To understand SAM-e a little further, SAM-e (S-Adenosyl methionine) is a cosubstrate involved in anabolic reactions such as methyl group transfers, transsulfuration, and aminopropylation. There are more than 40 methyl transfers from SAM-e that are known, to various substrates such as nucleic acids, proteins, lipids and secondary metabolites. SAM-e is made from adenosine triphosphate (ATP) and methionine by methionine adenosyltransferase. These transfers occur throughout the body, but most SAM-e is produced and consumed in the liver.

What does it all mean? The physiological role of SAMe

SAMe is an important, metabolically pleiotropic molecule that participates in multiple cellular reactions and influences numerous cellular functions. Biochemically, it participates in three types of reaction: transmethylation, transsulfuration and aminopropylation [22] and [23]. A comprehensive discussion of these metabolic pathways falls outside the scope of this review however, the key reactions will be briefly summarized.

SAMe is the principle methyl donor required for methylation of nucleic acids, phospholipids, histones, biogenic amines, and proteins [23]. In standard conditions, the majority of SAMe generated is used in transmethylation reactions (Fig. 1). Glycine-N-methyl transferase (GNMT; EC 2.1.1.20) is the most abundant methyltransferase in the liver and is also present in the exocrine pancreas and prostate. Irrespective of the specific enzyme mediating the reaction, a common product is S-adenosylhomocysteine (SAH). Clearance of SAH by conversion into homocysteine and adenosine in a reversible reaction catalysed by SAH hydrolase (EC 3.3.1.1) is essential as many SAMe-dependent methylation reactions are strongly inhibited by SAH accumulation.

Homocysteine lies at the intersection of the remethylation pathway and the transsulfuration pathway through which homocysteine may be processed to form the primary endogenous cellular antioxidant, glutathione (Fig. 1) [10]. In the former, homocysteine is remethylated by methionine synthase (MS; EC 2.1.1.13) in a process coupled to the folate cycle or betaine methyltransferase (BHMT; EC 2.1.1.5) to re-form methionine; although it should be noted that the role of BHMT is of much less significance in primates than in rodents [23]. Alternatively, the conversion of homocysteine to crystathionine by crystathionine β-synthase (CBS; EC 4.2.1.22) begins the transsulfuration pathway through which the methionine derived sulphur atom in SAMe is processed stepwise into cysteine and ultimately glutathione (Fig. 1). These pathways are autoregulated by hepatic SAMe concentration which acts as a potent inhibitor of MS and BHMT activity and an activator of CBS so that excess SAMe is preferentially partitioned into glutathione [24]. Folic acid and the co-factors vitamin B6 and B12 are required for functioning of MS, CBS, and BHMT, respectively, and so their availability will limit enzymatic activity and thus homocysteine levels and hepatic methionine handling (Fig. 1) [10]. SAMe is also the precursor for the synthesis of polyamines that are needed to preserve cell viability and proliferation. Here, SAMe is decarboxylated by SAMe decarboxylase (EC 4.1.1.50) and the aminopropyl group used to from polyamines including the biologically active metabolite 5’-methylthioadenosine (MTA). [13]

13. Anstee, Quentin M.; Day, Christopher P. (2012). “S-adenosylmethionine (SAMe) therapy in liver disease: A review of current evidence and clinical utility” (PDF). Journal of hepatology 57 (5): 1097–1109. doi:10.1016/j.jhep.2012.04.041. Retrieved 18 June 2014.

Some research, including multiple clinical trials, has indicated taking SAM-e on a regular basis may help in the following ways:

Anti-depression Studies

Despite the increasingly large array of antidepressants available to treat major depressive disorder, patients continue to experience relatively modest response and remission rates. In addition, patients may experience adverse side effects from pharmacotherapy that not only hinder treatment compliance and adherence but, in some cases, may also contribute to increased disability, patient suffering, morbidity, and mortality. In order to enhance treatment efficacy and tolerability, patients and clinicians have become increasingly interested in nonpharmaceutical supplements for treating depression. One of the best-studied of these supplements is S-adenosyl-L-methionine (SAM-e), a naturally occurring molecule present in all living cells and a major methyl group donor in the human body. Controlled trials have found SAM-e to be more efficacious than placebo and equal in efficacy to the tricyclic antidepressants for treating major depressive disorder (MDD) when administered parenterally (either intravenously or intramuscularly). Less evidence supports the use of oral SAM-e, although some trials have demonstrated its efficacy as well. In addition, there is a paucity of evidence examining whether oral forms of SAM-e can be safe, well tolerated, and efficacious when used as adjunctive treatment for antidepressant nonresponders with MDD. Although preliminary data suggest SAM-e may be useful as an adjunctive therapy to antidepressants, controlled studies are needed to confirm or refute these preliminary findings.

8. [Papakostas, GI (Nov 2002). “Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence”. Am J Clin Nutr. 76(5): 1158S–61S. doi:10.4088/JCP.8157su1c.04. PMID 19909689.]

Abstract

INTRODUCTION:

S-adenosyl-l-methionine (SAMe) is a naturally-occurring substance which is a major source of methyl groups in the brain.

MATERIAL AND METHODS:

We conducted a meta-analysis of the studies on SAMe to assess the efficacy of this compound in the treatment of depression compared with placebo and standard tricyclic antidepressants.

RESULTS:

Our meta-analysis showed a greater response rate with SAMe when compared with placebo, with a global effect size ranging from 17% to 38% depending on the definition of response, and an antidepressant effect comparable with that of standard tricyclic antidepressants.

CONCLUSION:

The efficacy of SAMe in treating depressive syndromes and disorders is superior with that of placebo and comparable to that of standard tricyclic antidepressants. Since SAMe is a naturally occurring compound with relatively few side-effects, it is a potentially important treatment for depression.

9. [Bressa, GM (1994). “S-adenosyl-l-methionine (SAMe) as antidepressant: meta-analysis of clinical studies”. Acta Neurol Scand Suppl. 154: 7–14. PMID 7941964.]

Methylation has been implicated in the etiology of psychiatric illness. Parenteral S-adenosylmethionine, a methyl group donor, has been shown to be an effective antidepressant. The authors studied the antidepressant effect of oral S-adenosylmethionine in a randomized, double-blind, placebo-controlled trial for 15 inpatients with major depression. The results suggest that oral S-adenosylmethionine is a safe, effective antidepressant with few side effects and a rapid onset of action… S-Adenosylmethionine may be useful for patients who cannot tolerate tricyclic anti-depressants. These findings support a role for methylation in the pathophysiology of depression.

11. a b Kagan, BL; Sultzer, DL; Rosenlicht, N; Gerner, RH (May 1, 1990). “Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial”. Am J Psychiatry 147 (5): 591–5. doi:10.1176/ajp.147.5.591. PMID 2183633. Retrieved 2007-02-16.

S-adenosyl-l-methionine (SAMe), a naturally occurring brain metabolite, has previously been found to be effective and tolerated well in parenteral form as a treatment of major depression. To explore the antidepressant potential of oral SAMe, we conducted an open trial in 20 outpatients with major depression, including those with (n = 9) and without (n = 11) prior history of antidepressant nonresponse. The group as a whole significantly improved with oral SAMe: 7 of 11 non-treatment-resistant and 2 of 9 treatment-resistant patients experienced full antidepressant response. Side effects were mild and transient.

12. [Rosenbaum, JF; Fava, M; Falk, WE; Pollack, MH; Cohen, LS; Cohen, BM; Zubenko, GS (May 1990). “The antidepressant potential of oral S-adenosyl-l-methionine”. Acta Psychiatrica Scandinavica 81 (5): 432–6. doi:10.1111/j.1600-0447.1990.tb05476.x. PMID 2113347.]

Osteoarthritis Studies

Abstract

Background

S-Adenosylmethionine (SAMe) is a dietary supplement used in the management of osteoarthritis (OA) symptoms. Studies evaluating SAMe in the management of OA have been limited to Non Steroidal Anti-inflammatory Drugs (NSAIDs) for comparison. The present study compares the effectiveness of SAMe to a cyclooxygenase-2 (COX-2) inhibitor (celecoxib) for pain control, functional improvement and to decrease side effects in people with osteoarthritis of the knee.

Methods

A randomized double-blind cross-over study, comparing SAMe (1200 mg) with celecoxib (Celebrex 200 mg) for 16 weeks to reduce pain associated with OA of the knee. Sixty-one adults diagnosed with OA of the knee were enrolled and 56 completed the study. Subjects were tested for pain, functional health, mood status, isometric joint function tests, and side effects.

Results

On the first month of Phase 1, celecoxib showed significantly more reduction in pain than SAMe (p = 0.024). By the second month of Phase 1, there was no significant difference between both groups (p < 0.01). The duration of treatment and the interaction of duration with type of treatment were statistically significant (ps ≤ 0.029). On most functional health measures both groups showed a notable improvement from baseline, however no significant difference between SAMe and celecoxib was observed. Isometric joint function tests appeared to be steadily improving over the entire study period regardless of treatment.

Conclusion

SAMe has a slower onset of action but is as effective as celecoxib in the management of symptoms of knee osteoarthritis. Longer studies are needed to evaluate the long-term effectiveness of SAMe and the optimal dose to be used. [21]

21. [Najm WI, Reinsch S, Hoehler F, Tobis JS, Harvey PW (February 2004). “S-Adenosyl methionine (SAMe) versus celecoxib for the treatment of osteoarthritis symptoms: A double-blind cross-over trial. ISRCTN36233495”. BMC Musculoskelet Disord 5: 6. doi:10.1186/1471-2474-5-6. PMC 387830. PMID 15102339.]

Abstract

OBJECTIVE:

We assessed the efficacy of S-adenosylmethionine (SAMe), a dietary supplement now available in the Unites States, compared with that of placebo or nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of osteoarthritis (OA).

STUDY DESIGN:

This was a meta-analysis of randomized controlled trials.

DATA SOURCES:

We identified randomized controlled trials of SAMe versus placebo or NSAIDS for the treatment of OA through computerized database searches and reference lists.

OUTCOMES MEASURED:

The outcomes considered were pain, functional limitation, and adverse effects.

RESULTS:

Eleven studies that met the inclusion criteria were weighted on the basis of precision and were combined for each outcome variable. When compared with placebo, SAMe is more effective in reducing functional limitation in patients with OA (effect size [ES] =.31; 95% confidence interval [CI],.099-.520), but not in reducing pain (ES =.22; 95% CI, -.247 to.693). This result, however, is based on only 2 studies. SAMe seems to be comparable with NSAIDs (pain: ES =.12; 95% CI, -.029 to.273; functional limitation: ES =.025; 95% CI, -.127 to.176). However, those treated with SAMe were less likely to report adverse effects than those receiving NSAIDs.

CONCLUSIONS:

SAMe appears to be as effective as NSAIDs in reducing pain and improving functional limitation in patients with OA without the adverse effects often associated with NSAID therapies. [XX]

XX [J Fam Pract. 2002 May;51(5):425-30. Safety and efficacy of S-adenosylmethionine (SAMe) for osteoarthritis. Soeken KL, Lee WL, Bausell RB, Agelli M, Berman BM.]

Liver Disease

Liver Disease

 

Summary

S-adenosyl-l-methionine (SAMe; AdoMet) is an important, metabolically pleiotropic molecule that participates in multiple cellular reactions as the precursor for the synthesis of glutathione and principle methyl donor required for methylation of nucleic acids, phospholipids, histones, biogenic amines, and proteins. SAMe synthesis is depressed in chronic liver disease and so there has been considerable interest in the utility of SAMe to ameliorate disease severity. Despite encouraging pre-clinical data confirming that SAMe depletion can exacerbate liver injury and supporting a hepatoprotective role for SAMe therapy, to date no large, high-quality randomized clinical trials have been performed that establish clinical utility in specific disease states. Here, we offer an in-depth review of the published scientific literature relating to the physiological and pathophysiological roles of SAMe and its therapeutic use in liver disease, critically assessing implications for clinical practice and offering recommendations for further research. [13]

13. [Anstee, Quentin M.; Day, Christopher P. (2012). “S-adenosylmethionine (SAMe) therapy in liver disease: A review of current evidence and clinical utility” (PDF). Journal of hepatology 57 (5): 1097–1109. doi:10.1016/j.jhep.2012.04.041. Retrieved 18 June 2014.]

Alzheimer’s and Cognitive Studies

Abstract

Cerebrospinal fluid (CSF) S-adenosylmethionine (SAM) levels were significantly lower in severely depressed patients than in a neurological control group. The administration of SAM either intravenously or orally is associated with a significant rise of CSF SAM, indicating that it crosses the blood-brain barrier in humans. These observations provide a rational basis for the antidepressant effect of SAM, which has been confirmed in several countries. CSF SAM levels were low in a group of patients with Alzheimer’s dementia suggesting a possible disturbance of methylation in such patients and the need for trials of SAM treatment. [16]

16. Bottiglieri T, Godfrey P, Flynn T, Carney MW, Toone BK, Reynolds EH (1990). “Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine”. J Neurol Neurosurg Psychiatry 53 (12): 1096–8. doi:10.1136/jnnp.53.12.1096. PMC 488323. PMID 2292704.

Alzheimer’s disease and epigenetics

Alzheimer’s disease (AD) is an age-related and slowly neurodegenerative disorder of the brain and the most common form of dementia in the elderly (Sezgin and Dincer, 2014). The disease is clinically characterized by progressive memory loss and cognitive impairment. Moreover, the histopathological features of AD are senile plaques composed of amyloid beta (Aβ) fibrils and neurofibrillary tangles composed of microtubule-associated protein tau, combined with massive cholinergic neuronal loss, mainly in the hippocampus and association regions of neocortex (Hardy, 2006; Ballatore et al., 2007). This disease currently affects approximately 2% of the population in industrialized countries and its incidence will increase dramatically over the time (Sezgin and Dincer, 2014).

AD is a multifactorial disease involving; genetic, metabolic, nutritional, environmental and social factors that are associated with onset and progression of the pathology. For this reason, and considering that the main risk factor of this disorder is aging, it is reasonable to think that life history such hypertension, diabetes, inflammation, obesity or head injury are closely related with AD (Marques et al., 2011). However, how these factors induce epigenetic changes that mediate the network genes involved in this disease is a question that remains to be answered.

At present, studies of epigenetic changes in AD are starting to emerge. As we mentioned before, aging is the most important risk factor for AD an epigenetic changes have been observed in aging tissues. Recently, it has been observed that environmental factors even transient ones in early life can induce AD-like pathogenesis in association with aging (Wu et al., 2008a). Furthermore, a difference in DNA methylation patterns typical of brain region and aging has been identified in this context (Balazs, 2014). In this regard, a recent study by Hernandez et al. examined the DNA methylation patterns in >27,000 CpG sites from donors ranging in age 4 months to 102 years and a strong relationship was found between DNA methylation and aging. Moreover, in the temporal and frontal cortices pons and cerebellum regions, more than 1,000 associations were found between DNA methylation at CpG sites and age and some associations were significant in all four regions. Interestingly, the majority of the association sites were in CpG islands and the pattern was similar in the frontal cortex, temporal cortex and pons, but different in cerebellum. These results suggest that and age-dependent increase in DNA methylation may be important for maintaining gene expression with age (Hernandez et al., 2011).

As it has been reported in many studies, memory can be compromised during aging. Preclinical and basic studies have shown that epigenetic mechanisms are involved in formation and maintenance of memory (for reviews, see Levenson and Sweatt, 2005; Zovkic et al., 2013; Jarome et al., 2014). For example, inhibition of DNA methylation has deleterious effects on neuronal plasticity together with histone modifications (Day and Sweatt, 2011; Zovkic et al., 2013). Moreover, it has been observed that associative learning was impaired in 16-month-old mice compared with that of 3-month-old mice which was associated with specific reduction in acetylation of H4K12 (Peleg et al., 2010).

Until now, most of the studies have analyzed DNA methylation in the brain of AD patients (Balazs, 2014). In this regard, a variety of studies suggest a genome-wide decrease in DNA methylation present in aging and AD patients (Table ​(Table2;2; Mastroeni et al., 2011). Interestingly, the folate/methionine metabolism is critically linked with DNA methylation mechanisms, consistently with this fact; studies show that folate and S-adenosyl methionine are significantly decreased in AD (Bottiglieri et al., 1990; Morrison et al., 1996). All this data indicates that AD patients produce a hypomethylation across the DNA genome. Recently, Bakulski et al. provided a semi-unbiased, quantitative, genome-wide localization of DNA epigenetic differences in frontal cortex of control and AD cases. These authors determined DNA methylation of 27, 587 CpG sites spanning 14,475 genes. Interestingly, they found that in control samples, the methylation state is markedly affected by age, with about the same number of sites being hypermethylated as hypomethylated with age. Compared with controls, 6% of genes featured on the array were differentially methylated in AD samples, but the mean difference was relatively modest (2.9%). Gene ontology analysis revealed a relationship between the main disease-specific methylation loci and several molecular functions and biological processes, including hypermethylation of genes involved in transcription and DNA replication, while membrane transporters were hypomethylated (Bakulski et al., 2012). [17]

17. Morrison LD, Smith DD, Kish SJ (1996). “Brain S-adenosylmethionine levels are severely decreased in Alzheimer’s disease”. J Neurochem. 67 (3): 1328–31. doi:10.1046/j.1471-4159.1996.67031328.x. PMID 8752143.

 

Abstract

A chemoenzymatic platform for the synthesis of S-adenosyl-L-methionine (SAM) analogues compatible with downstream SAM-utilizing enzymes is reported. Forty-four non-native S/Se-alkylated Met analogues were synthesized and applied to probing the substrate specificity of five diverse methionine adenosyltransferases (MATs). Human MAT II was among the most permissive of the MATs analyzed and enabled the chemoenzymatic synthesis of 29 non-native SAM analogues. As a proof of concept for the feasibility of natural product “alkylrandomization”, a small set of differentially-alkylated indolocarbazole analogues was generated by using a coupled hMAT2-RebM system (RebM is the sugar C4′-O-methyltransferase that is involved in rebeccamycin biosynthesis). The ability to couple SAM synthesis and utilization in a single vessel circumvents issues associated with the rapid decomposition of SAM analogues and thereby opens the door for the further interrogation of a wide range of SAM utilizing enzymes. [20]

20. Singh, S; Zhang, J; Huber, TD; Sunkara, M; Hurley, K; Goff, RD; Wang, G; Zhang, W; Liu, C; Rohr, J; Van Lanen, SG; Morris, AJ; Thorson, JS (7 April 2014). “Facile chemoenzymatic strategies for the synthesis and utilization of S-adenosyl-(L)-methionine analogues.”. Angewandte Chemie International Edition in English 53 (15): 3965–9. doi:10.1002/anie.201308272. PMID 24616228.

 

8. Papakostas, GI (Nov 2002). “Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence”. Am J Clin Nutr. 76(5): 1158S–61S. doi:10.4088/JCP.8157su1c.04. PMID 19909689.
9. Bressa, GM (1994). “S-adenosyl-l-methionine (SAMe) as antidepressant: meta-analysis of clinical studies”. Acta Neurol Scand Suppl. 154: 7–14. PMID 7941964.
10. a b Kagan, BL; Sultzer, DL; Rosenlicht, N; Gerner, RH (May 1, 1990). “Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial”. Am J Psychiatry 147 (5): 591–5. doi:10.1176/ajp.147.5.591. PMID 2183633. Retrieved 2007-02-16.
11. Rosenbaum, JF; Fava, M; Falk, WE; Pollack, MH; Cohen, LS; Cohen, BM; Zubenko, GS (May 1990). “The antidepressant potential of oral S-adenosyl-l-methionine”. Acta Psychiatrica Scandinavica 81 (5): 432–6. doi:10.1111/j.1600-0447.1990.tb05476.x. PMID 2113347.
12. Anstee, Quentin M.; Day, Christopher P. (2012). “S-adenosylmethionine (SAMe) therapy in liver disease: A review of current evidence and clinical utility” (PDF). Journal of hepatology 57 (5): 1097–1109. doi:10.1016/j.jhep.2012.04.041. Retrieved 18 June 2014.
13. Bottiglieri T, Godfrey P, Flynn T, Carney MW, Toone BK, Reynolds EH (1990). “Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine”. J Neurol Neurosurg Psychiatry 53 (12): 1096–8. doi:10.1136/jnnp.53.12.1096. PMC 488323. PMID 2292704.
14. Morrison LD, Smith DD, Kish SJ (1996). “Brain S-adenosylmethionine levels are severely decreased in Alzheimer’s disease”. J Neurochem. 67 (3): 1328–31. doi:10.1046/j.1471-4159.1996.67031328.x. PMID 8752143.
15. Singh, S; Zhang, J; Huber, TD; Sunkara, M; Hurley, K; Goff, RD; Wang, G; Zhang, W; Liu, C; Rohr, J; Van Lanen, SG; Morris, AJ; Thorson, JS (7 April 2014). “Facile chemoenzymatic strategies for the synthesis and utilization of S-adenosyl-(L)-methionine analogues.”. Angewandte Chemie International Edition in English 53 (15): 3965–9. doi:10.1002/anie.201308272. PMID 24616228.
16. a b c d Najm WI, Reinsch S, Hoehler F, Tobis JS, Harvey PW (February 2004). “S-Adenosyl methionine (SAMe) versus celecoxib for the treatment of osteoarthritis symptoms: A double-blind cross-over trial. ISRCTN36233495”. BMC Musculoskelet Disord 5: 6. doi:10.1186/1471-2474-5-6. PMC 387830. PMID 15102339.
17. a b c “S-Adenosylmethionine (SAMe)”. University of Maryland Medical Center. 2004. Retrieved 2009-11-09.
18. Thompson MA, Bauer BA, Loehrer LL, et al. (May 2009). “Dietary supplement S-adenosyl-L-methionine (AdoMet) effects on plasma homocysteine levels in healthy human subjects: a double-blind, placebo-controlled, randomized clinical trial”. J Altern Complement Med 15 (5): 523–9. doi:10.1089/acm.2008.0402. PMC 2875864. PMID 19422296.
19. Mischoulon, D; Fava, M (November 2002). “Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence” (PDF). Am J Clin Nutr 76 (5): 1158S–61S. PMID 12420702. Retrieved 2006-12-07.
20. Janicak PG, Lipinski J, Davis JM, Altman E, Sharma RP (1989). “Parenteral S-adenosyl-methionine (SAMe) in depression: literature review and preliminary data”. Psychopharmacology bulletin 25 (2): 238–42. PMID 2690166.

 

 

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