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International Journal of Molecular... Oct 2020Eukaryotic 5-methylcytosine RNA methyltransferases catalyze the transfer of a methyl group to the fifth carbon of a cytosine base in RNA sequences to produce... (Review)
Review
Eukaryotic 5-methylcytosine RNA methyltransferases catalyze the transfer of a methyl group to the fifth carbon of a cytosine base in RNA sequences to produce 5-methylcytosine (mC). mC RNA methyltransferases play a crucial role in the maintenance of functionality and stability of RNA. Viruses have developed a number of strategies to suppress host innate immunity and ensure efficient transcription and translation for the replication of new virions. One such viral strategy is to use host mC RNA methyltransferases to modify viral RNA and thus to affect antiviral host responses. Here, we summarize the latest findings concerning the roles of mC RNA methyltransferases, namely, NOL1/NOP2/SUN domain (NSUN) proteins and DNA methyltransferase 2/tRNA methyltransferase 1 (DNMT2/TRDMT1) during viral infections. Moreover, the use of mC RNA methyltransferase inhibitors as an antiviral therapy is discussed.
Topics: 5-Methylcytosine; Animals; Humans; Methyltransferases; RNA Processing, Post-Transcriptional; RNA, Viral; Virus Diseases
PubMed: 33142933
DOI: 10.3390/ijms21218176 -
Nature Communications Jul 2023Lytic polysaccharide monooxygenases (LPMOs) are oxidative enzymes that help break down lignocellulose, making them highly attractive for improving biomass utilization in...
Lytic polysaccharide monooxygenases (LPMOs) are oxidative enzymes that help break down lignocellulose, making them highly attractive for improving biomass utilization in industrial biotechnology. The catalytically essential N-terminal histidine (His1) of LPMOs is post-translationally modified by methylation in filamentous fungi to protect them from auto-oxidative inactivation, however, the responsible methyltransferase enzyme is unknown. Using mass-spectrometry-based quantitative proteomics in combination with systematic CRISPR/Cas9 knockout screening in Aspergillus nidulans, we identify the N-terminal histidine methyltransferase (NHMT) encoded by the gene AN4663. Targeted proteomics confirm that NHMT was solely responsible for His1 methylation of LPMOs. NHMT is predicted to encode a unique seven-transmembrane segment anchoring a soluble methyltransferase domain. Co-localization studies show endoplasmic reticulum residence of NHMT and co-expression in the industrial production yeast Komagataella phaffii with LPMOs results in His1 methylation of the LPMOs. This demonstrates the biotechnological potential of recombinant production of proteins and peptides harbouring this specific post-translational modification.
Topics: Mixed Function Oxygenases; Histidine; Methylation; Methyltransferases; Polysaccharides; Protein Processing, Post-Translational
PubMed: 37452022
DOI: 10.1038/s41467-023-39875-7 -
Experimental Biology and Medicine... Jan 2007Metabolic conversion of inorganic arsenic into methylated products is a multistep process that yields mono-, di-, and trimethylated arsenicals. In recent years, it has... (Review)
Review
Metabolic conversion of inorganic arsenic into methylated products is a multistep process that yields mono-, di-, and trimethylated arsenicals. In recent years, it has become apparent that formation of methylated metabolites of inorganic arsenic is not necessarily a detoxification process. Intermediates and products formed in this pathway may be more reactive and toxic than inorganic arsenic. Like all metabolic pathways, understanding the pathway for arsenic methylation involves identification of each individual step in the process and the characterization of the molecules which participate in each step. Among several arsenic methyltransferases that have been identified, arsenic (+3 oxidation state) methyltransferase is the one best characterized at the genetic and functional levels. This review focuses on phylogenetic relationships in the deuterostomal lineage for this enzyme and on the relation between genotype for arsenic (+3 oxidation state) methyltransferase and phenotype for conversion of inorganic arsenic to methylated metabolites. Two conceptual models for function of arsenic (+3 oxidation state) methyltransferase which posit different roles for cellular reductants in the conversion of inorganic arsenic to methylated metabolites are compared. Although each model accurately represents some aspects of enzyme's role in the pathway for arsenic methylation, neither model is a fully satisfactory representation of all the steps in this metabolic pathway. Additional information on the structure and function of the enzyme will be needed to develop a more comprehensive model for this pathway.
Topics: Amino Acid Sequence; Animals; Arsenicals; Glutathione; Humans; Methylation; Methyltransferases; Molecular Sequence Data; Oxidation-Reduction
PubMed: 17202581
DOI: No ID Found -
Cellular and Molecular Life Sciences :... Aug 2019The methylation of proteins is integral to the execution of many important biological functions, including cell signalling and transcriptional regulation. Protein... (Review)
Review
The methylation of proteins is integral to the execution of many important biological functions, including cell signalling and transcriptional regulation. Protein methyltransferases (PMTs) are a large class of enzymes that carry out the addition of methyl marks to a broad range of substrates. PMTs are critical for normal cellular physiology and their dysregulation is frequently observed in human disease. As such, PMTs have emerged as promising therapeutic targets with several inhibitors now in clinical trials for oncology indications. The discovery of chemical inhibitors and antagonists of protein methylation signalling has also profoundly impacted our general understanding of PMT biology and pharmacology. In this review, we present general principles for drugging protein methyltransferases or their downstream effectors containing methyl-binding modules, as well as best-in-class examples of the compounds discovered and their impact both at the bench and in the clinic.
Topics: Allosteric Regulation; Binding Sites; Catalytic Domain; Enzyme Inhibitors; Histone-Lysine N-Methyltransferase; Humans; Neoplasms; Precision Medicine; Protein Processing, Post-Translational; Protein-Arginine N-Methyltransferases
PubMed: 31104094
DOI: 10.1007/s00018-019-03147-9 -
Biomolecules Jul 2022As the most abundant internal mRNA modification in eukaryotic cells, -methyladenosine (mA) has emerged as an important regulator of gene expression and has a profound... (Review)
Review
As the most abundant internal mRNA modification in eukaryotic cells, -methyladenosine (mA) has emerged as an important regulator of gene expression and has a profound impact on cancer initiation and progression. mRNA mA modification is regulated by mA methyltransferases, demethylases and reader proteins to fine tune gene expression at the post-transcriptional level. The most well-studied mA methyltransferase, METTL3, plays critical roles in regulating gene expression and affecting the outcome of various cancers. In this review, we discuss the multifaceted roles of METTL3 in regulating specific molecular signaling pathways in different types of cancers and the recent progress on how METTL3 impacts the tumor immune microenvironment. Finally, we discuss future directions and the potential for therapeutic targeting of METTL3 in cancer treatment.
Topics: Adenosine; Humans; Methyltransferases; Neoplasms; RNA, Messenger; Tumor Microenvironment
PubMed: 36008936
DOI: 10.3390/biom12081042 -
Angewandte Chemie (International Ed. in... Apr 2022Nicotinamide N-methyltransferase (NNMT) methylates nicotinamide and has been associated with various diseases. Herein, we report the first cell-potent NNMT bisubstrate...
Nicotinamide N-methyltransferase (NNMT) methylates nicotinamide and has been associated with various diseases. Herein, we report the first cell-potent NNMT bisubstrate inhibitor II399, demonstrating a K of 5.9 nM in a biochemical assay and a cellular IC value of 1.9 μM. The inhibition mechanism and cocrystal structure confirmed II399 engages both the substrate and cofactor binding pockets. Computational modeling and binding data reveal a balancing act between enthalpic and entropic components that lead to II399's low nM binding affinity. Notably, II399 is 1 000-fold more selective for NNMT than closely related methyltransferases. We expect that II399 would serve as a valuable probe to elucidate NNMT biology. Furthermore, this strategy provides the first case of introducing unconventional SAM mimics, which can be adopted to develop cell-potent inhibitors for other SAM-dependent methyltransferases.
Topics: Enzyme Inhibitors; Methyltransferases; Niacinamide; Nicotinamide N-Methyltransferase
PubMed: 35134268
DOI: 10.1002/anie.202114813 -
ACS Chemical Biology Apr 2022Histone methyltransferases (HMTs) are enzymes that catalyze the methylation of lysine or arginine residues of histone proteins, a key post-translational modification... (Review)
Review
Histone methyltransferases (HMTs) are enzymes that catalyze the methylation of lysine or arginine residues of histone proteins, a key post-translational modification (PTM). Aberrant expression or activity of these enzymes can lead to abnormal histone methylation of cancer-related genes and thus promote tumorigenesis. Histone methyltransferases have been implicated in chemotherapeutic resistance and immune stimulation, making these enzymes potential therapeutic targets of interest, and chemically targeting these proteins provides an avenue for novel drug development in cancer therapy. This Review aims to discuss the evolution of chemical approaches that have emerged in the past five years to design probes targeting these enzymes, including inhibition through noncovalent inhibitors, covalent inhibitors, and targeted protein degradation through proteolysis targeting chimeras (PROTACs). This Review also highlights how these compounds have been used to study the myriad of HMT functions in cancer progression and treatment response. The recent advancement of some of these drugs into human clinical investigation and even to regulatory approval highlights HMTs as a promising class of targets for chemical intervention and novel therapy development.
Topics: Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Histones; Humans; Methylation; Methyltransferases; Neoplasms
PubMed: 35363464
DOI: 10.1021/acschembio.2c00062 -
Blood Cancer Discovery May 2022Dnmt3a-mutant stem cells gain a competitive advantage via upregulation of a Txnip-p53-p21 axis and protection from IFNγ induced exhaustion. See related article by Zhang...
Dnmt3a-mutant stem cells gain a competitive advantage via upregulation of a Txnip-p53-p21 axis and protection from IFNγ induced exhaustion. See related article by Zhang et al., p. 220 (5).
Topics: Cells, Cultured; DNA (Cytosine-5-)-Methyltransferases; DNA Methyltransferase 3A; DNA Modification Methylases; Hematopoietic Stem Cells
PubMed: 35394495
DOI: 10.1158/2643-3230.BCD-22-0025 -
The Journal of Biological Chemistry Oct 2022The SpoU-TrmD (SPOUT) methyltransferase superfamily was designated when structural similarity was identified between the transfer RNA-modifying enzymes TrmH (SpoU) and... (Review)
Review
The SpoU-TrmD (SPOUT) methyltransferase superfamily was designated when structural similarity was identified between the transfer RNA-modifying enzymes TrmH (SpoU) and TrmD. SPOUT methyltransferases are found in all domains of life and predominantly modify transfer RNA or ribosomal RNA substrates, though one instance of an enzyme with a protein substrate has been reported. Modifications placed by SPOUT methyltransferases play diverse roles in regulating cellular processes such as ensuring translational fidelity, altering RNA stability, and conferring bacterial resistance to antibiotics. This large collection of S-adenosyl-L-methionine-dependent methyltransferases is defined by a unique α/β fold with a deep trefoil knot in their catalytic (SPOUT) domain. Herein, we describe current knowledge of SPOUT enzyme structure, domain architecture, and key elements of catalytic function, including S-adenosyl-L-methionine co-substrate binding, beginning with a new sequence alignment that divides the SPOUT methyltransferase superfamily into four major clades. Finally, a major focus of this review will be on our growing understanding of how these diverse enzymes accomplish the molecular feat of specific substrate recognition and modification, as highlighted by recent advances in our knowledge of protein-RNA complex structures and the discovery of the dependence of one SPOUT methyltransferase on metal ion binding for catalysis. Considering the broad biological roles of RNA modifications, developing a deeper understanding of the process of substrate recognition by the SPOUT enzymes will be critical for defining many facets of fundamental RNA biology with implications for human disease.
Topics: Humans; Methyltransferases; Models, Molecular; RNA, Transfer; S-Adenosylmethionine; Substrate Specificity; tRNA Methyltransferases
PubMed: 35988649
DOI: 10.1016/j.jbc.2022.102393 -
Biological & Pharmaceutical Bulletin 2012The metabolism of arsenicals, including their reduction and methylation has been extensively studied, and both classical and novel pathways of arsenic methylation are... (Review)
Review
The metabolism of arsenicals, including their reduction and methylation has been extensively studied, and both classical and novel pathways of arsenic methylation are proposed. Arsenic methylation has been considered to be a detoxification process of inorganic arsenicals, although recent studies have indicated that trivalent methylated arsenicals, the intermediate products of arsenic methylation, are more toxic than inorganic arsenicals. In 2002, arsenite (+3 oxidation state) methyltransferase (As3MT) was discovered to be an enzyme responsible for arsenic methylation. This review focuses on current information on the function, genetic polymorphism, and alternative splicing of As3MT, all of which contribute to arsenic metabolism and toxicity.
Topics: Alternative Splicing; Animals; Arsenic; Environmental Pollutants; Humans; Methyltransferases; Polymorphism, Genetic
PubMed: 23123458
DOI: 10.1248/bpb.b212015