S-Adenosyl methionine
Cantoni.G.L (1952) discovered S-adenosyl methionine through a reaction between ATP and Methionine with methionineadenosyl transferase as a catalyst. S- adenosyl methionine or SAMe is a compound that occurs naturally and it plays an important role in the metabolic processes of the body. SAMe is an important compound that occurs in all the types of tissues and fluids of the human body. The compound is produced endogenously from the amino acid methionine and Adenosine triphosphate or ATP.SAMe is an important donor of the methyl group that plays a key role in the enzymatic transmethylation reactions. These play an essential role in the biosynthesis of phospholipids and these phospholipids are important in maintaining the integrity of the cell membrane. (Najm.W.L,et.al, 2004)In the metabolic processes, it breaks down the compounds such as serotonin, dopamine, and melatonin. The compound shows its high activity with vitamin B12 and folate and the deficiency of these two vitamins reduce the activity of the compound. (Alpert JE, Mischoulon D, Nierenberg AA, Fava M,2000)
The biochemical pathway of SAMe includes methylation since the compound is the principal source of methyl groups in the body. Anssulfuration is a process where the SAMe forms S-adenosylhomocysteine that can be converted to stathionine and then to cysteine and SO4 that is donated to the other metabolic intermediates. Aminopropylation is a pathway where the SAMe plays a key role in synthesizing polyamines that can eventually form and recycle methionine. (Bottiglieri T S, 2002).
Synthesis of SAMe
SAMe is synthesized from the amino acid L-methionine and Adenosien triphosphate or ATP mediated by the enzyme adenosylmethionine synthetase through a metabolic pathway namely one carbon cycle, and this pathway requires adequate concentrations of folate and vitamin B12.(Mischoulon.D and Fava.M, 2002). SAMe is synthesized as a part of the multistep pathway in which includes vitamins folic acid and vitaminB12. The SAMe donates methyl groups for the reactions involved in the synthesis of the important neurotransmitters such as serotonin, norepinephrine, and dopamine.
Biological activity of SAMe
The SAMe compound is important for the survival and the function of the cell. It plays an important role in three cell functions that include transmethylation, transsulfuration, and the polyamine synthesis. In the transmethylation reaction, the methyl group of the SAMe is accepted by wide variety of substrates that include DNA, phospholipids, and proteins. These reactions interfere in a large spectrum of processes that range from gene expression to the fluidity of the membranes. In transsulfuration process, the sulfur atom of the SAMe is converted to cysteine through a series of reactions and the cysteine becomes the precursor for taurine and a major cellular anti-oxidant, glutathione. Polyamines are required for the normal growth of the cell. It is now evident that SAMe plays an important role in the major tissue functions of the body. This compound is investigated as a therauptic agent in the treatment of a variety of clinical disorders. (Shelly.C.Lu,2000). Being a methyl donor SAMe modifies various methyl transferases that can modify DNA, RNA, histones, and the other types of proteins. SAMe serves as a cofactor for the nucleases like the type 1 restriction enzyme ECOK 1 that cannot restrict DNA in the absence of SAM.
Therauptic uses of SAMe
Many research studies have shown that SAMe helps in relieving the pain due to arthritis and it also helps in the treatment of depression. Researchers have observed that there is some possibility of using SAMe in the treatment of fibromyalgia, liver disease and Alzheimers disease.
(S-adenosylmethionine, 2009). Some research results have shown that there is some relationship between the SAMe and the Parkinsons disease, migraine headaches. A significant relationship was found between the levels of SAMe in the normal persons and the persons with Parkinsons disease.(Cheng.H et.al,1997). Decreased levels of SAMe were observed in the patients with neurological disorders such as Alzheimers disease.
Isolation of the compound SAMe
There are research reports of the isolation of SAMe from the yeasts. The concentration of the sulfonium compound in the cells is increased by exposing them to methionine, this is further extracted with the perchloric acid, chromatography and the precipitation with the phosphotungstic acid yields the product. The product has no impurities as detected by the conventional methods. (Shelenk.F and Depalma.R.E, 1957).
Altnernative applications and the commercial availability of SAMe for its alternative applications
SAMe dictates the genetic processes such as replication, the fidelity of transcription and translation, mismatch repair, chromatin modeling, epigenetic modifications and imprinting, which are of great interest in the research aspects of cancer and aging. SAMe has the ability to bind to certain RNA structures namely riboswitches that are able to control transcription or translation, and by this way, the multiple gene expression can be regulated in a SAMe dependent manner and this opens up new avenues in gene control. One such example is the tetracycline dependent riboswitch that regulates the translation of reporter gene in yeast. The riboswitch responds to the tetracycline in the cell in a reversible manner. (Leonen.W.A.M, 2006). The subject of the alternative applications of SAMe is still in the research and the future research confirms its commercial applicability and availability.
Available forms of the compound
SAMe is available in enteric-coated tablets that are dependable, and stable in terms of the amount of the compound in the pills. It is suggested that the tablets should be stored in the cool and dry place but not in the refrigerator. The tablets should be kept in the blister pack.
Usage
The enteric-coated tablets are more readily absorbed by the body and are chemically stable for longer periods. The butanedisulfonate salts are preferred to the tosylate salts because of their stability and the bioavailability. (S-adenosyl methionine, 2009). The compound is best absorbed with empty stomach and it is effective when consumed with a plenty of water. It is the recommendation of the clinicians that the drug should be taken orally with vitamin B12, folic acid, methionine,
Side effects
The drug has potential side effects and it is advisable to consume it along with the dietary supplements under the supervision of a knowledgeable physician. The side effects include nausea, dry mouth, gas, diarrhea, headache, anxiety, and feeling of elation, restlessness and insomnia. The higher doses may cause mania and it is not recommended for the pregnant and breast feeding women. The people with bipolar disorder may worsen manic episodes with the consumption of SAMe.(SAMe,2009)
Structural activity studies of SAMe
The source of a diverse chemical groups used for the modification and the biosynthesis of almost every class of biomolecules is S-adenosyl methionine. A large class of S-adenosyl methionine-dependent methyltransferases mediate the transfer of the methyl group and researchers have focused their studies on their structure-function. SAMe binding proteins are about 22 distinct sequences of structural families of proteins that perform a variety of reactions. Some of these are ancient and some more have been invented later on in the evolution process. The known SAM-binding proteins belong to 15 families or folds, that comprise at least 20 more sequence families. 1- Rosamann fold, 2-Metsynthase activating domain, 3-Porphyrin C-methyl transferase , 4-SPOUT methyltransferase, 5-SET domain methyl transferase, 6- isoprenylcystiene carboxyl methyl transferase , 7-flourinating enzyme, 8- t-RNA ribosyltransferase isomerase (QueA), 9-SAM decarboxylase, 10- SAM-synthetase, 11-ACC synthase and DAPA synthase, 12- N-acyl-homoserine lactone synthase, 13- Met-repressor, 14-CBS-domain, 15-SAM-dependent radical. All these folds belong to a group four large structural classes(Murzin AG, et al,1995), eventhough there is a distinct excess of , and especially - folds. It is broad picture when fold classes and molecular functions are compared, where there is a complex interplay between the sequence divergence and functional convergence in the evolution of SAM-binding proteins and SAM-dependent molecular functions.
Toxic effects of SAMe
SAMe has many functions with regard to liver, that includes serving as a precursor for cystiene 1 of 3-aminoacids of glutathione the major physiologic mechanism against the oxidative stress. The accumulation of methionine because of decreased activity of the enzyme reduces the activity of SAM, which is responsible for liver disorders. This happens when there is a deficiency of nutritional supplements.(Charles.S.L,2002)
Summary and conclusions
Recent years have witnessed a surge of popularity for natural or alternative medications however, there is limited information on the effectiveness of these medicines. Research on the effectiveness of SAMe is better studied among the natural remedies. It is synthesized endogenously with the help of methionine and ATP, and being a methyl donor it is involved in the synthesis of the neurotransmitters in the brain. Researchers have postulated that the compound has some anti-depressant properties and the oral doses of around 200-1600mgd of it are more effective than placebo. In addition to this, the compound may also protect the body from the negative effects of the Alzheimers disease. When compared to the other anti-depressants, SAMe is supposed to be safe, tolerable with low side effects. It can be safely used as a dietary supplement along with the vitamins such as VitaminB12 and folate.
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