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Physiological Reviews Oct 2012S-adenosylmethionine (AdoMet, also known as SAM and SAMe) is the principal biological methyl donor synthesized in all mammalian cells but most abundantly in the liver.... (Review)
Review
S-adenosylmethionine (AdoMet, also known as SAM and SAMe) is the principal biological methyl donor synthesized in all mammalian cells but most abundantly in the liver. Biosynthesis of AdoMet requires the enzyme methionine adenosyltransferase (MAT). In mammals, two genes, MAT1A that is largely expressed by normal liver and MAT2A that is expressed by all extrahepatic tissues, encode MAT. Patients with chronic liver disease have reduced MAT activity and AdoMet levels. Mice lacking Mat1a have reduced hepatic AdoMet levels and develop oxidative stress, steatohepatitis, and hepatocellular carcinoma (HCC). In these mice, several signaling pathways are abnormal that can contribute to HCC formation. However, injury and HCC also occur if hepatic AdoMet level is excessive chronically. This can result from inactive mutation of the enzyme glycine N-methyltransferase (GNMT). Children with GNMT mutation have elevated liver transaminases, and Gnmt knockout mice develop liver injury, fibrosis, and HCC. Thus a normal hepatic AdoMet level is necessary to maintain liver health and prevent injury and HCC. AdoMet is effective in cholestasis of pregnancy, and its role in other human liver diseases remains to be better defined. In experimental models, it is effective as a chemopreventive agent in HCC and perhaps other forms of cancer as well.
Topics: Animals; Humans; Liver; Liver Diseases; Liver Neoplasms; Methionine Adenosyltransferase; S-Adenosylmethionine
PubMed: 23073625
DOI: 10.1152/physrev.00047.2011 -
Cells Jan 2022Alterations of methionine cycle in steatohepatitis, cirrhosis, and hepatocellular carcinoma induce MAT1A decrease and MAT2A increase expressions with the consequent... (Review)
Review
Alterations of methionine cycle in steatohepatitis, cirrhosis, and hepatocellular carcinoma induce MAT1A decrease and MAT2A increase expressions with the consequent decrease of S-adenosyl-L-methionine (SAM). This causes non-alcoholic fatty liver disease (NAFLD). SAM administration antagonizes pathological conditions, including galactosamine, acetaminophen, and ethanol intoxications, characterized by decreased intracellular SAM. Positive therapeutic effects of SAM/vitamin E or SAM/ursodeoxycholic acid in animal models with NAFLD and intrahepatic cholestasis were not confirmed in humans. In in vitro experiments, SAM and betaine potentiate PegIFN-alpha-2a/2b plus ribavirin antiviral effects. SAM plus betaine improves early viral kinetics and increases interferon-stimulated gene expression in patients with viral hepatitis non-responders to pegIFNα/ribavirin. SAM prevents hepatic cirrhosis, induced by CCl4, inhibits experimental tumors growth and is proapoptotic for hepatocellular carcinoma and MCF-7 breast cancer cells. SAM plus Decitabine arrest cancer growth and potentiate doxorubicin effects on breast, head, and neck cancers. Furthermore, SAM enhances the antitumor effect of gemcitabine against pancreatic cancer cells, inhibits growth of human prostate cancer PC-3, colorectal cancer, and osteosarcoma LM-7 and MG-63 cell lines; increases genomic stability of SW480 cells. SAM reduces colorectal cancer progression and inhibits the proliferation of preneoplastic rat liver cells in vivo. The discrepancy between positive results of SAM treatment of experimental tumors and modest effects against human disease may depend on more advanced human disease stage at moment of diagnosis.
Topics: Animals; Antiviral Agents; Betaine; Carcinogenesis; Carcinoma, Hepatocellular; Cell Transformation, Neoplastic; Colorectal Neoplasms; Humans; Liver Neoplasms; Male; Methionine Adenosyltransferase; Non-alcoholic Fatty Liver Disease; Rats; Ribavirin; S-Adenosylmethionine
PubMed: 35159219
DOI: 10.3390/cells11030409 -
The Journal of Nutrition Jun 2006Methionine, cysteine, homocysteine, and taurine are the 4 common sulfur-containing amino acids, but only the first 2 are incorporated into proteins. Sulfur belongs to... (Review)
Review
Methionine, cysteine, homocysteine, and taurine are the 4 common sulfur-containing amino acids, but only the first 2 are incorporated into proteins. Sulfur belongs to the same group in the periodic table as oxygen but is much less electronegative. This difference accounts for some of the distinctive properties of the sulfur-containing amino acids. Methionine is the initiating amino acid in the synthesis of virtually all eukaryotic proteins; N-formylmethionine serves the same function in prokaryotes. Within proteins, many of the methionine residues are buried in the hydrophobic core, but some, which are exposed, are susceptible to oxidative damage. Cysteine, by virtue of its ability to form disulfide bonds, plays a crucial role in protein structure and in protein-folding pathways. Methionine metabolism begins with its activation to S-adenosylmethionine. This is a cofactor of extraordinary versatility, playing roles in methyl group transfer, 5'-deoxyadenosyl group transfer, polyamine synthesis, ethylene synthesis in plants, and many others. In animals, the great bulk of S-adenosylmethionine is used in methylation reactions. S-Adenosylhomocysteine, which is a product of these methyltransferases, gives rise to homocysteine. Homocysteine may be remethylated to methionine or converted to cysteine by the transsulfuration pathway. Methionine may also be metabolized by a transamination pathway. This pathway, which is significant only at high methionine concentrations, produces a number of toxic endproducts. Cysteine may be converted to such important products as glutathione and taurine. Taurine is present in many tissues at higher concentrations than any of the other amino acids. It is an essential nutrient for cats.
Topics: Allosteric Regulation; Amino Acids, Sulfur; Animals; Cysteine; Gene Expression Regulation; Homocysteine; Humans; Methionine; Proteins; S-Adenosylmethionine; Taurine
PubMed: 16702333
DOI: 10.1093/jn/136.6.1636S -
The Primary Care Companion For CNS... Jun 2020To assess the effects of the combination of SAMe (S-adenosylmethionine) 200 mg and Lactobacillus plantarum (L. plantarum) HEAL9 1 × 10⁹ CFU for the overall... (Randomized Controlled Trial)
Randomized Controlled Trial
Oral Administration of S-Adenosylmethionine (SAMe) and Lactobacillus Plantarum HEAL9 Improves the Mild-To-Moderate Symptoms of Depression: A Randomized, Double-Blind, Placebo-Controlled Study.
OBJECTIVE
To assess the effects of the combination of SAMe (S-adenosylmethionine) 200 mg and Lactobacillus plantarum (L. plantarum) HEAL9 1 × 10⁹ CFU for the overall symptomatology of mild-to-moderate depression.
METHODS
This 6-week randomized, double-blind, placebo-controlled study included subjects aged 18-60 years with mild-to-moderate depression (according to ICD-10 diagnostic criteria) recruited from September 17, 2018, to October 5, 2018. Difference between groups in change from baseline to treatment week 6 on the Zung Self-Rating Depression Scale (Z-SDS) was the primary outcome. Comparisons between groups in change from baseline to treatment week 2 of the Z-SDS and from baseline to treatment weeks 2 and 6 of other scales (related to insomnia, anxiety, irritable bowel syndrome, and health status) were also analyzed.
RESULTS
Ninety patients were randomized to SAMe plus L. plantarum HEAL9 (n = 46) or placebo (n = 44) groups. A greater reduction for the new combination compared to placebo was seen at treatment week 6 in the Z-SDS total score (P = .0165) and the core depression subdomain (P = .0247). A significant reduction in favor of the combination was shown at treatment week 2 for the Z-SDS total score (P = .0330), the cognitive and anxiety subdomains (P = .0133 and P = .0459, respectively), and the anxiety questionnaire (P = .0345). No treatment-related adverse events occurred.
CONCLUSIONS
Supplementation of SAMe and L. plantarum HEAL9 in adults with subthreshold or mild-to-moderate symptoms of depression resulted in fast and clinically relevant effects after 2 weeks. The combination was safe and significantly improved symptoms of depression, anxiety, and cognitive and somatic components. The effect of this novel product is independent from the severity of the symptoms unlike traditional antidepressants available on the market that have minimal benefits for subthreshold or mild-to-moderate symptoms.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT03932474.
Topics: Adolescent; Adult; Depression; Depressive Disorder; Dietary Supplements; Double-Blind Method; Drug Combinations; Female; Humans; Lactobacillus plantarum; Male; Middle Aged; Outcome Assessment, Health Care; Probiotics; S-Adenosylmethionine; Severity of Illness Index; Young Adult
PubMed: 32589828
DOI: 10.4088/PCC.19m02578 -
Chembiochem : a European Journal of... Sep 2022In this review the current state-of-the-art of S-adenosylmethionine (SAM)-dependent methyltransferases and SAM are evaluated. Their structural classification and... (Review)
Review
In this review the current state-of-the-art of S-adenosylmethionine (SAM)-dependent methyltransferases and SAM are evaluated. Their structural classification and diversity is introduced and key mechanistic aspects presented which are then detailed further. Then, catalytic SAM as a target for drugs, and approaches to utilise SAM as a cofactor in synthesis are introduced with different supply and regeneration approaches evaluated. The use of SAM analogues are also described. Finally O-, N-, C- and S-MTs, their synthetic applications and potential for compound diversification is given.
Topics: Methyltransferases; S-Adenosylmethionine
PubMed: 35691829
DOI: 10.1002/cbic.202200212 -
Blood Nov 2022Targeting altered tumor cell metabolism might provide an attractive opportunity for patients with acute myeloid leukemia (AML). An amino acid dropout screen on primary...
Targeting altered tumor cell metabolism might provide an attractive opportunity for patients with acute myeloid leukemia (AML). An amino acid dropout screen on primary leukemic stem cells and progenitor populations revealed a number of amino acid dependencies, of which methionine was one of the strongest. By using various metabolite rescue experiments, nuclear magnetic resonance-based metabolite quantifications and 13C-tracing, polysomal profiling, and chromatin immunoprecipitation sequencing, we identified that methionine is used predominantly for protein translation and to provide methyl groups to histones via S-adenosylmethionine for epigenetic marking. H3K36me3 was consistently the most heavily impacted mark following loss of methionine. Methionine depletion also reduced total RNA levels, enhanced apoptosis, and induced a cell cycle block. Reactive oxygen species levels were not increased following methionine depletion, and replacement of methionine with glutathione or N-acetylcysteine could not rescue phenotypes, excluding a role for methionine in controlling redox balance control in AML. Although considered to be an essential amino acid, methionine can be recycled from homocysteine. We uncovered that this is primarily performed by the enzyme methionine synthase and only when methionine availability becomes limiting. In vivo, dietary methionine starvation was not only tolerated by mice, but also significantly delayed both cell line and patient-derived AML progression. Finally, we show that inhibition of the H3K36-specific methyltransferase SETD2 phenocopies much of the cytotoxic effects of methionine depletion, providing a more targeted therapeutic approach. In conclusion, we show that methionine depletion is a vulnerability in AML that can be exploited therapeutically, and we provide mechanistic insight into how cells metabolize and recycle methionine.
Topics: Mice; Animals; Methionine; Leukemia, Myeloid, Acute; S-Adenosylmethionine; Histones; Racemethionine
PubMed: 35984907
DOI: 10.1182/blood.2022017575 -
Biomolecules Sep 2022Many viruses from the realm infecting eukaryotic hosts encode protein domains with sequence similarity to S-adenosylmethionine-dependent methyltransferases. These...
Many viruses from the realm infecting eukaryotic hosts encode protein domains with sequence similarity to S-adenosylmethionine-dependent methyltransferases. These protein domains are thought to be involved in methylation of the 5'-terminal cap structures in virus mRNAs. Some methyltransferase-like domains of are homologous to the widespread cellular FtsJ/RrmJ-like methyltransferases involved in modification of cellular RNAs; other methyltransferases, found in a subset of positive-strand RNA viruses, have been assigned to a separate "Sindbis-like" family; and coronavirus-specific Nsp13/14-like methyltransferases appeared to be different from both those classes. The representative structures of proteins from all three groups belong to a specific variety of the Rossmann fold with a seven-stranded β-sheet, but it was unclear whether this structural similarity extends to the level of conserved sequence signatures. Here I survey methyltransferases in and derive a joint sequence alignment model that covers all groups of virus methyltransferases and subsumes the previously defined conserved sequence motifs. Analysis of the spatial structures indicates that two highly conserved residues, a lysine and an aspartate, frequently contact a water molecule, which is located in the enzyme active center next to the methyl group of S-adenosylmethionine cofactor and could play a key role in the catalytic mechanism of the enzyme. Phylogenetic evidence indicates a likely origin of all methyltransferases of from cellular RrmJ-like enzymes and their rapid divergence with infrequent horizontal transfer between distantly related viruses.
Topics: Amino Acid Sequence; Aspartic Acid; Lysine; Methyltransferases; Phylogeny; S-Adenosylmethionine; Water
PubMed: 36139088
DOI: 10.3390/biom12091247 -
Methods in Enzymology 2018
Topics: Biocatalysis; Enzymes; Free Radicals; Protein Domains; S-Adenosylmethionine
PubMed: 30097107
DOI: 10.1016/S0076-6879(18)30276-3 -
Chemical Reviews Apr 2014
Review
Topics: Animals; Biocatalysis; Enzyme Activation; Enzymes; Free Radicals; Humans; Iron-Sulfur Proteins; S-Adenosylmethionine
PubMed: 24476342
DOI: 10.1021/cr4004709 -
Annals of Hepatology 2013Methionine is an essential amino acid that is metabolized mainly by the liver where it is converted to S-adenosylmethionine (SAMe) by the enzyme methionine... (Review)
Review
Methionine is an essential amino acid that is metabolized mainly by the liver where it is converted to S-adenosylmethionine (SAMe) by the enzyme methionine adenosyltransferase. Although all mammalian cells synthesize SAMe, the liver is where the bulk of SAMe is generated as it is the organ where about 50% of all dietary methionine is metabolized. SAMe is mainly needed for methylation of a large variety of substrates (DNA, proteins, lipids and many other small molecules) and polyamine synthesis, so if the concentration of SAMe falls below a certain level or rises too much the normal function of the liver will be also affected. There are physiological conditions that can affect the hepatic content of SAMe. Consequently, to control these fluctuations, the rate at which the liver both synthesizes and catabolizes SAMe is tightly regulated. In mice, failure to do this can lead to fatty liver disease and to the development of hepatocellular carcinoma (HCC). Therefore, maintaining SAMe homeostasis may be a therapeutic target in nonalcoholic steatohepatitis, alcoholic- and non-alcoholic liver cirrhosis, and for the chemoprevention of HCC formation.
Topics: Animals; Carcinoma, Hepatocellular; Fatty Liver; Homeostasis; Humans; Liver; Liver Cirrhosis, Alcoholic; Liver Diseases; Liver Neoplasms; Non-alcoholic Fatty Liver Disease; S-Adenosylmethionine
PubMed: 23396728
DOI: No ID Found