SAMe - And other methyl donor molecules

(Pronounced "Sammy" / S-adenosyl methionine)

SAMe - Precursor to 3 main pathways

SAMe provides an IMPORTANT precursor molecule to 3 main pathways of all cellular metabolism: transmethylation, transulfuration, and aminopropylation.

-    A sufficiency of SAMe sustains their normal function - which depends on the daily availability of methionine obtained mainly from breakdown of dietary proteins or synthesized by the body (involving folate (methyl-tretrahydrofolate) and vitamin B-12).

SAMe - In Transmethylation

Without methylation, there is no life

SAMe donates a methyl group (CH3) to another molecule to make it bio-active

Produced by all living cells, SAMe serves an important biological function as a universal methyl donor in a multitude of cellular methylation reactions - other methyl donors include: folate, B12, TMG (Betaine), DMGand DMAE. Also, some vegetables (E.g. onions, garlic, beets) contain methyl donors

A methyl group (CH₃, a 4-atom appendage to the methione sulfur atom in SAMe) is donated to a neighbor molecule, to stimulate biochemical reactions that transform the recipient molecule into a bio-active substance -E.g. Methyl groups transferred from SAMe to certain phospholipids produce phosphatidylcholine. The presence or absence of this important lipid found in all cell membranes controls membrane accessibility to outside signals, and thus affects how cells react to outside stimuli.

SAMe functions as a donor of methyl groups in > 100 different reactions catalyzed by methlytransferase enzymes - Most cells contain numerous SAMe-dependent methyltransferases that can transfer the methyl group (CH₃) to the oxygen, nitrogen, or sulfur atoms of both small and large molecules. Cheng, 1999; Chang, 1996

Without methylation there is no life - occurring billions of times/second in the body:

-    Affects fetal development, brain function. Maloney, 2012; Morse, 2012

-    Regulates gene expression

-    Preserves the fatty cell membranes - the greater the amount of SAMe-produced phosphatidylcholine (via phospholipid methylation), the more fluid or less viscous the cell membrane, which may facilitate the lateral movement of proteins, such as receptors, within the lipid bilayer. Crews, 1982

-   SAMe serves as the methylating agent (donates methyl groups) in the synthesis of:

• Various hormones and neurotransmitters - including SEROTONIN,  MELATONIN, NOREPINEPHRINE (adrenaline),  EPINEPHRINE. DOPAMINE, and HISTAMINE;  SAMe is also an important cofactor in the conversion of  NOREPINEPHRINE (adrenaline) ➔  EPINEPHRINE. (see Appendix, label 3). In doubleblind, randomized clinical studies, it has been shown to:

• Reduce low mood symptoms  Pancheri, 2002; Papakostas, 2010

• Support cognitive function  Levkovitz, 2011

•   Above two studies also suggest that patients who do not adequately respond to attempts to modulate serotonin function may benefit greatly from methylation support by supplementing with SAMe

• DNA/RNA

• Protein

• Creatine (an important energy reservoir in muscle tissue)

• Phospholipids

Thus, methyl donors, such as SAMe enhance sleeping, mood, energy, wellbeing, alertness, and concentration.

Reference on SAMe methylation

SAMe - In transulfuration

SAMe is the precursor for synthesis of cysteine, glutathione and taurine in the transulfuration pathway;

SAMe - In aminopropylation

SAMe and arginine serve as precursor molecules to the aminopropylation pathway - which leads to the synthesis of polyaminesspermine, spermidine and putrescine, which are involved in the control of cell growth, gene expression, calcium homeostasis and neuron regeneration. They were also shown to have analgesic and anti-inflammatory properties. Herby, 1981; Oyanagui , 1984

This pathway, like transulfuration, also salvages and conserves methionine.

SAMe synthesis and metabolism

SAMe is synthesized in the body (mainly in the liver) - from methionine (an amino acid) catalyzed by the MAT enzyme (methionine S-adenosyltransferase) using ATP molecule

SAMe <=> methionine (an amino acid in protein-rich foods) - Body makes SAMe from methionine and then recycles it. Once a SAMe molecule loses its methyl group, it breaks down to form homocysteine, which is potentially toxic if it builds up within cells.

Several B vitamins (B6, B12 and folate) are required for:

(1) Transulfuration (requires B6) - Convert Homocysteine ➔  Glutathione (body's important ”in-house”antioxidant);

or (2) Remethylation (requires B12, folate) - "Remethylate" homocysteine ➔  (back into) Methionine.

Sitaram BR, Sitaram M, Traut M and CB Chapman. 1995. Neurochem 65: 1887-1894.

References

Cheng X, Blumenthal RM.  (1999) S-Adenosylmethionine-dependent methyltransferases: structures and functions. World Scientific Publication Co,

Chiang PK, Gordon RK, Tal J, et al. (1996) S-Adenosylmethionine and methylation. FASEB J 10:471-80.[Abstract]

Crews FT (1982) Effects of membrane fluidity on secretion and receptor stimulation. Psychopharmacol Bull. 18:135-43.[Medline]

Levkovitz, Y., Alpert, J.E., Brintz, C.E., Mischoulon, D., Papakostas, G.I. (2011). Effects of S-adenosylmethionine augmentation of serotonin-reuptake inhibitor antidepressants on cognitive symptoms of major depressive disorder. Eur Psychiatry, 136(3), 1174-8.

Herby O. (1981) Role of polyamines in the control of cell proliferation and differentiation. Differentiation:19:1-20.[Medline]

Maloney C.A., Hay S.M., Reid M.D., Duncan G., Nicol F., Sinclair K.D., Rees W.D. (2012). A methyl-deficient diet fed to rats during the pre- and peri-conception periods of development modifies the hepatic proteome in the adult offspring. Genes Nutr., Aug 21.

Morse N.L. (2012). Benefits of docosahexaenoic acid, folic acid, vitamin D and iodine on foetal and infant brain development and function following maternal supplementation during pregnancy and lactation. Nutrients, 4(7):799- 840

Oyanagui Y. (1984) Anti-inflammatory effects of polyamines in serotonin and carrageenan paw edemata—possible mechanism to increase vascular permeability inhibitory protein level which is regulated by glucocorticoids and superoxide radical. Agents Actions;14:228-37.[Medline]

Pancheri, P., Scapicchio, P., Chiaie, R.D. (2002). A double-blind, randomized parallel-group, efficacy and safety study of intramuscular S-adenosyl-L-methionine 1,4-butanedisulphonate

Papakostas, G.I., Mischoulon, D., Shyu, I., Alpert, J.E., Fava, M. (2010). S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. Am J Psychiatry, 167(8), 942-8.