Vitamin B12 Deficiency and Reduced Methylation

There are over 200 enzymes in the body involved in methylation
The major methyl donor for methylation is S-Adenosyl-Methionine (SAM).
Maintenance of methylation is critically dependent upon MethylCo(III)B12 and the enzyme methionine synthase (MTR)
The methylation cycle is also dependent upon two enzymes that require functional B2 sufficiency, MTHFR and MTRR
Maintenance of functional vitamin B12 requires functional B2 deficiency,
Lack of functional B2 in leads to functional B12 deficiency and a reduction in methylation activities
Functional Vitamin B2 deficiency can lead to functional B6 deficiency, exacerbating functional B12 deficiency
Functional Vitamin B2 deficiency and associated functional B12 deficiency, can lead to functional folate deficiency.
Reduced methylation has been associated with many conditions including dementia, Parkinson's disease, Autism, Chronic Fatigue Syndrome.
Methylation deficiency results in lower production of creatine, leading to problems with cognitive function, learning, memory, attention, speech and language.

Vitamin B12 and the Methylation cycle

Vitamin B12, or more specifically methylcobalamin (also known as Methyl B12 or more accurately MethylCo(III)B12) is an essential co-factor (helper) in maintaining the activity of the methylation cycle. There are approximately 200 methylation reactions in the body that depend upon S-Adenosylmethionine (SAM) as the methyl donor for these methylation reactions. Methylation using SAM as a cofactor is the second most important use of a cofactor after ATP (Ducker and Rabinowitz, 2017). Maintenance of sufficient SAM requires repeated regeneration of methionine from homocysteine, by the MethylCo(III)B12-dependent enzyme Methionine Synthase (MTR).

Homocysteine + MethylCo(III)B12-[MTR] => methionine + Co(I)B12-MTR.

In order to regenerate MethylCo(III)B12, from Co(I)B12 the enzyme MTR is able to use 5-Methyl-THF as the "methyl" donor, and so initiate the "back-reaction"

Co(I)B12-[MTR] + 5MTHF => MethylCo(III)B12-[MTR] + THF

The tetrahydrofolate (THF), so generated then proceeds into the folate cycle where it is used in a variety of reactions including the synthesis of purines, the conversion of Deoxyuridine to thymidine, or to the regeneration of 5MTHF for use in the methylation cycle. The first step in the pathway arguably starts with the reaction of serine with THF to form 5,10-methylene-THF plus glycine using the vitamin B6 dependent enzyme, Serine-hydroxymethyltransferase (SHMT). In functional vitamin B2 deficiency, due to Iodine or Selenium deficiency (see B2), there can be a deficiency in the active form of vitamin B6 - PLP, and so the initiation of methylation is reduced. It will also be reduced in dietary folate deficiency!

THF + Serine-[SHMT-PLP] => 5,10-methylene-THF + Gly-[SHMT-PLP]. (NB PLP is often referred to as Pyridoxal-5-Phosphate - P5P).

Note, that the sudden activation of SHMT by restoring active B2 (as FMN), which then can activate dietary vitamin B6, can greatly amplify methylation and so rapidly increase many methylation reactions, such as the production of adrenalin.

At this stage 5,10-methylene-THF is stuck or trapped within the folate cycle, and must be processed by the FAD/NADP-dependent enzyme Methylene Tetrahydrofolate reductase (MTHFR), which converts 5,10-methylene-THF to 5-methyl-THF (5MTHF). This reaction can be reduced or blocked in functional B2 deficiency, and can be greatly reduced by certain mutations in the gene MTHFR, leading to the formation of the MTHFR protein with much lower reaction rates.

5,10-methylene-THF-[MTHFR-FAD/NADPH] => 5MTHF- [MTHFR-FAD/NAD]

Methionine, either produced by methylation of homocysteine, or from dietary intake is then used as an acceptor of Adenosine to make the universal Methylation donor, S-Adenosylmethionine (SAM), which then is involved in over 200 methylation reactions in the body, including the methylation of DNA, histones, myelinbasic protein, lysine, and in the production of creatine, adrenalin, CoQ10 and melatonin.

If methylCo(III)B12 is deficient, the methylation cycle is slowed and there is an increase in the level of homocysteine, and a increased ratio of SAH:SAM. There is also a reduced production of melatonin and more importantly CoQ10 and creatine, leading to continual reduced energy output, with resultant fatigue (CFS) and developmental delay in children.

MTRR and oxidation of Co(II)B12

In the reaction Homocysteine + MethylCo(III)B12-[MTR] => methionine + Co(I)B12-MTR, if there is no incoming 5MTHF for the back-reaction, the Co(I)B12-MTR is rapidly oxidized to Co(II)B12 which cannot partake in methylation. The Co(II)B12 can be "rescued" by the enzyme methionine synthase reductase (MTRR) in combination with SAM. The enzyme requires both FMN and FAD as well as NADPH.

{MTRR-FMN/FAD/NADPH}Co(II)B12-MTR + SAM => {MTRR-FMN/FAD/NAD}Co(III)B12-MTR + SAH

Hence in functional vitamin B2 deficiency, there is both a decrease in the amount of 5MTHF that is produced by MTHFR, and as well there is a decreased activity of the enzyme MTRR, with the result that the amount of oxidized Co(II)B12 increases. This is subsequently released from MTR and MTRR and excreted from the cell, where it is rapidly bound by Haptocorrin, thereby contributing to an increase in circulating inactive Co(II)B12-Haptocorin, and contributes to elevated serum B12 levels seen in Paradoxical B12 deficiency (see https://b12oils.com/paradoxical.htm ). Of note, the activity of methionine synthase is critically dependent upon the presence of active MTRR, as lack of MTRR per se, or the presence of inactive MTRR results in the rapid inactivation of MTR (Yamada et al, 2006).

Dietary deficiency of riboflavin, Iodine, Selenium and/or Molybdenum and Methylation

Activation of dietary or supplemental vitamin B2 (riboflavin) requires a series of activation steps involving Thyroid Stimulating Hormone (TSH), thyroid hormone (T4), deiodinated T4 - triiodothyronine (T3), activation of riboflavin to FMN and finally modification of FMN to form FAD. Hence dietary insufficiency of any of Iodine, Selenium, Molybdenum or Riboflavin will lead to reduced activity of two of the major enzymes involved in maintenance of Methyl Co(III)B12 activity, MTHFR and MTRR. Reduction in MTHFR activity due to functional vitamin B2 deficiency, causes 5,10-methylene-THF to be stuck or trapped within the folate cycle, and there is an increase in 5,10-methylene-THF and a reduction in 5MTHF (Nijoult etal, 2004). Deficiency in the activity of MTHFR, MTR, and MTRR in the neonate leads to poor feeding, failure to thrive, vomiting, developmental delay, cerebral atrophy, hypotonia, ataxia, nystagmus, neonatal seizures and can cause visual disturbances (Hoffmann and Kolker, 2013). Knock-out of MTHFR alone results in defects in brain development (Ducker and Robinowitz, 2017).

Vitamin B2 deficiency and vitamin B6 deficiency

The activation of vitamin B6 is dependent upon FMN, one of the active forms of vitamin B2. FMN acts as a cofactor for the enzyme pyridoxine 5'-phosphate oxidase, which is involved in the conversion of pyridoxine to Pyridoxamine-5'-phosphate, the active form of vitamin B6. Deficiency of riboflavin, Iodine and/or Selenium will thereby affect the ability to activate vitamin B6 (Jungert etal, 2020). This in turn will lead to reduced activity of Serine Hydroxy Methyl Transferase (SHMT), and then a reduced production of 5,10-methylene-THF, with resultant drop in formation of 5MTHF and reduced methylation.

Elevated Homocysteine

Functional MethylCo(III)B12 deficiency is commonly associated with elevated homocysteine, as the rescue reaction using MTR is reduced

Homocysteine + MethylCo(III)B12-MTR => methionine + Co(I)B12-MTR.

Elevated homocysteine has been associated with many conditions including neural tube defects, Impaired childhood cognition (autism), macular degeneration, stroke, depression and anxiety (Chung etal, 2017) and cognitive impairment in the elderly. The association though may not be causative, but rather reflect potential deficiencies in active B2 as well as a reduction in over 200 methylation reactions in the body.

Homocysteine sits at a fork in the methylation cycle. One fork goes to the regeneration of methionine via methionine synthase, and is dependent upon Methyl Co(III)B12, whilst the other fork goes to the sulphation cycle via the enzyme cystathione beta synthase (CBS), and cystathione gamma lyase (CGL), both of which are dependent upon heme iron and the active form of vitamin B6, P5P. Hence deficiency in the active form of B2, FMN, will lead to reduced production of P5P and hence lead to reduced activity of CBS and CGL, as well as reduced regeneration of Methyl Co(III)B12 and so lead to elevated homocysteine.

Genetics and Methylation

Mutations in genes coding for SHMT, MTHFR, MTRR, CBS, and MTR can all affect or reduce the rate of methylation. The effect on genetics is much higher in conditions of vitamin B6 deficiency (CBS, SHMT), vitamin B2 deficiency (MTHFR, MTRR) and vitamin B12 (MTR).

The importance of the folate and methylation cycles for Methylation

It is essential that the both the folate and methylation cycles are working optimally in order to satisfy daily methylation requirements. Hence to process the 1.5 gm of methionine per day that enters the methylation cycle (around 10mmoles) you would need to make 10 mmoles of methyl B12, to donate the methyl group to homocysteine, and regenerate methionine. However, the RDA for methylcobalamin is only around 1.34 ug/day or 1 nmol/day, so you need to cycle B12 10,000,000 times per day, this then would need the same amount of folate, but the RDA is only around 441 ug/day or 1 umol, so folate has to cycle 10,000 times per day, just to process the 1.5 gm of methionine once. Now if all of the methyl groups on methionine only went to make the bodys' creatine usage (1.3 gm per day), this might be sufficient, BUT, you use 2-3 times this amount of creatine, and production of creatine is only about 40% of all methylation, so you have to cycle methionine at least 5-10 times, so there has to be an extensive cycling of both folate and B12.This is assuming optimal function of SHMT (vitamin B6 dependent), MTHFR (vitamin B2/B3 dependent) and MTRR (vitamin B2/B3 dependent).

Memory, Learning and Methylation

Many studies have shown the importance of histone methylation, specifically H3K4- methylation, in learning and memory (Collins etal, 2019; Gupta et al, 2010; Parkel etal, 2013; Poon etal, 2020; Kennedy etal, 2016; Morris etal, Pirisoto etal, 2016), and that reduced methylation, such as is seen in autism (due to functional B2/B12 deficiency), and in dementia is associated with intellectual disability (Parkel etal, 2013). Methylation deficiency results in lower production of creatine, leading to problems with cognitive function, learning, memory, attention, speech and language (Kondo et al, 2011z; Martine et al, 2009; Stork and Renshaw, 2005; Wood et al, 2009; Yildiz-Yesiloglu and Ankerst, 2006; Young et al, 2009),

Methylation and Sleep Disorders

Synthesis of Melatonin from N-ActeylSerotonin by the enzyme Hydroxyindole-O-methyl Transferase (HIOMT). N-AcetylSerotonin-[HIOMT] + SAM => Melatonin=[HIOMT] + SAH. (Gallardo and Tamezzani 1975; Klein and Lines, 1969; Urry etal, 1972; Quay 1965;Kuwano and Takahashi, 1980; Yokim and Wallen 1975; )Deficiency in SAM leads to conditions such as poor sleep, poor maturation of the gut wall, and developmental delay due to lack of activation of neuronal stem cells and subsequent differentiation into myelin-producing oligodendrocytes in the brain. Sleep disorders are very common in those with functional B12 deficiency and are particularly prevalent in conditions such as autism (53-80%, Ballester etal, 2020) and dementia (Benca and Teodorescu., 2019'; Cipriani etal, 2015; Shenker and Sing, 2017). Despite the obvious role of methylation in the formation of melatonin, and its role in promotion of sleep, few researchers seem to understand this.

Melatonin and analogs that bind to the melatonin receptors are important because of their role in the management of depression, insomnia, epilepsy, Alzheimer�s disease (AD), diabetes, obesity, alopecia, migraine, cancer, and immune and cardiac disorders.

Methylation, melatonin and Gut Disorders

Maturation of the cells that line the Gastrointestinal Tract requires the action of Melatonin. Lack of melatonin production has been associated with reduced uptake of calcium from the gut (Carpentieri et al, 2014), as well as increased incidence of ulcerative colitis (Necefli etal, 2006; Tasdemir etl, 2013), and reduced production of a number of saccharidases including lactase, sucrase, glucoamylase, isomaltase, and maltase (Trotta etal, 2021; Li etal, 2017). Poor gut health is a feature of conditions such as ASD. Deficiency of Melatonin due to its role in maturation of the gut mucosa leads to IBS-like symptoms, and sensitivity to histamine, and can lead to MCAS. Deficiency of melatonin also results in reduced expression of the Divalent Metal Ion transporter, with reduction in uptake of ion such as calcium, magnesium, zinc, manganese and Strontium. Deficiencies of which are characteristic of both Autism and CFS. See https://b12oils.com/melatonin.htm

Methylation and Depression

Lack of methylation, leads to reduced synthesis of Melatonin. This then results in over-production of serotonin, which leads to symptoms such as depression, due to down-regulation of serotonin receptors. Subsequent treatment with SSRIs is common, however it is wrong. The treatment should be the resolution of the functional B12 deficiency,

Methylation and Anxiety

Lack of methylation, leads to reduced synthesis of adrenalin. This then results in over-production of dopamine and nor-adrenalin. Over-production of dopamine leads to the anxiety, which is common in conditions associated with vitamin B12 deficiency, such as autism, CFS, and dementia (Richdale etal, 2023).

Methylation, melatonin and Myelination in the brain

Maturation of neuronal stem cells requires the combined action of Melatonin and vitamin D. Lack of myelination has been associated with poor myelination in the brain, and developmental and mental delay in conditions such as ASD and in mental deterioration such as in dementia. Delayed myelination of Broca's area in the brain is associated with lack of development of articulated speech, a common feature of the Autism Spectrum Disorders (ASD).

Increase in homocysteine and reduction in Methylation with reducing levels of active B2.

Potential modelling of reduced activity of MTR/MTRR activity in reducing levels of active B2.

Common Methylation reactions

Synthesis of creatine by Guanidinoacetate-N-Methyl transferase (GNMT, GAMT) S-Adenosyl-L-methionine + Guanidinoacetate - [GAMT] => SAH + Creatine. Creatine is involved in the transfer of ATP from within the mitochondria into the cell. Lack of activity of the enzyme GAMT has been shown to give rise to many of the symptoms of autism. In addition lack of activity of GAMT leads to prolonged fatigue, similar to that in Chronic Fatigue Syndrome. Lack of activity of GNMT enzyme is associated with many symptoms associated with Autism and Alzheimer's Disease. In children GAMT deficiency can cause mental retardation, speech delay, seizures, behavioral changes, and movement disorders, including Muscular hypotonia, mild spasticity, and coordination disturbances (Longo etal, 2011; Pacheva etal, 2016; St�ckler et al, 1994; Mercimek-Mahmutoglu et al, 2006; Stockler-Ipsiroglu et al, 2014; Mercimek-Mahmutoglu et al 2014; O'Rourke et al, 2009; Ara�jo et al, 2005; Lion-Fran�ois et al, 2006; Mercimek-Mahmutoglu et al, 2009; Leuzzi et al, 2013 Schulze et al, 2006;Verbruggen et al 2007; Morris et al, 2007; Item etal, 2004). Lower levels of vitamin B12 have been found in the brains of children with autism, suggesting a strong causal relationship (Zhang etal, 2016). Supplementation of creatine + Guanidinoacetate was found to be superior for muscle performance than creatine alone, possibly reflecting better transport of guanidinoacetate than creatine. Subjects were, however, functionally sufficient in vitamin B12, the same effect would not be expected in those who are methylation deficient (Semeredi, 2019). Studies on brain supplementation have shown better activity with GAA, BUT, this was also in B12 replete individuals (Ostojic etal, 2016; 2017; 2018). Further it does not seem possible to load either muscle or brain with GAA (Ostojic etal, 2018)

Synthesis of Adrenalin from Nor-Adrenalin by the enzyme Phenylethanolamine-N-Methyl Transferase (PNMT). Noradrenalin-[PNMT] + SAM => Adrenalin-[PNMT] + SAH. Deficiency in SAM leads to adrenal fatigue

Inactivation of histamine by the enzyme Histamine-N-Methyl Transferase. Histamine-[HNMT] + SAM => N-methylhistamine + SAH. Deficiency in SAM leads to histamine intolerance and in extreme cases can lead to a condition mistakenly named Mast Cell Activation Syndrome.

Synthesis of Phospatidylcholine (PC) from phosphatidylethanolamine (PEA) by the enzyme phosphatidylethanolamine N-methyltransferase. Phosphatidylcholine is a precursor to the synthesis of choline, for production of acetylcholine (Vance et al, 1997)- Reduced Acetylcholine production is common in Alzheimer's disease and autism (Ferri etal, 2005; Stanciu etal, 2019; Grossberg, 2017; Perry 1988; Dumas and Newhouse, 2011; Bartus etal, 1982). Conversion of PC to PEA has been proposed as being one of the biggest users of SAM in the body (Ducker and Rabonowitz, 2017).

Aspartate-N-methyl transferase (DDNMT), which produces NMDA from D-Aspartate. NMDA is involved in memory and learning. Lack of methylation potentially would cause a reduced ability for memory and learning and early signs of dementia.

Methylation of catecholamines using Catecholamine-O-Methyltransferase (COMT). Inactivation of catecholamine neurotransmitters. COMT is also involved in the inactivation of estrogen, and steroid hormones. Reduced COMT activity has been associated with a range of conditions, including anxiety (Desbonnet etal, 2012), preeclampsia (Pertegal et al, 2016), and several cancers (Matos etal, 2016).

Formation of Carnitine, following trimethylation of lysine with SAM and N-Lysine-methyltransferase. This is the precursor for the synthesis of carnitine, an essential carrier for transport of long chain fatty acids into mitochondria.

Numerous other enzymes see N-methyltransferase - Wikipedia

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Methylating Enzymes

From Wikipeida N-methyltransferase - Wikipedia

N-methyltransferase may refer to: