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Deep Neural Network Classifier for Virtual Screening Inhibitors of (S)-Adenosyl-L-Methionine (SAM)-Dependent Methyltransferase Family.

ABSTRACT: 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.

SUBMITTER: Li F

PROVIDER: S-EPMC6524412 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Structural mechanism of S-adenosyl methionine binding to catechol O-methyltransferase.

Project description:Methyltransferases possess a homologous domain that requires both a divalent metal cation and S-adenosyl-L-methionine (SAM) to catalyze its reactions. The kinetics of several methyltransferases has been well characterized; however, the details regarding their structural mechanisms have remained unclear to date. Using catechol O-methyltransferase (COMT) as a model, we perform discrete molecular dynamics and computational docking simulations to elucidate the initial stages of cofactor binding. We find that COMT binds SAM via an induced-fit mechanism, where SAM adopts a different docking pose in the absence of metal and substrate in comparison to the holoenzyme. Flexible modeling of the active site side-chains is essential for observing the lowest energy state in the apoenzyme; rigid docking tools are unable to recapitulate the pose unless the appropriate side-chain conformations are given a priori. From our docking results, we hypothesize that the metal reorients SAM in a conformation suitable for donating its methyl substituent to the recipient ligand. The proposed mechanism enables a general understanding of how divalent metal cations contribute to methyltransferase function.

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Crystal structure of dengue virus methyltransferase without S-adenosyl-L-methionine.

Project description:Flavivirus methyltransferase is a genetically-validated antiviral target. Crystal structures of almost all available flavivirus methyltransferases contain S-adenosyl-L-methionine (SAM), the methyl donor molecule that co-purifies with the enzymes. This raises a possibility that SAM is an integral structural component required for the folding of dengue virus (DENV) methyltransferase. Here we exclude this possibility by solving the crystal structure of DENV methyltransferase without SAM. The SAM ligand was removed from the enzyme through a urea-mediated denaturation-and-renaturation protocol. The crystal structure of the SAM-depleted enzyme exhibits a vacant SAM-binding pocket, with a conformation identical to that of the SAM-enzyme co-crystal structure. Functionally, equivalent enzymatic activities (N-7 methylation, 2'-O methylation, and GMP-enzyme complex formation) were detected for the SAM-depleted and SAM-containing recombinant proteins. These results clearly indicate that the SAM molecule is not an essential component for the correct folding of DENV methyltransferase. Furthermore, the results imply a potential antiviral approach to search for inhibitors that can bind to the SAM-binding pocket and compete against SAM binding. To demonstrate this potential, we have soaked crystals of DENV methyltransferase without a bound SAM with the natural product Sinefungin and show that preformed crystals are capable of binding ligands in this pocket.

| S-EPMC7113791 | biostudies-literature

Refolding of a fully functional flavivirus methyltransferase revealed that S-adenosyl methionine but not S-adenosyl homocysteine is copurified with flavivirus methyltransferase.

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Targeting the methionine-methionine adenosyl transferase 2A- S -adenosyl methionine axis for cancer therapy.

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Profiling substrates of protein arginine N-methyltransferase 3 with S-adenosyl-L-methionine analogues.

Project description:Protein arginine N-methyltransferase 3 (PRMT3) belongs to the family of type I PRMTs and harbors the activity to use S-adenosyl-l-methionine (SAM) as a methyl-donor cofactor for protein arginine labeling. However, PRMT3's functions remain elusive with the lacked knowledge of its target scope in cellular settings. Inspired by the emerging Bioorthogonal Profiling of Protein Methylation (BPPM) using engineered methyltransferases and SAM analogues for target identification, the current work documents the endeavor to systematically explore the SAM-binding pocket of PRMT3 and identify suitable PRMT3 variants for BPPM. The M233G single point mutation transforms PRMT3 into a promiscuous alkyltransferase using sp(2)-?-sulfonium-containing SAM analogues as cofactor surrogates. Here the conserved methionine was defined as a hot spot that can be engineered alone or in combination with nearby residues to render cofactor promiscuity of multiple type I PRMTs. With this promiscuous variant and the matched 4-propargyloxy-but-2-enyl (Pob)-SAM analogue as the BPPM reagents, more than 80 novel proteins were readily uncovered as potential targets of PRMT3 in the cellular context. Subsequent target validation and functional analysis correlated the PRMT3 methylation to several biological processes such as cytoskeleton dynamics, whose roles might be compensated by other PRMTs. These BPPM-revealed substrates are primarily localized but not restricted in cytoplasm, the preferred site of PRMT3. The broad localization pattern may implicate the diverse roles of PRMT3 in the cellular setting. The revelation of PRMT3 targets and the transformative character of BPPM for other PRMTs present unprecedented pathways toward elucidating physiological and pathological roles of diverse PRMTs.

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Transcriptomic analysis of engineered and improved Pichia pastoris for S-adenosyl-l-methionine (SAM) production

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

Dietary Inhibitors of CYP3A4 Are Revealed Using Virtual Screening by Using a New Deep-Learning Classifier.

Project description:CYP3A4 is the main human enzyme responsible for phase I metabolism of dietary compounds, prescribed drugs and xenobiotics, steroid hormones, and bile acids. The inhibition of CYP3A4 activity might impair physiological mechanisms, including the endocrine system and response to drug admission. Here, we aimed to discover new CYP3A4 inhibitors from food and dietary supplements. A deep-learning model was built that classifies compounds as either an inhibitor or noninhibitor, with a high specificity of 0.997. We used this classifier to virtually screen ∼60,000 dietary compounds. Of the 115 identified potential inhibitors, only 31 were previously suggested. Many herbals, as predicted here, might cause impaired metabolism of drugs, and endogenous hormones and bile acids. Additionally, by applying Lipinski's rules of five, 17 compounds were also classified as potential intestine local inhibitors. New CYP3A4 inhibitors predicted by the model, bilobetin and picropodophyllin, were assayed in vitro.

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Conformational heterogeneity of the SAM-I riboswitch transcriptional ON state: a chaperone-like role for S-adenosyl methionine.

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

S-adenosyl-methionine (SAM) alters the transcriptome and methylome and specifically blocks growth and invasiveness of liver cancer cells.

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

S-adenosyl methionine is necessary for inhibition of the methyltransferase G9a by the lysine 9 to methionine mutation on histone H3.

Project description:Lysine to methionine (K-to-M) mutations in genes encoding histone H3 are thought to drive a subset of pediatric brain and bone cancers. These high-frequency K-to-M mutations occur at sites of methylation on histone H3, and tumors containing the mutant histones exhibit a global loss of specific histone methylation marks. Previous studies showed that K-to-M mutant histones, also known as oncohistones, are potent orthosteric inhibitors of specific Su(var)3-9, Enhancer-of-zeste, Trithorax (SET) domain methyltransferases. However, the biochemical and biophysical details of the interaction between K-to-M mutant histones and the respective SET domain methyltransferases are currently unknown. Here, we use the histone H3K9-directed methyltransferase G9a as a model to explore the mechanism of inhibition by K-to-M oncohistones. X-ray cocrystal structures revealed that the K9M residue of histone H3 occupies the active site cavity of G9a, and kinetic analysis indicates competitive inhibition of G9a by histone H3K9M. Additionally, we find that the cofactor S-adenosyl methionine (SAM) is necessary for stable interaction between G9a and H3K9M histone. Consistent with the formation of a ternary complex, we find that the inhibitory peptide is uncompetitive with regard to SAM. These data and others indicate that K-to-M oncohistones promote global loss of specific lysine methylation through sequestration and inhibition of SAM-bound SET domain methyltransferases.

| S-EPMC4896705 | biostudies-literature

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