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Methionine and Methylation: Chicken or the Egg

Methionine and Methylation: Chicken or the Egg

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Published by Dr. Amy Yasko

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Published by: Dr. Amy Yasko on Aug 28, 2011
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METHYLATION AS A GLOBALREGULATORY PROCESS
You may be familiar with some version of thepathway in Figure 1. It is an extremely simplifiedrepresentation of the intersection of threeimportant biochemical pathways, the methioninecycle (A), the transsulfuration pathway (B) and thefolate cycle (C). Many critical physiologic andneurologic functions are affected or facilitatedby these conjoined pathways. As a result, inspite of their complexity, their proper functioningis intimately related to optimal health andwellbeing. Imbalances in the products of thesepathways have been related to stroke, Downsyndrome, neural tube defects, cancer, and evenaggression and cognitive performance.One of the end results of this pathway systemis the production of methyl groups. They aregenerated in the methionine cycle. There aremany more substrates that are necessary forits functioning than are represented in Figure1. The term substrate is a general term for anyinitial substance involved in a chemical reaction.Essentially, it is a starting material, a materialthat needs to be present for the reaction to startand/or keep going. In an organic system, thesematerials can be amino acids, carbohydrates,lipids, vitamins, minerals, enzymes, cofactors,etc., in other words, any element or molecule thatis involved in the reaction.Methyl group production in the methioninecycle is intimately linked to other portions of thesystem, namely to folate and sulfate metabolism.These pathways cannot be isolated from oneanother. They supply each other with substratesand work together like gears, so if one cycle isn’tmoving in a progressive direction, the other twomay not be either. Neither are these pathwaysisolated from other biochemical processesin the body. Hence, the idea is for all three ofthese cycles to have the starting materials theyneed and enough of their various substratesto optimally produce their final end products,including methyl groups.Methyl group attachment to another molecule iscalled
methylation
. A methyl group is the structuredepicted in Figure 2. It is not that different from awater molecule. You are familiar with the idea ofH2O, two hydrogens with a single oxygen. Themethyl group is another small structure. It is threehydrogens and a carbon, like the carbon in coalor diamonds. In spite of its size, when a methylgroup attaches to or is detached from anothermolecule, it can produce significant changes inthe character or function of that molecule.DNA methylation, as depicted in Figure 3,is crucial for
epigenetic modification
of thegenome. This is a critical concept as yourgenetic make up cannot change, but epigeneticscan change. Epigenetics involves the way theenvironment impacts the molecules in your body,and the subsequent impact that those moleculeshave on your genes. Epigenetics is like a secondchance that allows the body to make changesto its genes. Epigenetics is involved in regulating
METHIONINE ANDMETHYLATION:CHICKEN OR THE EGG
BY NANCY MULLAN, MD AND AMY YASKO PHD, AMD, FAAIM
many cellular processes including embryonicdevelopment, genome transcription, andchromosome stability. The role of epigenetics isso crucial that it can make the difference betweenthe presence or absence of disease in otherwisegenetically identical twins.Epigenetic modifications produce changes ingene expression patterns that are lasting andinheritable, but that do not change the sequenceof the genes themselves. A growing number ofhuman diseases have been found to be associatedwith aberrant DNA methylation. For example,DNA methylation patterns are globally disruptedin cancer with genome-wide hypomethylationand gene specific hypermethylation eventsoccurring simultaneously in the same cell. Pro-oxidant conditions in the cellular environmentalso have significant epigenetic consequence.Examples of epigenetic modification are themethylation reactions that function to edit andrepair DNA. They may also perform a silencingfunction. At any time, 80% of the DNA in your
CAB
PurinesTHF
5,10Methylene THF5 MethylTHFMethionineSAMedUMPThymidinesynthesisadenosine
methylationDNA, RNAProtein Ipise
SAHcystasthionineHomocysteineAmmoniaCysteine & KBglutathionesulfitetaurinesulfate
Figure 1:
The interactions ofthe methionine cycle (A), thetranssulfuration pathway (B), and thefolate cycle (C) have an impact onthe function of many organ systems.
 
 
body should not be expressing. The attachmentof methyl groups to certain molecules in the DNAinactivates it. Methylation also silences viral DNA,keeping the virus from replicating, expressing, andmaking you ill with syndromes that range from acold or flu to cancer. Alternately, methylation canturn on genes that are normally inactive.Aside from the importance of methyl groupsin terms of epigenetics, they also play a directrole in a number of other functions in the body.The building blocks for DNA and RNA, purinesand pyrimidines, are produced by balanced andprogressive function of the methionine and folatecycles. Any reduced capacity for methylationand/or for purine and pyrimidine synthesis,reduces DNA and RNA production. This meansthat new cell synthesis may be impaired. For anorganism to live it must create new cells as fastas cells die. This requires that the body makemillions of cells every minute. Reduced capacityfor synthesis of DNA and RNA is a particularissue for cells, such as bone marrow cells,lymphocytes, erythrocytes, and some brain cells,that may normally have difficulties meeting theirneeds for these substrates. Intestinal mucosal cellsalso cannot make all of the building blocks theyneed and must be supplied.Stress and cell repair after injury alsoincreases the need for DNA and RNA, as doesimmune system activation. Poorly regulated andineffective immune cell responses may resultfrom insufficient DNA and RNA production.Antibodies meant to deal with foreign antigensmay cross react with your own cells. Alternately,your immune response may become hyperactiveand react excessively to an exogenous antigen,like peanuts or shellfish. Your response to foreignbodies may also become exaggerated. Besidesthese factors, methylation deactivates histamine,an amino acid intimately involved with theallergic response. If methyl group productionis compromised and histamine cannot bedeactivated, excessive allergic reactions result.Methylation also deactivates noradrenalin, aneurotransmitter associated with cortisol and thestress response.When you are startled and alerted fordanger, methylation activates adrenalin andincreases the activity of your sympathetic nervoussystem. When the threat is over, methylationinactivates adrenaline and increases theactivity of your parasympathetic nervous systemproducing relaxation. Because of its action onneurotransmitters, methylation impacts everyimportant organ function and system includingbalance, movement, blood pressure regulation,pulse rate, respiratory rate, gastrointestinal andurinary tract function. Methylation is necessaryfor the proper myelination of nerves, recoveryfrom anesthesia, and reducing blood levelsof homocysteine, a molecule associated withcardiovascular disease. It is also necessary formetal detoxification, cell membrane function, andenergy production.The management of methylation hasbeen an important focus in the alternativetherapeutics of psychiatric disorders. Becauseof its action on dopamine, norepinephrine andserotonin, methylation impacts mood, memory,concentration and sleep. Methylation has alsobeen carefully scrutinized by researchers andclinicians interested in autism and chronic fatiguesyndrome.
HOW METHYL GROUPSARE PRODUCED
The major source of methyl group production inthe body is the methionine cycle (Figure 4, cycleA). Methionine is an amino acid that comes fromprotein in your diet. It cannot be synthesizedin the body. It is the “first among equals” ofessential amino acids, those that must be in thediet because they cannot be synthesized in thebody. It has several important functions, andcells optimally will have an abundance of it. Anycondition that impairs digestion and absorption ofnutrients including poor quality diet and disordersof digestion and absorption, may result in lowlevels of this critical amino acid. Methioninecontains both a methyl and a sulfur group.The methyl group is important for methylationreactions and the sulfur for detoxification throughthe transsulfuration pathway (Figure 4, cycle B).Methionine acquires another simple molecule,an adenosyl group, which allows it to becomeS-adenosylmethionine (SAM). SAM is the body’smain methyl group donor. SAM gives up its methylgroup and becomes S-adenosylhomocysteine(SAH). Optimally, the cycle is going in itsprogressive direction, so SAH gives up itsadenosyl group and becomes homocysteine.Homocysteine then can use one of two pathwaysto acquire a methyl group again and becomemethionine. Methionine transits these pathways
Methyl group –CH3
HHH
C
CAB
PurinesTHF
5,10Methylene THF5 MethylTHFMethionineSAMedUMPThymidinesynthesisadenosine
methylationDNA, RNAProtein Ipise
SAHcystasthionineHomocysteineAmmoniaCysteine & KBglutathionesulfitetaurinesulfate
D
BHMTMTHFRMTR MTRRDMGTMG
Figure 4:
Methionine initiatesactivity in the metabolic pathwaythat produces methyl groups (cycleA). The transsulfuration pathway(B) is also represented, as are thefolate cycle (C) and the BHMTpathway (D).
Figure 3:
A methyl group bonding to cytosine,converting the molecule into 5-methyl-cytosine,may change the activity of the genome itself.
Figure 2:
A representation of the one-carbonthree-hydrogen methyl group CH3.
 
 
repeatedly to produce the optimal number ofmethyl groups for your body. This happensthousands of times a day in every functioningmethionine cycle. There should be functioningmethionine cycles in every cell in your body.The folate cycle (Figure 4, cycle C) is thesource for the methyl group that re-methylateshomocysteine back into methionine. When themethionine cycle moves in a clockwise direction,the folate cycle can move counterclockwise.Then tetrahydrofolate (THF) becomes 5,10methylenetetrahydrofolate (5,10 methylene THF).Optimally, 5,10 methylene THF is acted on bythe enzyme methylenetetrahydrofolate reductase(MTHFR) and becomes 5 methyltetrahydrofolate(5 methyl THF). It is 5 methyl THF that passes itsmethyl group to hydroxycobalamin, vitamin B12.Hydroxy B12 then becomes methyl B12 whichdonates its methyl group to homocysteine. Thisreaction is mediated by the enzyme methioninesynthase (MTR).
ENZYMES AND THEIR EXIGENCIES
Because the functions of methyl group productionand methylation are central to organ systems’function, MTR has been extensively studied.This enzyme is deactivated by many factors.It is profoundly sensitive to mercury. Extremelylow levels of mercury, nanogram levels, willcompletely inhibit MTR. How long MTR remainsinactive depends on the amount of mercurypresent and how efficient your body is at excretingit. Lead, cadmium, arsenic and aluminum will dothe same. Any condition that increases oxidativestress in the cell will inhibit MTR. If MTR becomesinactive, homocysteine may use a secondarypathway (Figure 4, pathway D) to go directlyto methionine. Or it may transit through thetranssulfuration pathway (Figure 4, pathway B),which then affects the production of an importantantioxidant, glutathione.When functioning optimally, the transsulfurationpathway generates glutathione (GSH). GSH isthe body’s main antioxidant and heavy metaldetoxification agent. Thus, the inactivationof MTR by pro-oxidant conditions mediatesincreased activity in the production of a significantantioxidant defense molecule. However helpfuloxidative inhibition of MTR may be for producingGSH, it reduces methyl group production andmethylation reactions which, as noted earlier,are critical. The function of the organism may benegatively impacted in many ways.There are two opposing reactions, oxidationwhich involves the loss of electrons, and reductionwhich involves their gain. The balance of thesetwo chemical processes is expressed in a ratiocalled the reduction/oxidation ratio, the redoxratio. Optimally, the redox ratio should behigh. The option of gaining electrons should beavailable. If a molecule loses electrons, it needsto be able to regain them. The loss of electrons,oxidation, is burning. Fire is oxidation. Firedestroys its substrates. There must be reducingagents, antioxidants, in the cell to protect itfrom pro-oxidants. Pro-oxidants unopposedby antioxidants cause oxidative stress whichthreatens the cell, its function, and perhaps theorganism. The cell and/or the organism maysuccumb and be destroyed.There are a number of redox pairs which canindicate the amount of oxidative stress affectingthe cell. The ratio of reduced glutathione (GSH)to oxidized glutathione (GSSH) is thought toreflect intracellular redox status. Extracellularredox status is measured by the ratio of cysteineto its oxidized form cystine. In addition to itsfunction in the methionine cycle, methionine isan active scavenger of pro-oxidants. The ratioof methionine to methionine oxide is anothergauge of intracellular redox status that alsogives information about methyl group productioncapacity.
GENETIC INFLUENCES ON METHYLGROUP PRODUCTION
Besides the fact that oxidizing conditions inhibitMTR, there are other ways in which enzymefunction in the methionine cycle can be disruptedand its ability to produce methyl groups impaired.Genes encode for the production of enzymes.Genes are made up of nucleotides, which codefor amino acid bases arranged in a specificorder. If the gene encodes a different amino acidsequence from the normal sequence, that mayaffect the function of the enzyme it produces. Theenzyme may not be affected at all, it may haveincreased activity, it may have reduced activity, orit may be totally inhibited by the change. Thereare two copies of each kind of gene in the cell’sgenetic material, the genome.The condition of having a different nucleotidebase from the one normally present at a particularlocation is called a SNP, a single nucleotidepolymorphism. The SNP can be present on oneor both of the genes. How much impact the SNPhas on enzyme function depends upon where theSNP occurs in the strand of genetic material, andwhether one or both genes have it. A SNP onthe MTR gene(s) may occur at position A2756C,which affects its activity and which makesincreased B12 supplementation important.The methionine cycle is also impactedby SNPs in the genes encoding for MTHFR(Figure 4, cycle C). A SNP at position C677Twill decrease the activity of the enzyme andreduce the amount of 5, 10 methylene THFthat becomes 5 methyl THF. 5 methyl THF iscritical for the remethylation of homocysteine,so this downregulating SNP is significant. Folinicacid, also called 5 formyltetrahydrofolate (5formyl THF), is the immediate precursor to 5,10methylene THF. Folinic acid is a form of folatefound in many supplements. Giving folinic acidwill not enhance methyl group production whenthis SNP is present. Supplementing 5 methyl THFitself makes this substrate available to MTR. Thereare genetic profiles which contraindicate thesupplementation of high levels of methyl groupdonating substrates. Optimal levels of methylgroup supplementation based on a particularindividual’s SNP profile can help determineappropriate supplementation.The MTHFR gene has another SNP locationat A1298C that impacts folate cycle function. ASNP at this location makes the gene insensitiveto regulation by SAM. Optimally, when theavailability of SAM is sufficient or high, theA1298C location functions to increase MTHFRenzyme activity in the clockwise direction. Thishas the impact of inducing retrograde functionin the methionine cycle reducing the amount ofSAM produced. When the gene is insensitiveto this regulatory input, clockwise function of thefolate cycle is impaired.One effect of this can be a reduction in theproduction of the neurotransmitters serotoninand dopamine. Tetrahydrobiopterin (BH4) isnecessary for the synthesis of both dopamineand serotonin. The A1298C mutation is reportedto reduce the amount of dihydrobiopterin (BH2)converting into tetrahydrobiopterin (BH4). Thelack of BH4 in turn can impact neurotransmitter
ere are two opposing reactions, oxidation which involves the loss of electrons,and reduction which involves their gain.
e balance of these two chemicalprocesses is expressed in a ratio called the reduction/oxidation ratio, the redoxratio. Optimally, the redox ratio should be high.
e option of gaining electronsshould be available. If a molecule loses electrons, it needs to be able to regain them.

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