-
Natural Product Reports Sep 2023Covering: from 2000 up to the very early part of 2023-Adenosyl-L-methionine (SAM) is a naturally occurring trialkyl sulfonium molecule that is typically associated with... (Review)
Review
Covering: from 2000 up to the very early part of 2023-Adenosyl-L-methionine (SAM) is a naturally occurring trialkyl sulfonium molecule that is typically associated with biological methyltransfer reactions. However, SAM is also known to donate methylene, aminocarboxypropyl, adenosyl and amino moieties during natural product biosynthetic reactions. The reaction scope is further expanded as SAM itself can be modified prior to the group transfer such that a SAM-derived carboxymethyl or aminopropyl moiety can also be transferred. Moreover, the sulfonium cation in SAM has itself been found to be critical for several other enzymatic transformations. Thus, while many SAM-dependent enzymes are characterized by a methyltransferase fold, not all of them are necessarily methyltransferases. Furthermore, other SAM-dependent enzymes do not possess such a structural feature suggesting diversification along different evolutionary lineages. Despite the biological versatility of SAM, it nevertheless parallels the chemistry of sulfonium compounds used in organic synthesis. The question thus becomes how enzymes catalyze distinct transformations subtle differences in their active sites. This review summarizes recent advances in the discovery of novel SAM utilizing enzymes that rely on Lewis acid/base chemistry as opposed to radical mechanisms of catalysis. The examples are categorized based on the presence of a methyltransferase fold and the role played by SAM within the context of known sulfonium chemistry.
Topics: S-Adenosylmethionine; Methyltransferases; Catalysis
PubMed: 36891755
DOI: 10.1039/d2np00086e -
Wiley Interdisciplinary Reviews. RNA 2011Riboswitches are regulatory elements commonly found in the 5' leader sequences of bacterial mRNAs that bind cellular metabolites to direct expression at either the... (Review)
Review
Riboswitches are regulatory elements commonly found in the 5' leader sequences of bacterial mRNAs that bind cellular metabolites to direct expression at either the transcriptional or translational level. The effectors of these RNAs are chemically diverse, including nucleobases and nucleosides, amino acids, cofactors, and second messenger molecules. Over the last few years, a number of structures have revealed the architectural means by which RNA creates binding pockets of high affinity and specificity for these compounds. For most effectors, there is a single class of associated riboswitches. However, eight individual classes of S-adenosylmethionine (SAM) and/or S-adenosylhomocysteine (SAH) responsive riboswitches that control various aspects of sulfur metabolism have been validated, revealing a diverse set of solutions to the recognition of these ubiquitous metabolites. This review focuses upon the structures of RNAs that bind SAM and SAH and how they discriminate between these compounds.
Topics: Animals; Base Sequence; Binding Sites; Humans; Models, Biological; Models, Molecular; Nucleic Acid Conformation; Protein Binding; Riboswitch; S-Adenosylmethionine; Substrate Specificity
PubMed: 21957011
DOI: 10.1002/wrna.63 -
Communications Biology Apr 2022The global dietary supplement market is valued at over USD 100 billion. One popular dietary supplement, S-adenosylmethionine, is marketed to improve joints, liver health...
The global dietary supplement market is valued at over USD 100 billion. One popular dietary supplement, S-adenosylmethionine, is marketed to improve joints, liver health and emotional well-being in the US since 1999, and has been a prescription drug in Europe to treat depression and arthritis since 1975, but recent studies questioned its efficacy. In our body, S-adenosylmethionine is critical for the methylation of nucleic acids, proteins and many other targets. The marketing of SAM implies that more S-adenosylmethionine is better since it would stimulate methylations and improve health. Previously, we have shown that methylation reactions regulate biological rhythms in many organisms. Here, using biological rhythms to assess the effects of exogenous S-adenosylmethionine, we reveal that excess S-adenosylmethionine disrupts rhythms and, rather than promoting methylation, is catabolized to adenine and methylthioadenosine, toxic methylation inhibitors. These findings further our understanding of methyl metabolism and question the safety of S-adenosylmethionine as a supplement.
Topics: Adenine; Dietary Supplements; Liver; Methylation; S-Adenosylmethionine
PubMed: 35383287
DOI: 10.1038/s42003-022-03280-5 -
The Journal of Biological Chemistry Feb 2015S-Adenosylmethionine (SAM, also known as AdoMet) radical enzymes use SAM and a [4Fe-4S] cluster to catalyze a diverse array of reactions. They adopt a partial... (Review)
Review
S-Adenosylmethionine (SAM, also known as AdoMet) radical enzymes use SAM and a [4Fe-4S] cluster to catalyze a diverse array of reactions. They adopt a partial triose-phosphate isomerase (TIM) barrel fold with N- and C-terminal extensions that tailor the structure of the enzyme to its specific function. One extension, termed a SPASM domain, binds two auxiliary [4Fe-4S] clusters and is present within peptide-modifying enzymes. The first structure of a SPASM-containing enzyme, anaerobic sulfatase-maturating enzyme (anSME), revealed unexpected similarities to two non-SPASM proteins, butirosin biosynthetic enzyme 2-deoxy-scyllo-inosamine dehydrogenase (BtrN) and molybdenum cofactor biosynthetic enzyme (MoaA). The latter two enzymes bind one auxiliary cluster and exhibit a partial SPASM motif, coined a Twitch domain. Here we review the structure and function of auxiliary cluster domains within the SAM radical enzyme superfamily.
Topics: Animals; Coenzymes; Free Radicals; Humans; Iron-Sulfur Proteins; Metalloproteins; Methylation; Molybdenum Cofactors; Protein Methyltransferases; Protein Structure, Tertiary; Pteridines; S-Adenosylmethionine; Sulfatases; Triose-Phosphate Isomerase
PubMed: 25477505
DOI: 10.1074/jbc.R114.581249 -
ELife Feb 2023Methylation is a widely occurring modification that requires the methyl donor S-adenosylmethionine (SAM) and acts in regulation of gene expression and other processes....
Methylation is a widely occurring modification that requires the methyl donor S-adenosylmethionine (SAM) and acts in regulation of gene expression and other processes. SAM is synthesized from methionine, which is imported or generated through the 1-carbon cycle (1 CC). Alterations in 1 CC function have clear effects on lifespan and stress responses, but the wide distribution of this modification has made identification of specific mechanistic links difficult. Exploiting a dynamic stress-induced transcription model, we find that two SAM synthases in , SAMS-1 and SAMS-4 contribute differently to modification of H3K4me3, gene expression and survival. We find that enhances H3K4me3 in heat shocked animals lacking , however, cannot compensate for , which is required to survive heat stress. This suggests that the regulatory functions of SAM depend on its enzymatic source and that provisioning of SAM may be an important regulatory step linking 1 CC function to phenotypes in aging and stress.
Topics: Animals; S-Adenosylmethionine; Histones; Caenorhabditis elegans; Heat-Shock Response; Gene Expression
PubMed: 36756948
DOI: 10.7554/eLife.79511 -
Biochemistry Oct 2017Ribosomally synthesized and post-translationally modified peptides (RiPPs) display a diverse range of structures and continue to expand as a natural product class.... (Review)
Review
Ribosomally synthesized and post-translationally modified peptides (RiPPs) display a diverse range of structures and continue to expand as a natural product class. Accordingly, RiPPs exhibit a wide array of bioactivities, acting as broad and narrow spectrum growth suppressors, antidiabetics, and antinociception and anticancer agents. Because of these properties, and the complex repertoire of post-translational modifications (PTMs) that give rise to these molecules, RiPP biosynthesis has been intensely studied. RiPP biosynthesis often involves enzymes that perform unique chemistry with intriguing reaction mechanisms, which attract chemists and biochemists alike to study and re-engineer these pathways. One particular type of RiPP biosynthetic enzyme is the so-called radical S-adenosylmethionine (rSAM) enzyme, which utilizes radical-based chemistry to install several distinct PTMs. Here, we describe the rSAM enzymes characterized over the past decade that catalyze six reaction types from several RiPP biosynthetic pathways. We present the current state of mechanistic understanding and conclude with possible directions for future characterization of this enzyme family.
Topics: Amino Acid Sequence; Biocatalysis; Enzymes; Humans; Peptides; Protein Processing, Post-Translational; S-Adenosylmethionine
PubMed: 28895719
DOI: 10.1021/acs.biochem.7b00771 -
Angewandte Chemie (International Ed. in... May 2019Enzyme-mediated cascade reactions are widespread in biosynthesis. To facilitate comparison with the mechanistic categorizations of cascade reactions by synthetic... (Review)
Review
Enzyme-mediated cascade reactions are widespread in biosynthesis. To facilitate comparison with the mechanistic categorizations of cascade reactions by synthetic chemists and delineate the common underlying chemistry, we discuss four types of enzymatic cascade reactions: those involving nucleophilic, electrophilic, pericyclic, and radical reactions. Two subtypes of enzymes that generate radical cascades exist at opposite ends of the oxygen abundance spectrum. Iron-based enzymes use O to generate high valent iron-oxo species to homolyze unactivated C-H bonds in substrates to initiate skeletal rearrangements. At anaerobic end, enzymes reversibly cleave S-adenosylmethionine (SAM) to generate the 5'-deoxyadenosyl radical as a powerful oxidant to initiate C-H bond homolysis in bound substrates. The latter enzymes are termed radical SAM enzymes. We categorize the former as "thwarted oxygenases".
Topics: Animals; Biological Products; Catalysis; Humans; Iron-Sulfur Proteins; S-Adenosylmethionine
PubMed: 30156048
DOI: 10.1002/anie.201807844 -
International Journal of Biological... 2020S-adenosylmethionine supplies methyl groups to many acceptors, including lipids, proteins, RNA, DNA, and a wide range of small molecules. It acts as the precursor in the... (Review)
Review
S-adenosylmethionine supplies methyl groups to many acceptors, including lipids, proteins, RNA, DNA, and a wide range of small molecules. It acts as the precursor in the biosynthesis of metal ion chelating compounds, such as nicotianamine and phytosiderophores, of the polyamines spermidine and spermine and of some plant hormones. Finally, it is the source of catalytic 5'-deoxyadenosyl radicals. Radical S-adenosylmethionine (SAM) enzymes (RS) represent one of the most abundant groups (more than 100,000) of enzymes, exerting a plethora of biological functions, some of which are still unknown. In this work, we will focus on two RS: CDK5RAP1 and CDKAL1, both of which are involved in tRNA modifications that result in important tRNA folding and stability and in maintaining high translational fidelity. Based on this crucial role, their impairment can be important in the development of different human diseases.
Topics: Humans; Proteins; RNA, Transfer; S-Adenosylmethionine
PubMed: 33061813
DOI: 10.7150/ijbs.49302 -
S-Adenosylmethionine affects ERK1/2 and STAT3 pathway in androgen-independent prostate cancer cells.Molecular Biology Reports Jun 2022The most critical point in the treatment of prostate cancer is the progression towards a hormone-refractory tumour, making research on alternative therapies necessary....
BACKGROUND
The most critical point in the treatment of prostate cancer is the progression towards a hormone-refractory tumour, making research on alternative therapies necessary. This study focused on the methyl donor S-adenosylmethionine (SAM), which is known to act as an antitumourigenic in several cancer cell lines. Though a genome-wide downregulation of proto-oncogenes in prostate cancer cell lines treated with SAM is obvious, the anticancer effects remain elusive. Thus, in this study, the impact of SAM treatment on the cell cycle, apoptosis and cancer-related pathways was investigated.
METHODS AND RESULTS
After performing SAM treatment on prostate cancer cell lines (PC-3 and DU145), a cell-cycle arrest during the S-phase, a downregulation of cyclin A protein levels and an upregulation of p21 cell cycle inhibitor were observed. The proapoptotic Bax/Bcl-2 ratio and the caspase-3 activity were elevated; additionally, the apoptosis rate of SAM treated cells increased significantly in a time-dependent manner. Moreover, immunoblots displayed a downregulation of Erk1/2 and STAT3 phosphorylation accompanied by a reduced expression of the STAT3 protein.
CONCLUSION
SAM caused changes in cancer-related pathways, probably leading to the effects on the cell cycle and apoptosis rate. These results provide deeper insights into the anticancer effects of SAM on prostate cancer cells.
Topics: Androgens; Apoptosis; Cell Line, Tumor; Humans; MAP Kinase Signaling System; Male; Prostatic Neoplasms; S-Adenosylmethionine; STAT3 Transcription Factor
PubMed: 35303200
DOI: 10.1007/s11033-022-07331-2 -
Current Opinion in Chemical Biology Aug 2013A subset of enzymes that belong to the radical S-adenosylmethionine (SAM) superfamily is able to catalyze methylation reactions. Substrates of these enzymes are distinct... (Review)
Review
A subset of enzymes that belong to the radical S-adenosylmethionine (SAM) superfamily is able to catalyze methylation reactions. Substrates of these enzymes are distinct from the nucleophilic substrates that undergo methylation by a polar mechanism. Recently, activities of several radical SAM methylating enzymes have been reconstituted in vitro and their mechanisms of catalysis investigated. The RNA modifying enzymes RlmN and Cfr catalyze methylation via a methyl synthase mechanism. These enzymes use SAM in two distinct roles: as a source of a methyl group transferred to a conserved cysteine and as a source of 5'-deoxyadenosyl radical (5'-dA). Hydrogen atom abstraction by this species generates a thiomethylene radical which adds into the RNA substrate, forming an enzyme-substrate covalent adduct. In another recent study, methylation of the indole moiety of tryptophan by the radical SAM and cobalamin-binding domain enzyme TsrM has been reconstituted. Methylcobalamin serves as an intermediate methyl donor in TsrM, and is proposed to transfer the methyl group as a methyl radical. Interestingly, despite the presence of the radical SAM motif, no reductive cleavage of SAM has been observed in this methylation. These important reconstitutions set the stage for further studies on mechanisms of radical methylation.
Topics: Free Radicals; Methylation; RNA; S-Adenosylmethionine; Substrate Specificity; Tryptophan
PubMed: 23835516
DOI: 10.1016/j.cbpa.2013.05.032