S-Adenosyl-L-methionine hydrolase (adenosine-forming), a conserved bacterial and archaeal protein related to SAM-dependent halogenases.
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ABSTRACT:
SUBMITTER: Eustaquio AS
PROVIDER: S-EPMC2692205 | biostudies-literature | 2008 Sep
REPOSITORIES: biostudies-literature
Publications
S-Adenosyl-L-methionine hydrolase (adenosine-forming), a conserved bacterial and archaeal protein related to SAM-dependent halogenases.
Eustáquio Alessandra S AS Härle Johannes J Noel Joseph P JP Moore Bradley S BS
Chembiochem : a European journal of chemical biology 20080901 14
Similar Datasets
Project description:Enzymatic methylation catalyzed by methyltransferases has a significant impact on many human biochemical reactions. As the second most ubiquitous cofactor in humans, S-adenosyl-l-methionine (SAM or AdoMet) serves as a methyl donor for SAM-dependent methyltransferases (MTases), which transfer a methyl group to a nucleophilic acceptor such as O, As, N, S, or C as the byproduct. SAM-dependent methyltransferases can be grouped into different types based on the substrates. Here we systematically reviewed eight types of methyltransferases associated with human diseases. Catechol O-methyltransferase (COMT), As(III) S-adenosylmethionine methyltransferase (AS3MT), indolethylamine N-methyltransferase (INMT), phenylethanolamine N-methyltransferase (PNMT), histamine N-methyltransferase (HNMT), nicotinamide N-methyltransferase (NNMT), thiopurine S-methyltransferase (TPMT) and DNA methyltansferase (DNMT) are classic SAM-dependent MTases. Correlations between genotypes and disease susceptibility can be partially explained by genetic polymorphisms. The physiological function, substrate specificity, genetic variants and disease susceptibility associated with these eight SAM-dependent methyltransferases are discussed in this review.
| S-EPMC8847900 | biostudies-literature
Project description:S-Adenosyl-L-homocysteine hydrolase (SAHH) catalyzes the reversible conversion of S-adenosyl-L-homocysteine (SAH) to adenosine (ADO) and L-homocysteine, promoting methyltransferase activity by relief of SAH inhibition. SAH catabolism is linked to S-adenosylmethionine metabolism, and the development of SAHH inhibitors is of interest for new therapeutics with anticancer or cholesterol-lowering effects. We have developed a continuous enzymatic assay for adenosine that facilitates high-throughput analysis of SAHH. This luciferase-based assay is 4000-fold more sensitive than former detection methods and is well suited for continuous monitoring of ADO formation in a 96-well-plate format. The high-affinity adenosine kinase from Anopheles gambiae efficiently converts adenosine to adenosine monophosphate (AMP) in the presence of guanosine triphosphate. AMP is converted to adenosine triphosphate and coupled to firefly luciferase. With this procedure, kinetic parameters (K(m), k(cat)) for SAHH were obtained, in good agreement with literature values. Assay characteristics include sustained light output combined with ultrasensitive detection (10(-7) unit of SAHH). The assay is documented with the characterization of slow-onset inhibition for inhibitors of the hydrolase. Application of this assay may facilitate the development of SAHH inhibitors and provide an ultrasensitive detection for the formation of adenosine from other biological reactions.
| S-EPMC3328629 | biostudies-literature
Project description:Purpose of reviewIn this review, we summarize the biological roles of methionine, methionine adenosyl transferase 2A (MAT2A) and S -adenosyl methionine (SAM) in methylation reactions during tumorigenesis. Newly emerged inhibitors targeting the methionine-MAT2A-SAM axis will be discussed.Recent findingsSAM is the critical and global methyl-donor for methylation reactions regulating gene expression, and in mammalian cells, it is synthesized by MAT2A using methionine. Recent studies have validated methionine and MAT2A as metabolic dependencies of cancer cells because of their essential roles in SAM biosynthesis. MAT2A inhibition leads to synthetic lethality in methylthioadenosine-phosphorylase (MTAP)-deleted cancers, which accounts for 15% of all cancer types. Of note, remarkable progress has been made in developing inhibitors targeting the methionine-MAT2A-SAM axis, as the first-in-class MAT2A inhibitors AG-270 and IDE397 enter clinical trials to treat cancer.SummaryThe methionine-MAT2A-SAM axis plays an important role in tumorigenesis by providing SAM as a critical substrate for abnormal protein as well as DNA and RNA methylation in cancer cells. Targeting SAM biosynthesis through MAT2A inhibition has emerged as a novel and promising strategy for cancer therapy.
| S-EPMC9365249 | biostudies-literature
Project description:The (S)-adenosyl-L-methionine (SAM)-dependent methyltransferases play essential roles in post-translational modifications (PTMs) and other miscellaneous biological processes, and are implicated in the pathogenesis of various genetic disorders and cancers. Increasing efforts have been committed toward discovering novel PTM inhibitors targeting the (S)-Adenosyl-L-methionine (SAM)-binding site and the substrate-binding site of methyltransferases, among which virtual screening (VS) and structure-based drug design (SBDD) are the most frequently used strategies. Here, we report the development of a target-specific scoring model for compound VS, which predict the likelihood of the compound being a potential inhibitor for the SAM-binding pocket of a given methyltransferase. Protein-ligand interaction characterized by Fingerprinting Triplets of Interaction Pseudoatoms was used as the input feature, and a binary classifier based on deep neural networks is trained to build the scoring model. This model enhances the efficiency of the existing strategies used for discovering novel chemical modulators of methyltransferase, which is crucial for understanding and exploring the complexity of epigenetic target space.
| S-EPMC6524412 | biostudies-literature
Project description:UnlabelledS-Adenosyl-L-homocysteine, the product of S-adenosyl-L-methionine (SAM) methyltransferases, is known to be a strong feedback inhibitor of these enzymes. A hydrolase specific for S-adenosyl-L-homocysteine produces L-homocysteine, which is remethylated to methionine and can be used to regenerate SAM. Here, we show that the annotated S-adenosyl-L-homocysteine hydrolase in Methanocaldococcus jannaschii is specific for the hydrolysis and synthesis of S-inosyl-L-homocysteine, not S-adenosyl-L-homocysteine. This is the first report of an enzyme specific for S-inosyl-L-homocysteine. As with S-adenosyl-L-homocysteine hydrolase, which shares greater than 45% sequence identity with the M. jannaschii homologue, the M. jannaschii enzyme was found to copurify with bound NAD(+) and has Km values of 0.64 ± 0.4 mM, 0.0054 ± 0.006 mM, and 0.22 ± 0.11 mM for inosine, L-homocysteine, and S-inosyl-L-homocysteine, respectively. No enzymatic activity was detected with S-adenosyl-L-homocysteine as the substrate in either the synthesis or hydrolysis direction. These results prompted us to redesignate the M. jannaschii enzyme an S-inosyl-L-homocysteine hydrolase (SIHH). Identification of SIHH demonstrates a modified pathway in this methanogen for the regeneration of SAM from S-adenosyl-L-homocysteine that uses the deamination of S-adenosyl-L-homocysteine to form S-inosyl-L-homocysteine.ImportanceIn strictly anaerobic methanogenic archaea, such as Methanocaldococcus jannaschii, canonical metabolic pathways are often not present, and instead, unique pathways that are deeply rooted on the phylogenetic tree are utilized by the organisms. Here, we discuss the recycling pathway for S-adenosyl-L-homocysteine, produced from S-adenosyl-L-methionine (SAM)-dependent methylation reactions, which uses a hydrolase specific for S-inosyl-L-homocysteine, an uncommon metabolite. Identification of the pathways and the enzymes involved in the unique pathways in the methanogens will provide insight into the biochemical reactions that were occurring when life originated.
| S-EPMC4524176 | biostudies-literature
Project description:Circadian gene expression driven by transcription activators CLOCK and BMAL1 is intimately associated with dynamic chromatin remodeling. However, how cellular metabolism directs circadian chromatin remodeling is virtually unexplored. We report that the S-adenosylhomocysteine (SAH) hydrolyzing enzyme adenosylhomocysteinase (AHCY) cyclically associates to CLOCK-BMAL1 at chromatin sites and promotes circadian transcriptional activity. SAH is a potent feedback inhibitor of S-adenosylmethionine (SAM)-dependent methyltransferases, and timely hydrolysis of SAH by AHCY is critical to sustain methylation reactions. We show that AHCY is essential for cyclic H3K4 trimethylation, genome-wide recruitment of BMAL1 to chromatin, and subsequent circadian transcription. Depletion or targeted pharmacological inhibition of AHCY in mammalian cells markedly decreases the amplitude of circadian gene expression. In mice, pharmacological inhibition of AHCY in the hypothalamus alters circadian locomotor activity and rhythmic transcription within the suprachiasmatic nucleus. These results reveal a previously unappreciated connection between cellular metabolism, chromatin dynamics, and circadian regulation.
| S-EPMC7744083 | biostudies-literature
Project description:Riboswitches are promising targets for the design of novel antibiotics and engineering of portable genetic regulatory elements. There is evidence that variability in riboswitch properties allows tuning of expression for genes involved in different stages of biosynthetic pathways by mechanisms that are not currently understood. Here, we explore the mechanism for tuning of S-adenosyl methionine (SAM)-I riboswitch folding. Most SAM-I riboswitches function at the transcriptional level by sensing the cognate ligand SAM. SAM-I riboswitches orchestrate the biosynthetic pathways of cysteine, methionine, SAM, and so forth. We use base-pair probability predictions to examine the secondary-structure folding landscape of several SAM-I riboswitch sequences. We predict different folding behaviors for different SAM-I riboswitch sequences. We identify several "decoy" base-pairing interactions involving 5' riboswitch residues that can compete with the formation of a P1 helix, a component of the ligand-bound "transcription OFF" state, in the absence of SAM. We hypothesize that blockage of these interactions through SAM contacts contributes to stabilization of the OFF state in the presence of ligand. We also probe folding patterns for a SAM-I riboswitch RNA using constructs with different 3' truncation points experimentally. Folding was monitored through fluorescence, susceptibility to base-catalyzed cleavage, nuclear magnetic resonance, and indirectly through SAM binding. We identify key decision windows at which SAM can affect the folding pathway towards the OFF state. The presence of decoy conformations and differential sensitivities to SAM at different transcript lengths is crucial for SAM-I riboswitches to modulate gene expression in the context of global cellular metabolism.
| S-EPMC4767528 | biostudies-literature
Project description:SAM is the principal methyl group donor in all living organisms, and has attracted much interest in clinical research. We improved SAM production in engineered P. pastoris strain GS115/DS56 by overexpression of the recombinant methionine adenosyltransferase (MAT) gene DS56, and further enhanced SAM prduction in G12-CBS by downregulation of the cystathionine β-synthase (CBS) gene CYS4 with a weak promoter G12. We performed the pairwise transcriptome comparisons between high-producing (HP) and low-producing (LP) strains, in order to understand the impact of SAM accumulation on the P. pastoris physiology and to identify genome-wide targets for further improving SAM production.
2018-09-01 | GSE114152 | GEO
Project description:S-adenosyl methionine (SAM) is a ubiquitous methyl donor that was reported to have chemo- protective activity against liver cancer, however the molecular footprint of SAM is unknown. We show here that SAM selectively inhibits growth, transformation and invasiveness of hepatocellular carcinoma cell lines but not normal primary liver cells. Analysis of the transcriptome of SAM treated and untreated liver cancer cell lines HepG2 and SKhep1 and primary liver cells reveals pathways involved in cancer and metastasis that are upregulated in cancer cells and are downregulated by SAM. Analysis of the methylome using bisulfite mapping of captured promoters and enhancers reveals that SAM hyper-methylates and downregulates genes in pathways of growth and metastasis that are upregulated in liver cancer cells. Depletion of two SAM downregulated genes STMN1 and TAF15 reduces cellular transformation and invasiveness, providing evidence that SAM targets are genes important for cancer growth and invasiveness. Taken together these data provide a molecular rationale for SAM as an anticancer agent.
| S-EPMC5762365 | biostudies-literature
Project description:S-Adenosyl-l-methionine (SAM) is the central cofactor in the radical SAM enzyme superfamily, responsible for a vast number of transformations in primary and secondary metabolism. In nearly all of these reactions, the reductive cleavage of SAM is proposed to produce a reactive species, 5'-deoxyadenosyl radical, which initiates catalysis. While the mechanistic details in many cases are well-understood, the reductive cleavage of SAM remains elusive. In this manuscript, we have measured the solution peak potential of SAM to be ∼-1.4 V (v SHE) and show that under controlled potential conditions, it undergoes irreversible fragmentation to the 5'-deoxyadenosyl radical. While the radical intermediate is not directly observed, its presence as an initial intermediate is inferred by the formation of 8,5'-cycloadenosine and by H atom incorporation into 5'-deoxyadenosine from solvent exchangeable site. Similarly, 2-aminobutyrate is also observed under electrolysis conditions. The implications of these results in the context of the reductive cleavage of SAM by radical SAM enzymes are discussed.
| S-EPMC7059804 | biostudies-literature