S-Adenosyl methionine
Encyclopedia
S-Adenosyl methionine (SAM, SAMe, SAM-e) is a common cosubstrate involved in methyl group
Methyl group
Methyl group is a functional group derived from methane, containing one carbon atom bonded to three hydrogen atoms —CH3. The group is often abbreviated Me. Such hydrocarbon groups occur in many organic compounds. The methyl group can be found in three forms: anion, cation and radical. The anion...

 transfers. SAM was first discovered in Italy by G. L. Cantoni in 1952. It is made from adenosine triphosphate
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...

 (ATP) and methionine
Methionine
Methionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...

 by methionine adenosyltransferase
Methionine adenosyltransferase
Methionine adenosyltransferase is an enzyme which catalyses the synthesis of S-adenosylmethionine from methionine and ATP.-External links:...

 (EC 2.5.1.6). Transmethylation, transsulfuration, and aminopropylation are the metabolic pathway
Metabolic pathway
In biochemistry, metabolic pathways are series of chemical reactions occurring within a cell. In each pathway, a principal chemical is modified by a series of chemical reactions. Enzymes catalyze these reactions, and often require dietary minerals, vitamins, and other cofactors in order to function...

s that use SAM. Although these anabolic reactions occur throughout the body, most SAM is produced and consumed in the liver.

The methyl group (CH3) attached to the methionine sulfur atom in SAM is chemically reactive. This allows donation of this group to an acceptor substrate in transmethylation
Transmethylation
Transmethylation is a biologically important organic chemical reaction in which a methyl group is transferred from one compound to another.An example of transmethylation is the recovery of methionine from homocysteine. In order to sustain sufficient reaction rates during metabolic stress, this...

 reactions. More than 40 metabolic
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...

 reactions involve the transfer of a methyl group from SAM to various substrates, such as nucleic acid
Nucleic acid
Nucleic acids are biological molecules essential for life, and include DNA and RNA . Together with proteins, nucleic acids make up the most important macromolecules; each is found in abundance in all living things, where they function in encoding, transmitting and expressing genetic information...

s, protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

s, lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...

s and secondary metabolite
Secondary metabolite
Secondary metabolites are organic compounds that are not directly involved in the normal growth, development, or reproduction of an organism. Unlike primary metabolites, absence of secondary metabolities does not result in immediate death, but rather in long-term impairment of the organism's...

s.

In bacteria, SAM is bound by the SAM riboswitch
SAM riboswitch (S box leader)
The SAM riboswitch is found upstream of a number of genes which code for proteins involved in methionine or cysteine biosynthesis in Gram-positive bacteria. Two SAM riboswitches in Bacillus subtilis that were experimentally studied act at the level of transcription termination control...

, which regulates genes involved in methionine
Methionine
Methionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...

 or cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...

 biosynthesis.

SAM cycle

The reactions that produce, consume, and regenerate SAM are called the SAM cycle. In the first step of this cycle, the SAM-dependent methylase
Methylase
A methylase is an enzyme that attaches a methyl group to a molecule.These are found in prokaryotes and eukaryotes. Bacteria use methylase to differentiate between foreign genetic material and their own, thus protecting their DNA from their own immune system...

s (EC 2.1.1) that use SAM as a substrate produce S-adenosyl homocysteine as a product. This is hydrolysed to homocysteine
Homocysteine
Homocysteine is a non-protein amino acid with the formula HSCH2CH2CHCO2H. It is a homologue of the amino acid cysteine, differing by an additional methylene group. It is biosynthesized from methionine by the removal of its terminal Cε methyl group...

 and adenosine by S-adenosylhomocysteine hydrolase EC 3.3.1.1 and the homocysteine recycled back to methionine
Methionine
Methionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...

 through transfer of a methyl group from 5-methyltetrahydrofolate
5-Methyltetrahydrofolate
Levomefolic acid or metafolin is the natural, active form of folic acid used at the cellular level for DNA reproduction, the cysteine cycle and the regulation of homocysteine among other functions. The un-methylated form, folic acid , is a synthetic form of folate found in nutritional supplements...

, by one of the two classes of methionine synthases (i.e. cobalamin-dependent (EC 2.1.1.13) or cobalamin-independent (EC 2.1.1.14)). This methionine can then be converted back to SAM, completing the cycle.

Polyamine biosynthesis

Another major role of SAM is in polyamine
Polyamine
A polyamine is an organic compound having two or more primary amino groups .This class of compounds includes several synthetic substances that are important feedstocks for the chemical industry, such as ethylene diamine , 1,3-diaminopropane , and hexamethylenediamine...

 biosynthesis. Here, SAM is decarboxylated by adenosylmethionine decarboxylase
Adenosylmethionine decarboxylase
Adenosylmethionine decarboxylase is an enzyme that catalyzes the conversion of S-adenosyl methionine to S-adenosylmethioninamine.Polyamines such as spermidine and spermine are essential for cellular growth under most conditions, being implicated in a large number of cellular processes including...

 (EC 4.1.1.50) to form S-adenosylmethioninamine
S-Adenosylmethioninamine
S-Adenosylmethioninamine is a substrate that is involved in the biosynthesis of polyamines including spermidine, spermine, and thermospermine.- See also :* ACAULIS5* Adenosylmethionine decarboxylase...

. This compound then donates its n-propylamine group in the biosynthesis of polyamines such as spermidine
Spermidine
Spermidine is a polyamine involved in cellular metabolism. Its known actions include:#Inhibition of neuronal nitric oxide synthase, nNOS#Assisting the in vitro process of transcribing RNA via stimulation of T4 polynucleotide kinase and T7 RNA polymerase activity; it binds to and precipitates DNA...

 and spermine
Spermine
Spermine is a polyamine involved in cellular metabolism found in all eukaryotic cells. Formed from spermidine, it is found in a wide variety of organisms and tissues and is an essential growth factor in some bacteria. It is found as a polycation at physiological pH...

 from putrescine
Putrescine
Putrescine is a foul-smelling organic chemical compound NH24NH2 that is related to cadaverine; both are produced by the breakdown of amino acids in living and dead organisms and both are toxic in large doses...

.

SAM is required for cellular growth and repair. It is also involved in the biosynthesis of several hormones and neurotransmitters that affect mood, such as dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...

 and serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...

. Methyltransferase
Methyltransferase
A methyltransferase is a type of transferase enzyme that transfers a methyl group from a donor to an acceptor.Methylation often occurs on nucleic bases in DNA or amino acids in protein structures...

s are also responsible for the addition of methyl groups to the 2' hydroxyls of the first and second nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...

s next to the 5' cap in messenger RNA
Messenger RNA
Messenger RNA is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein...

.

Therapeutic uses

In the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...

 and Canada
Canada
Canada is a North American country consisting of ten provinces and three territories. Located in the northern part of the continent, it extends from the Atlantic Ocean in the east to the Pacific Ocean in the west, and northward into the Arctic Ocean...

, SAM is sold as a nutritional supplement
Dietary supplement
A dietary supplement, also known as food supplement or nutritional supplement, is a preparation intended to supplement the diet and provide nutrients, such as vitamins, minerals, fiber, fatty acids, or amino acids, that may be missing or may not be consumed in sufficient quantities in a person's diet...

 under the marketing name SAM-e (also spelled SAME or SAMe; pronounced "sam ee" or "Sammy"). SAM is also marketed under the Gumbaral, Samyr, Adomet, Heptral and Admethionine brand names as a prescription drug approved in Russia, Italy, and Germany. Some research, including multiple clinical trials, has indicated taking SAM on a regular basis may help fight depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...

, liver disease
Liver disease
Liver disease is a broad term describing any single number of diseases affecting the liver.-Diseases:* Hepatitis, inflammation of the liver, caused mainly by various viruses but also by some poisons , autoimmunity or hereditary conditions...

, and the pain of osteoarthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....

. All other indications are not yet proven.

Therapeutic use of SAM has increased in the US, as dietary supplements have gained in popularity, especially after the Dietary Supplement Health and Education Act was passed in 1994. This law allowed the distribution of SAM as a dietary supplement, and therefore allowed it to bypass the regulatory requirements for drugs of the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

 (FDA).

At first, a line of evidence suggested abnormally low levels of endogenous
Endogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...

 SAM may play an important role in the development of Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...

 (AD), and that SAM may therefore have therapeutic potential in the treatment of AD. However, further research has indicated this effect is likely due to vitamin B12
Vitamin B12
Vitamin B12, vitamin B12 or vitamin B-12, also called cobalamin, is a water-soluble vitamin with a key role in the normal functioning of the brain and nervous system, and for the formation of blood. It is one of the eight B vitamins...

 deficiencies, which result in neurologic defects due to the inability to conduct one carbon transfers (with folate) in the absence of B12. Severely low levels of SAM have been found in the cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...

 and in all brain regions of AD patients examined. Preliminary research suggests SAM may have therapeutic potential in treating AD patients and a recent study using a mouse model of AD found that supplementary SAM prevented oxidative damage and cognitive impairment.

Oral forms

Oral SAM achieves peak plasma concentrations three to five hours after ingestion of an enteric-coated tablet (400–1000 mg). The half-life is about 100 minutes. It may require up to one month for it to reach full effectiveness in treating osteoarthritis. Because of structural instability, stable salt forms of SAM are required for its use as an oral drug. The University of Maryland lists the commonly used salts: tosylate, butanedisulfonate, disulfate tosylate, disulfate ditosylate, and disulfate monotosylate.

With the advent of FDA-mandated good manufacturing practices (GMPs) in 2008, manufacturers are required to confirm their products contain what is listed on the label through the end of shelf life. Whether they achieve this goal or not has been questioned. This testing has shown that properly produced and packaged SAM has a shelf life in excess of three years; however, most manufacturers label for a two-year shelf life.

Claims that the SAM butanedisulfonate salt is more stable or better absorbed are not supported by the references usually cited as evidence. Different salts have successfully been used in clinical trials, but there is no published head-to-head comparison.

Usage

SAM is best absorbed on an empty stomach. Enteric-coated
Enteric coating
An enteric coating is a barrier applied to oral medication that controls the location in the digestive system, where it is absorbed. Enteric refers to the small intestine, therefore enteric coatings prevent release of medication before it reaches the small intestine.Most enteric coatings work by...

 tablets packaged in foil or foil blister packs increase stability and improve absorption. SAM should be stored in a cool, dry place to prevent deterioration.

Adverse effects

Gastrointestinal disorder, dyspepsia
Dyspepsia
Dyspepsia , also known as upset stomach or indigestion, refers to a condition of impaired digestion. It is a medical condition characterized by chronic or recurrent pain in the upper abdomen, upper abdominal fullness and feeling full earlier than expected when eating...

 and anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...

 can occur with SAM consumption. Long-term effects are unknown. SAM is a weak DNA-alkylating
Alkylation
Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion or a carbene . Alkylating agents are widely used in chemistry because the alkyl group is probably the most common group encountered in...

 agent.

Possible side effects

Once SAM donates its methyl group to choline, in the formation of creatine, carnitine, DNA, tRNA, norepinephrine, and other compounds, it is transformed into S-adenosyl-homocysteine, (SAH). Under normal circumstances, homocysteine
Homocysteine
Homocysteine is a non-protein amino acid with the formula HSCH2CH2CHCO2H. It is a homologue of the amino acid cysteine, differing by an additional methylene group. It is biosynthesized from methionine by the removal of its terminal Cε methyl group...

, in the presence of vitamin B6
Vitamin B6
Vitamin B6 is a water-soluble vitamin and is part of the vitamin B complex group. Several forms of the vitamin are known, but pyridoxal phosphate is the active form and is a cofactor in many reactions of amino acid metabolism, including transamination, deamination, and decarboxylation...

, vitamin B12
Vitamin B12
Vitamin B12, vitamin B12 or vitamin B-12, also called cobalamin, is a water-soluble vitamin with a key role in the normal functioning of the brain and nervous system, and for the formation of blood. It is one of the eight B vitamins...

, and folic acid
Folic acid
Folic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9...

 (SAM's main cofactors), will eventually be converted back into methionine, SAM, or cysteine, glutathione, and other useful substances. However, if adequate amounts of these vitamins are not present, SAM may not break down properly. As a consequence, its full benefits will not be obtained, and homocysteine
Homocysteine
Homocysteine is a non-protein amino acid with the formula HSCH2CH2CHCO2H. It is a homologue of the amino acid cysteine, differing by an additional methylene group. It is biosynthesized from methionine by the removal of its terminal Cε methyl group...

 may increase to unsafe levels. Small studies have not shown a consistent effect of SAM on homocysteine levels, but more research is needed.

High levels of homocysteine
Homocysteine
Homocysteine is a non-protein amino acid with the formula HSCH2CH2CHCO2H. It is a homologue of the amino acid cysteine, differing by an additional methylene group. It is biosynthesized from methionine by the removal of its terminal Cε methyl group...

 have been associated with atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...

 (hardening and narrowing of the arteries), as well as an increased risk of heart attacks, strokes, liver damage, and possibly Alzheimer's disease. Therefore, vitamin B supplements are often taken along with SAM. These vitamins help metabolize the homocysteine
Homocysteine
Homocysteine is a non-protein amino acid with the formula HSCH2CH2CHCO2H. It is a homologue of the amino acid cysteine, differing by an additional methylene group. It is biosynthesized from methionine by the removal of its terminal Cε methyl group...

 into other useful compounds.

Another reported side effect of SAM is insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...

; therefore, the supplement is often taken in the morning. Other reports of mild side effects include lack of appetite, constipation, nausea, dry mouth, sweating, and anxiety/nervousness, but in placebo-controlled studies, these side effects occur at about the same incidence in the placebo groups. Some users report increased anxiety with as little as 50 mg/day.

Therapeutic doses range from 400 mg/day to 1600 mg/day, although higher doses are used in some cases. Some physicians recommend even lower doses, ranging from 50 to 200 mg/day, to treat mild depression without triggering negative side effects.

Induction of mania

In an extensive MEDLINE search on SAM, Kagan found induction of mania
Mania
Mania, the presence of which is a criterion for certain psychiatric diagnoses, is a state of abnormally elevated or irritable mood, arousal, and/ or energy levels. In a sense, it is the opposite of depression...

 in one patient out of 15 treated with parenteral
Parenteral
Parenteral is a route of administration that involves piercing the skin or mucous membrane. Parenteral nutrition refers to providing nutrition via the veins.-Etymology:...

 SAM. In the same review, Lipinski found the apparent induction of mania in two patients with bipolar disorder (total of nine depressed patients studied). Both depression and mania can be life-threatening conditions that may cause cognitive dysfunction
Cognitive dysfunction
Cognitive dysfunction is defined as unusually poor mental function, associated with confusion, forgetfulness and difficulty concentrating...

 even after remission. There is concern that antidepressants in general can induce mania or hypomania
Hypomania
Hypomania is a mood state characterized by persistent and pervasive elevated or irritable mood, as well as thoughts and behaviors that are consistent with such a mood state...

 in bipolar persons.

Interactions and contraindications

  • SAM reduces insulin resistance
    Insulin resistance
    Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...

    . This may lead to hypoglycemia
    Hypoglycemia
    Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...

     when used with antidiabetic drugs.

External links

  • About.com SAM-e Resource Index at About.com
    About.com
    About.com is an online source for original information and advice. It is written in English, and is aimed primarily at North Americans. It is owned by The New York Times Company....

  • list of known SAM-e drug interactions and precautions in use at University of Maryland
    University of Maryland, Baltimore
    University of Maryland, Baltimore, was founded in 1807. It comprises some of the oldest professional schools in the nation and world. It is the original campus of the University System of Maryland. Located on 60 acres in downtown Baltimore, Maryland, it is part of the University System of Maryland...

    Medical Centers
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