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Methylation cycle hypothesis
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==Theory== [[File:One-carbon metabolism and the transsulfuration pathway.jpg|540px|right|frame|One-carbon metabolism and the transsulfuration pathway]] A methyl group is a carbon atom that is bonded to three hydrogen atoms. Therefore, the process of methylation is the addition of a CH3 group to a pre-existing chemical structure; and methyl donors are chemicals that can carry and then transfer methyl groups to other molecules. Methylation is important because the presence of methyl groups on a molecule can block or encourage certain chemical reactions, functioning as a switch with the potential to turn a biological process on or off. From a genetic standpoint, methylation can cause genes to either express, or become "silent". The methylation cycle is a series of chemical changes that occur in the body, the primary purpose of which is to regulate neurotransmitters, regulate genetic repair and expression, and generate energy-rich molecules such as [[adenosine triphosphate|ATP]]. Many other important biological cyclical processes intersect with the methylation cycle. The methylation cycle begins in the blood vessels with [[folate]] (B9) obtained from diet. When [[methylenetetrahydrofolate reductase]] (MTHFR) acts on folate, it picks up a methyl group, transforming into [[methyltetrahydrofolate]] (MTHF). MTHF is able to methylate homocysteine to methionine. [[L-methionine|Methionine]] becomes [[SAM]], a second methyl donor. SAM acts as a [[methyl donor]] for multiple chemicals in the body, including DNA and [[RNA]]. Therefore, methylation is crucial to the synthesis and repair of genetic material, as well as the epigenetic regulation of gene expression. The donation of SAM's methyl group reduces it to [[SAM-e]] (S-adenosylmethionine), which reforms homocysteine, and the cycle begins again.<ref name="Bhargava">{{Cite journal | last1 = Bhargava | first1 = S | authorlink1 = | last2 = Tyagi | first2 = SC | authorlink2 = | title = Nutriepigenetic regulation by folate–homocysteine–methionine axis: a review| journal = Mol Cell Biochem | volume = 387 | issue = 1 | pages = 55-6 | date = Feb 2014 | pmid = 24213682 | doi = 10.1007/s11010-013-1869-2}}</ref> Various [[B vitamin]]s act as cofactors for methylation, including [[Riboflavin|B2]] and [[Cobalamin|B12]]. If methylation is not working properly due to various [[B vitamin]] deficiencies, disease states, or genetic mishap, higher levels of homocysteine may result. [[Homocysteine]] is an inflammatory marker that may increase risk of [[thrombosis]] and [[endothelial dysfunction]], cause errors in vascular smooth muscle proliferation<ref name="Tanaka" /> and skeletal muscle metabolism <ref name="Bhargava" />, and contribute to heart disease.<ref name="Tanaka">{{Cite journal | last1 = Tanaka | first1 = T | authorlink1 = Toshiko Tanaka | last2 = Scheet | first2 = P | authorlink2 = Paul Scheet | last3 = Giusti | first3 = B | authorlink3 = Betti Giusti | last4 = Bandinelli | first4 = S | authorlink4 = Stefania Bandinelli | last5 = Piras | first5 = MG | authorlink5 = Maria Grazia Piras | last6 = Usala | first6 = G | authorlink6 = Gianluca Usala | last7 =Lai | first7 = S | authorlink7 = Sandra Lai | last8 =Mulas | first8 = A | authorlink8 = Antonella Mulas | last9 =Corsi | first9 = AM | authorlink9 = Anna Maria Corsi | last10 = Vestrini | first10 = A | authorlink10 = Anna Vestrini | last11 = Sofi | first11 = F | authorlink11 = Francesco Sofi | last12 = Gori | first12 = AM | authorlink12 = Anna Maria Gori | last13 = Abbate | first13 = R | authorlink13 = Rosanna Abbate | last14 = Guralnik | first14 = J | authorlink14 = Jack Guralnik | last15 = Singleton | first15 = A | authorlink15 = Andrew Singleton | last16 = Abecasis | first16 = GR | authorlink16 = Goncalo Abecasis | last17 = Schlessinger | first17 = D | authorlink17 = David Schlessinger | last18 = Uda | first18 = M | authorlink18 = Manuela Uda | last19 = Ferrucci | first19 = L | authorlink19 = Luigi Ferrucci | title = Genome-wide association study of vitamin B6, vitamin B12, folate, and homocysteine blood concentrations| journal = Am J Hum Genet | volume = 84 | issue = 5 | pages = 712 | date = May 2009 | pmid = 19303062 | doi = 10.1016/j.ajhg.2009.02.011 }}</ref> Poor methylation can negatively impact the body's ability to produce and regulate glutathione, produce high-energy molecules, regulate [[Neurotransmitter]]s, repair DNA, and convert [[serotonin]] to [[melatonin]].<ref name="Nathan2011">{{Cite web | last1 = Nathan | first1 = N | authorlink1 = Neil Nathan| title = A Simplified Methylation Protocol is Effective for the Treatment of Chronic Fatigue Syndrome and Fibromyalgia | website = ProHealth | date = May 11, 2011| url = http://www.prohealth.com/library/print.cfm?libid=16138 }}</ref> The methylation cycle hypothesis states that many if not all of the symptoms of CFS are caused by errors in the genes that regulate or have a strong impact on one-carbon metabolism, such as [[MTHFR]], [[Cystathionine beta synthase|CBS]], [[Dihydropteridine reductase|DHPR]], [[methionine synthase reductase|MTRR]], or [[monoamine_oxidase#MAO-A|MAO-A]]. Through knowledge obtained by their genetic [[SNP]]s, patients can address inconsistencies in their one-carbon metabolism by supplementing nutrients in which they are deficient, or that encourage bypassing problematic aspects of the cycle, such as folinic acid, in order to optimize the efficiency of the methylation and related cycles.<ref name="Yasko_2013">{{Citation | last1 = Yasko | first1 = Amy | authorlink1 = Amy Yasko | title = Your SIMPLIFIED Road Map to Health | journal = Neurological Research Institute | date = 2013 | url = https://www.knowyourgenetics.com/media/pdf/Simplified%20Protocol.pdf }}</ref>
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