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Journal of Hematology & Oncology Jul 2021N6-methyladenosine (m6A) has emerged as an abundant modification throughout the transcriptome with widespread functions in protein-coding and noncoding RNAs. It affects... (Review)
Review
N6-methyladenosine (m6A) has emerged as an abundant modification throughout the transcriptome with widespread functions in protein-coding and noncoding RNAs. It affects the fates of modified RNAs, including their stability, splicing, and/or translation, and thus plays important roles in posttranscriptional regulation. To date, m6A methyltransferases have been reported to execute m6A deposition on distinct RNAs by their own or forming different complexes with additional partner proteins. In this review, we summarize the function of these m6A methyltransferases or complexes in regulating the key genes and pathways of cancer biology. We also highlight the progress in the use of m6A methyltransferases in mediating therapy resistance, including chemotherapy, targeted therapy, immunotherapy and radiotherapy. Finally, we discuss the current approaches and clinical potential of m6A methyltransferase-targeting strategies.
Topics: Adenosine; Animals; Gene Expression Regulation, Neoplastic; Humans; Methyltransferases; Molecular Targeted Therapy; Neoplasms; Signal Transduction
PubMed: 34315512
DOI: 10.1186/s13045-021-01129-8 -
Angewandte Chemie (International Ed. in... May 2017Methyltransferases (MTases) form a large family of enzymes that methylate a diverse set of targets, ranging from the three major biopolymers to small molecules. Most of... (Review)
Review
Methyltransferases (MTases) form a large family of enzymes that methylate a diverse set of targets, ranging from the three major biopolymers to small molecules. Most of these MTases use the cofactor S-adenosyl-l-Methionine (AdoMet) as a methyl source. In recent years, there have been significant efforts toward the development of AdoMet analogues with the aim of transferring moieties other than simple methyl groups. Two major classes of AdoMet analogues currently exist: doubly-activated molecules and aziridine based molecules, each of which employs a different approach to achieve transalkylation rather than transmethylation. In this review, we discuss the various strategies for labelling and functionalizing biomolecules using AdoMet-dependent MTases and AdoMet analogues. We cover the synthetic routes to AdoMet analogues, their stability in biological environments and their application in transalkylation reactions. Finally, some perspectives are presented for the potential use of AdoMet analogues in biology research, (epi)genetics and nanotechnology.
Topics: Biopolymers; Methyltransferases; Small Molecule Libraries
PubMed: 27943567
DOI: 10.1002/anie.201608625 -
Frontiers in Endocrinology 2023SET domain-containing 5 (SETD5) is an uncharacterized member of the protein lysine methyltransferase family and is best known for its transcription machinery by... (Review)
Review
SET domain-containing 5 (SETD5) is an uncharacterized member of the protein lysine methyltransferase family and is best known for its transcription machinery by methylating histone H3 on lysine 36 (H3K36). These well-characterized functions of SETD5 are transcription regulation, euchromatin formation, and RNA elongation and splicing. SETD5 is frequently mutated and hyperactive in both human neurodevelopmental disorders and cancer, and could be down-regulated by degradation through the ubiquitin-proteasome pathway, but the biochemical mechanisms underlying such dysregulation are rarely understood. Herein, we provide an update on the particularities of SETD5 enzymatic activity and substrate specificity concerning its biological importance, as well as its molecular and cellular impact on normal physiology and disease, with potential therapeutic options.
Topics: Humans; Histones; Lysine; Methyltransferases; Neurodevelopmental Disorders
PubMed: 36875494
DOI: 10.3389/fendo.2023.1089527 -
ACS Chemical Biology Apr 2023Target class profiling (TCP) is a chemical biology approach to investigate understudied biological target classes. TCP is achieved by developing a generalizable assay...
Target class profiling (TCP) is a chemical biology approach to investigate understudied biological target classes. TCP is achieved by developing a generalizable assay platform and screening curated compound libraries to interrogate the chemical biological space of members of an enzyme family. In this work, we took a TCP approach to investigate inhibitory activity across a set of small-molecule methyltransferases (SMMTases), a subclass of methyltransferase enzymes, with the goal of creating a launchpad to explore this largely understudied target class. Using the representative enzymes nicotinamide -methyltransferase (NNMT), phenylethanolamine -methyltransferase (PNMT), histamine -methyltransferase (HNMT), glycine -methyltransferase (GNMT), catechol -methyltransferase (COMT), and guanidinoacetate -methyltransferase (GAMT), we optimized high-throughput screening (HTS)-amenable assays to screen 27,574 unique small molecules against all targets. From this data set, we identified a novel inhibitor which selectively inhibits the SMMTase HNMT and demonstrated how this platform approach can be leveraged for a targeted drug discovery campaign using the example of HNMT.
Topics: Methyltransferases; Histamine N-Methyltransferase; High-Throughput Screening Assays; Drug Discovery
PubMed: 36976909
DOI: 10.1021/acschembio.3c00124 -
Molecules (Basel, Switzerland) Nov 2018Sacred lotus ( Gaertn.) is an ancient aquatic plant used throughout Asia for its nutritional and medicinal properties. Benzylisoquinoline alkaloids (BIAs), mostly within... (Review)
Review
Sacred lotus ( Gaertn.) is an ancient aquatic plant used throughout Asia for its nutritional and medicinal properties. Benzylisoquinoline alkaloids (BIAs), mostly within the aporphine and bisbenzylisoquinoline structural categories, are among the main bioactive constituents in the plant. The alkaloids of sacred lotus exhibit promising anti-cancer, anti-arrhythmic, anti-HIV, and anti-malarial properties. Despite their pharmacological significance, BIA metabolism in this non-model plant has not been extensively investigated. In this review, we examine the diversity of BIAs in sacred lotus, with an emphasis on the distinctive stereochemistry of alkaloids found in this species. Additionally, we discuss our current understanding of the biosynthetic genes and enzymes involved in the formation of 1-benzylisoquinoline, aporphine, and bisbenzylisoquinoline alkaloids in the plant. We conclude that a comprehensive functional characterization of alkaloid biosynthetic enzymes using both in vitro and in vivo methods is required to advance our limited knowledge of BIA metabolism in the sacred lotus.
Topics: Alkaloids; Genome, Plant; Methyltransferases; Nelumbo; Stereoisomerism
PubMed: 30404216
DOI: 10.3390/molecules23112899 -
Cell Chemical Biology Dec 2023We report a novel translation-regulatory function of G9a, a histone methyltransferase and well-understood transcriptional repressor, in promoting hyperinflammation and...
We report a novel translation-regulatory function of G9a, a histone methyltransferase and well-understood transcriptional repressor, in promoting hyperinflammation and lymphopenia; two hallmarks of endotoxin tolerance (ET)-associated chronic inflammatory complications. Using multiple approaches, we demonstrate that G9a interacts with multiple translation regulators during ET, particularly the N6-methyladenosine (mA) RNA methyltransferase METTL3, to co-upregulate expression of certain mA-modified mRNAs that encode immune-checkpoint and anti-inflammatory proteins. Mechanistically, G9a promotes mA methyltransferase activity of METTL3 at translational/post-translational level by regulating its expression, its methylation, and its cytosolic localization during ET. Additionally, from a broader view extended from the G9a-METTL3-mA translation regulatory axis, our translatome proteomics approach identified numerous "G9a-translated" proteins that unite the networks associated with inflammation dysregulation, T cell dysfunction, and systemic cytokine response. In sum, we identified a previously unrecognized function of G9a in protein-specific translation that can be leveraged to treat ET-related chronic inflammatory diseases.
Topics: Humans; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Inflammation; Methylation; Methyltransferases; Histocompatibility Antigens
PubMed: 37858336
DOI: 10.1016/j.chembiol.2023.09.012 -
Current Opinion in Chemical Biology Apr 2017S-adenosyl-L-methionine-dependent methyltransferses are ubiquitous in nature, methylating a vast range of small molecule metabolites, as well as biopolymers. This review... (Review)
Review
S-adenosyl-L-methionine-dependent methyltransferses are ubiquitous in nature, methylating a vast range of small molecule metabolites, as well as biopolymers. This review covers the recent advances in the development of methyltransferase enzymes for synthetic applications, focusing on the methyltransferase catalyzed transformations with S-adenosyl methionine analogs, as well as non-native substrates. We discuss how metabolic engineering approaches have been used to enhance S-adenosyl methionine production in vivo. Enzymatic approaches that enable the more efficient generation of S-adenosyl methionine analogs, including more stable analogs, will also be described; this has expanded the biocatalytic repertoire of methyltransferases from methylation to a broader range of alkylation reactions. The review also examines how the selectivity of the methyltransferase enzymes can be improved through structure guided mutagenesis approaches. Finally, we will discuss how methyltransferases can be deployed in multi-enzyme cascade reactions and suggest future challenges and avenues for further investigation.
Topics: Animals; Biocatalysis; Biotransformation; Coenzymes; Humans; Methyltransferases; Substrate Specificity
PubMed: 28259085
DOI: 10.1016/j.cbpa.2017.01.020 -
Advances in Microbial Physiology 2023The membranous quinone/quinol pool is essential for the majority of life forms and its composition has been widely used as a biomarker in microbial taxonomy. The most...
The membranous quinone/quinol pool is essential for the majority of life forms and its composition has been widely used as a biomarker in microbial taxonomy. The most abundant quinone is menaquinone (MK), which serves as an essential redox mediator in various electron transport chains of aerobic and anaerobic respiration. Several methylated derivatives of MK, designated methylmenaquinones (MMKs), have been reported to be present in members of various microbial phyla possessing either the classical MK biosynthesis pathway (Men) or the futalosine pathway (Mqn). Due to their low redox midpoint potentials, MMKs have been proposed to be specifically involved in appropriate electron transport chains of anaerobic respiration. The class C radical SAM methyltransferases MqnK, MenK and MenK2 have recently been shown to catalyse specific MK methylation reactions at position C-8 (MqnK/MenK) or C-7 (MenK2) to synthesise 8-MMK, 7-MMK and 7,8-dimethylmenaquinone (DMMK). MqnK, MenK and MenK2 from organisms such as Wolinella succinogenes, Adlercreutzia equolifaciens, Collinsella tanakaei, Ferrimonas marina and Syntrophus aciditrophicus have been functionally produced in Escherichia coli, enabling extensive quinone/quinol pool engineering of the native MK and 2-demethylmenaquinone (DMK). Cluster and phylogenetic analyses of available MK and MMK methyltransferase sequences revealed signature motifs that allowed the discrimination of MenK/MqnK/MenK2 family enzymes from other radical SAM enzymes and the identification of C-7-specific menaquinone methyltransferases of the MenK2 subfamily. It is envisaged that this knowledge will help to predict the methylation status of the menaquinone/menaquinol pool of any microbial species (or even a microbial community) from its (meta)genome.
Topics: Humans; Vitamin K 2; Hydroquinones; Phylogeny; Quinones; Methyltransferases; Electron Transport
PubMed: 37507157
DOI: 10.1016/bs.ampbs.2023.05.002 -
Sheng Wu Gong Cheng Xue Bao = Chinese... Jun 2022Monolignin alcohols (type H, type G and type S) are the basic units of lignin and lignans in plants, and their composition differences directly determine the chemical...
Monolignin alcohols (type H, type G and type S) are the basic units of lignin and lignans in plants, and their composition differences directly determine the chemical diversity and biological activity of lignin and lignans. Caffeic acid -methyltransferase (COMT) catalyzes the methylation of oxygen atoms on the hydroxyl groups of phenylpropanoids, playing a critical role in the composition of different types of monolignin alcohols, and thus acting as a key enzyme involved in the biosynthesis pathway of lignin and lignans. A previous review published in 2010 mainly introduced the gene characteristics of COMT and its regulatory role in lignin biosynthesis. This article summarized the latest research progress of COMT in the past decade, including the gene characteristics, expression characteristics, structural characteristics of COMT and its regulatory effects, and prospected future research and application of COMT.
Topics: Alcohols; Caffeic Acids; Lignans; Lignin; Methyltransferases; Plants
PubMed: 35786471
DOI: 10.13345/j.cjb.210818 -
Planta Jun 2017The present review compiles the up-to-date knowledge on vanillin biosynthesis in plant systems to focus principally on the enzymatic reactions of in planta vanillin... (Review)
Review
The present review compiles the up-to-date knowledge on vanillin biosynthesis in plant systems to focus principally on the enzymatic reactions of in planta vanillin biosynthetic pathway and to find out its impact and prospect in future research in this field. Vanillin, a very popular flavouring compound, is widely used throughout the world. The principal natural resource of vanillin is the cured vanilla pods. Due to the high demand of vanillin as a flavouring agent, it is necessary to explore its biosynthetic enzymes and genes, so that improvement in its commercial production can be achieved through metabolic engineering. In spite of significant advancement in elucidating vanillin biosynthetic pathway in the last two decades, no conclusive demonstration had been reported yet for plant system. Several biosynthetic enzymes have been worked upon but divergences in published reports, particularly in characterizing the crucial biochemical steps of vanillin biosynthesis, such as side-chain shortening, methylation, and glucoside formation and have created a space for discussion. Recently, published reviews on vanillin biosynthesis have focused mainly on the biotechnological approaches and bioconversion in microbial systems. This review, however, aims to compile in brief the overall vanillin biosynthetic route and present a comparative as well as comprehensive description of enzymes involved in the pathway in Vanilla planifolia and other plants. Special emphasis has been given on the key enzymatic biochemical reactions that have been investigated extensively. Finally, the present standpoint and future prospects have been highlighted.
Topics: Benzaldehydes; Biosynthetic Pathways; Biotechnology; Methyltransferases
PubMed: 28357540
DOI: 10.1007/s00425-017-2684-x