SAM

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Introduction

Discovered in 1952, S-Adenosyl-L-methionine (SAM) is formed from the essential amino acid methionine and adenosine triphosphate. SAM is ubiquitous in every living cell and functions as a donor of methyl groups in more than 100 reactions catalyzed by methyltransferase enzymes. SAM can also act as a precursor molecule in the aminopropylation and transsulfuration pathways. The native form of SAM is labile and degrades rapidly. In contrast, stable salts of SAM have been patented for their excellent properties. Among them, SAM in the form of toluenedisulfonate and 1,4-butanedisulfonate has been used in pharmaceutical development and preclinical and clinical studies have been conducted. Numerous studies have shown that SAM is effective in treating depression, osteoarthritis, and liver disease. It is worth mentioning that SAM has very favorable side effects, so SAM can be used as an alternative to standard medications.

SAM was marketed in the United States in 1993 as an over-the-counter supplement under the Dietary Supplement and Health Education Act. Before that, it was available in Italy starting since 1979, in Spain since 1985, and in Germany since 1989. Currently, research on SAM is mainly focused on further understanding its biological importance and its impact on cellular metabolism and physiology.

Figure 1. The structure of SAM

Biological importance of SAM

SAM acts as a precursor molecule in the three pathways of methylation, transsulfuration and aminopropylation, which in turn occupies a central position in the metabolism of all cells. Therefore, in order to sustain the normal function of these pathways, it is necessary to ensure a sufficient source of SAM. The amount of SAM your body required each day depends on the amount of methionine (including methyltetrahydrofolate and vitamin B-12) that is produced de novo, as well as the methionine obtained from the breakdown of protein in the diet.

• Methylation

In the methylation reaction, SAM plays an important biological function as the sole methyl donor. Most cells contain a large number of SAM-dependent methyltransferases, which are responsible for transferring methyl groups (CH3) to oxygen, nitrogen or sulfur atoms of other molecules. Including the synthesis of epinephrine from norepinephrine, and the methylation of carboxyl residues of various proteins and cytosine residues of DNA, SAM is used as a methyl donor.

• Transsulfuration

The product of all SAM-dependent methylation reactions is S-adenosylhomocysteine. Subsequently, S-adenosylhomocysteine is rapidly metabolized to homocysteine, which may be converted to cystathionine in a reaction with vitamin B-6 as a cofactor. Alternatively, homocysteine can act as a methyl acceptor for betaine-homocysteine methyltransferase (EC 2.1.15) and methionine synthase (EC 2.1.1.13) reactions. During the reaction, most of the homocysteine skeleton is efficiently reused, e.g., methyl groups are conserved for an average of 1.9 turnovers in males and 1.5 turnovers in females.

• Aminopropylation

Another important role of SAM is in the synthesis of polyamines via the aminopropylation pathway. In this pathway, SAM is converted to decarboxylated SAM and the aminopropyl group is converted to putrescine, followed by the formation of the polyamines spermidine and spermine. Methylthioadenosine produced during this process is converted back to methionine. So this pathway is a salvage route that conserves methionine and also ensures rapid removal of methylthioadenosine.

Figure 2. Metabolism of S-adenosylmethionine (Bottiglieri, T. 2002)

Biochemical basis for the clinical use of SAM - Neurologic disorders

Several studies have shown that central nervous system methyl group deficiency may play an important role in the etiology of Alzheimer’s disease (AD). Reduced concentrations of SAM are found in the cerebrospinal fluid and several different regions of the brain of patients with AD. Also, decreased phosphatidylcholine concentrations were found in postmortem brain tissue of AD patients. Deficiencies of folate and vitamin B-12 are common in the elderly, which may lead to lower CNS SAM concentrations. In 3 independent studies, SAM concentrations were found to be reduced in the cerebrospinal fluid in HIV-infected patients. The reason for the decreased CSF SAM concentration in HIV-infected patients is currently unknown, but it has been suggested that the resulting methyl-group deficiency may be a pathogenic mechanism involved in the etiology of vacuolar myelopathy, which is often part of AIDS dementia. In addition, extensive research data demonstrate that cortical brain proteins are hypermethylated in HIV-positive patients.