited from a parent or acquired. A hereditary mutation is a mistake that is present in the DNA of virtually all body cells. Hereditary mutations are also called germline mutations because the gene change exists in the reproductive cells (germ cells) and can be passed from generation to generation, from parent to newborn. Moreover, the mutation is copied every time body cells divide.

Acquired mutations are changes in DNA that develop throughout a person’s life. In contrast to hereditary mutations, acquired mutations arise in the DNA of individual cells; the genetic errors are passed only to direct descendants of those cells only and not all the cells in the body. Mutations are often the result of errors that crop up during cell division, when the cell is making a copy of itself and dividing into two. Acquired mutations can also be the byproducts of environmental stresses such as radiation or toxins.

Some mutations are silent; they affect neither the structure of the encoded protein nor its function. Other mutations result in an altered protein. In some instances, the protein is normal enough to function, but not well. In other instances, the protein can be totally disabled. The outcome of a particular mutation depends not only on how it alters a protein’s function but also on how vital that particular protein is to survival.

Mutations can happen in enzyme-genes. When there is an enzyme-gene mutation and the enzyme that is produced by that gene can’t properly methylate (see below) the chemical or protein and many parts of the body can be affected. An example is the case of the MTHFRgene mutation (more on that later) that adversely affects metabolic pathways and biological processes which lead to problems in the body, including ulcerative colitis.

Mutations can happen in all the types of genes. There are many types of mutations that can happen within one gene pair. Methylation can be affected. Depending on the type of mutation, you can become a high methylator or a low methylator to different degrees.

18. Methylation: Methylation is a process where a specific group of atoms called a methyl group binds to a specific molecule to change it into what the cells need. Sometimes the methyl group is given to a molecule to make it easier for it to pass through the cell membrane. Sometimes it is given to create new methyl group to be used somewhere else in the body. Sometimes it is given to create a new chemical to be used in our cells.

In the body, methylation occurs when a hydrogen atom is replaced by the methyl group and bound to the molecule. The methyl group can be bound to different kinds of molecules and turn them into different kinds of chemicals. An enzyme/protein that has the methyl group in it and gives it to a molecule or chemical is called a methyl donor.

Methylation is critical to life and without it we would die. Methylation changes molecules into substances that can be used by cells in the body. There are different kinds of methylations. There are different kinds of DNA methylations and different kinds of protein methylations. There are also promoter methylations. Methylation can occur in cells, genes, at promoter sites, and all over the body. Methylation can be involved in modification of heavy metals (such as copper), regulation of gene expression, regulation of protein function, and RNA (I am not getting RNA right now) metabolism.

Methylation reactions are essential for the detoxification, healing and functions in the body. Methylation is directly affected by how genes do their job. Methylation is catalyzed by enzymes. Enzyme-genes must function properly for proper methylation to occur. You can be a high methylator or a low methylator or just a normal methylator where everything methylates as it should. Most people with UC are low methylators.

20. MTHFR Enzyme: The MTHFR enzyme is a methyl donor for the methylation of the vitamin folate/B9 (folic acid). Specifically, this enzyme methylates 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate (methylated vitamin B9/folate/folic acid).

19. MTHFR Gene: The MTHFR gene is an enzyme-gene. It produces the enzyme called Methylenetetrahydrofolate reductase (MTHFR) (don’t be afraid of the name, it explains its atoms that it is made of and what it does) and provides instructions for methylating 5,10-methylenetetrahydrofolate (folate/folic acid/vitamin B9) to 5-methyltetrahydrofolate (methylated folate). The MTHFR gene, like other genes, can be mutated in many different ways causing different levels of methylation issues involving the lack of methylation of folate. The enzyme MTHFR that is produced by the MTHFR gene is kept in a special place in our cells.

MTHFR Gene Mutation: In this case of the MTHFR mutation proper methylation is not happening. Toxins and metals specifically copper build up. The inability to properly methylate folic acid cascades down to copper unbound landing in the colon causing a copper toxicity, causing larger spaces in the intestinal wall, (leaky gut syndrome) causing large particles of waste to escape into the blood stream, causing the white blood cells to go crazy trying to keep up, massive amounts of white blood cells are creating massive amounts of waste (metabolic waste with no or little cysteine to help because of the mutation) creating more white blood cells to attack their own waste because the liver can’t do it effectively because it is overloaded and the methionine and cysteine are not there to help because of the mutation, the body is out of whack and getting worse…. all because of a tiny little gene that can’t do it’s job correctly. Wow!

With a MTHFR gene mutation (discussed later) you will have to supplement B12, but not just any B12. With the MTHFR gene mutation your body can’t activate the B12 so giving yourself supplements of unactivated B12 (cyanocobalamin) will produce little or no results. Unactivated B12 is what is mostly sold over the counter in the drug stores. In a normal body “swallowing 500 micrograms of B12 in the over the counter form of cyanocobalamin can result in absorption of as little as 1.8 microgram”, so you can understand why, with the MTHFR mutation, you need to give your body B12 in the form of methycobalamin B12 (it’s activated form. A sublingual form of B12 is also good.

21. Methylated Folic Acid: Called 5-methyltetrahydrofolate. Notice the parts of the name, methyl, and folate. From the name you can tell it has a methyl group and came from folate. It is now a methyl donor itself. Not all chemical names let you know that they are methyl donors.

Methylated folate donates its methyl group to vitamin B12 that comes from the metabolized compound named Cyanocobalamin (un-methylated B12) found in foods and over the counter supplements.

 

22. Methylated B12: When methylated by methylated folic, B12 becomes methylcobalamin (notice the name with the methyl in it) and also adenosylcobalamin. To gain access to the body parts and cross cell membranes B12 must be in activated/methylated form.

B12 is critical in the synthesis (making) of DNA and red blood cells (which UC’ers need desperately because of the bleeding) and is vitally important in maintaining the health of the insulation covering (myelin sheath) that surrounds nerve cells. Protein depends upon B12 for proper cycling through the body (you now know how important that is).

Vitamin B12 cannot be synthesized (created) in the body. It has to be gotten from food or supplement. B12 is the most chemically complex of all the vitamins. Un-methylated Vitamin B12 is found in foods including meat (especially liver and shellfish), eggs, and milk products. Fortified breakfast cereals are a particularly valuable source of vitamin B12 for vegetarians and vegans.

If you have a mutated MTHFR gene, your methylation of B12 can be affected. The severity of your B12 deficiency depends on the type of mutation and how slowly you methylate it because of the mutation. B12 deficiency is the cause of several forms of anemia (a deficiency in red blood cells) including pernicious anemia. Lack of B12 can also be the underlying cause of depression and fatigue. Homocysteine(discussed later) levels are high in B12 deficiency. Irreversible nerve cell death can result in extreme cases. B12 deficiency is mentioned in studifes regarding auto-immune conditions of Alzheimer’s, UC, Chron’s, IBD, AIDS, multiple sclerosis, tinnitus, diabetic neuropathy. Studies show that once supplemented with folic acid and activated B12 and B6 these conditions can start to improve. Research is ongoing.

B12 donates its methyl group to Methionine.

23. Methionine is a sulfur containing essential amino acid and chelating (another way of breaking down) agent. It is the source of sulfur for numerous compounds in the body, including the amino acids cysteine and taurine. The body uses sulfur to influence hair follicles and promote healthy hair, skin, and nail growth. Sulfur also increases the liver’s production of lecithin (which reduces cholesterol), reduces liver fat, protects the kidneys, helps the body to excrete heavy metals, and reduces bladder irritation by regulating the formation of ammonia in the urine.

Methionine is a lipotropic—a nutrient that helps prevent fat accumulation in the liver, and helps detoxify metabolic wastes and toxins. The methionine derivative S-adenosyl methionine (SAM) serves as a methyl donor.

Methionine, needed to methylate homocysteine, is a It is the source of sulfur for numerous compounds in the body, including the amino acids cysteine and taurine. The body uses sulfur to influence hair follicles and promote healthy hair (some UC’ers are having trouble with hair falling out), skin, and nail growth. Sulfur also increases the liver’s production of lecithin (which reduces cholesterol), reduces liver fat, protects the kidneys, helps the body to excrete heavy metals (copper is a heavy metal), and reduces bladder irritation by regulating the formation of ammonia in the urine. Methionine is a lipotropic—a nutrient that helps prevent fat accumulation in the liver, and helps detoxify metabolic wastes (wastes produced by the body) and toxins.

24. 5-Methyltetrahydrofolate-homocysteine methyltransferase or (MTR) is an enzyme responsible for the production of methionine from homocysteine. MTR forms part of the S-adenosyl methionine cycle and is also called methionine synthase.

This reaction is required for the multistep process that converts the amino acid homocysteine to another amino acid, methionine. High levels of homocysteine are toxic to the body and have been associated with heart problems. Methionine is used in the body to make proteins and other important compounds.

A high content of 400mg of folic acid, 25mg of vitamin B6 and 1mg of B12 can lower Homocysteine levels. Sometimes just 5mg of folate treatment can lower the homocysteine levels. Or a daily prescription multiple vitamin can be taken for two months. Homocysteine levels should be checked prior to taking the vitamin.

Elevated blood levels of homocysteine (a sulfur-containing amino acid) have been linked to increased risk of premature coronary artery disease, stroke, and thromboembolism (venous blood clots), even among people who have normal cholesterol levels. Abnormal homocysteine levels appear to contribute to atherosclerosis. (3)

Homocysteine methylates cysteine.

25. Cysteine: Cysteine methylated from methionine is a sulfur based amino acid and does many things, one of which is to help the body absorb nutrients. Cysteine in methylated form is given to people with malabsobtion problems. Cysteine methylates gluthione.

26. Glutathione: Glutathione helps the liver get rid of waste. It is needed for detoxification (detox of heavy metals including copper) and methylates many other different molecules affecting other systems in the body. It is also an anti-oxidant. Lack of it causes lack of the body’s ability to heal properly, among other things.

Which brings us back to the copper toxicity. Without one of its supports, glutathione, the liver has trouble ridding itself of metals and toxins. Unbound copper builds up because of the Methylation issues that precede it.

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