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.