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Leukemia & Lymphoma Feb 2020DNA methyltransferases (DNMTs) are highly conserved DNA-modifying enzymes that play important roles in epigenetic regulation and they are involved in cell proliferation,... (Review)
Review
DNA methyltransferases (DNMTs) are highly conserved DNA-modifying enzymes that play important roles in epigenetic regulation and they are involved in cell proliferation, differentiation, and apoptosis. In mammalian cells, three active DNMTs have been identified: DNMT1 acts as a maintenance methyltransferase to replicate preexisting methylation patterns, whereas DNMT3A and DNMT3B primarily act as methyltransferases that are responsible for establishing DNA methylation patterns by adding a methyl group to cytosine bases. The expression of is widespread in a variety of hematological cells and it is altered in each type of leukemia, which is associated with its pathogenesis, progression, treatment, and prognosis. Here, we review current information on DNMT3B in leukemia, including its expression, single-nucleotide polymorphisms, mutations, regulation, function, and clinical value for anti-leukemic therapy and prognosis.
Topics: Animals; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; Epigenesis, Genetic; Humans; Leukemia; Methyltransferases; Protein Processing, Post-Translational; DNA Methyltransferase 3B
PubMed: 31547729
DOI: 10.1080/10428194.2019.1666377 -
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 -
Pharmacology & Therapeutics 1989
Review
Topics: Animals; Humans; Methylation; Methyltransferases; Pharmacogenetics
PubMed: 2675130
DOI: 10.1016/0163-7258(89)90048-x -
Mutation Research. Reviews in Mutation... 2021Enzymatic methylation catalyzed by methyltransferases has a significant impact on many human biochemical reactions. As the second most ubiquitous cofactor in humans,... (Review)
Review
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.
Topics: Animals; Humans; Metabolism, Inborn Errors; Methyltransferases; Polymorphism, Single Nucleotide; S-Adenosylmethionine
PubMed: 34893161
DOI: 10.1016/j.mrrev.2021.108396 -
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 -
European Journal of Medicinal Chemistry Feb 2022Methyltransferase complex, such as METTL3/METTL14/WTP, catalyze N-methyladenosine (mA), which is the most abundant mRNA modification in mammals. Besides acting as a mA... (Review)
Review
Methyltransferase complex, such as METTL3/METTL14/WTP, catalyze N-methyladenosine (mA), which is the most abundant mRNA modification in mammals. Besides acting as a mA methyltransferase, METTL3 also regulates mRNA translation and other biological processes. Studies have identified numerous roles and molecular mechanisms associated with METTL3 in multiple biological processes especially in tumors in recent years. Furthermore, targeting METTL3 as an efficient therapeutic way for the treatment of different kinds of tumors has gained a lot of attention. However, these findings and researches have not been summarized. In this review, the most recent important roles of METTL3 in various tumors including acute myeloid leukemia, lung cancer, breast cancer, liver cancer, gastric cancer, pancreatic cancer, colorectal cancer, bladder cancer, prostate cancer and glioblastoma were systematically summarized. In addition, disclosed METTL3 inhibitors recently were also summarized and discussed for medicinal chemists investigating METTL3 inhibitors with different skeleton structures for the application of human cancer therapy.
Topics: Adenosine; Animals; Antineoplastic Agents; Drug Development; Humans; Methyltransferases; Neoplasms; Protein Biosynthesis
PubMed: 35063732
DOI: 10.1016/j.ejmech.2022.114118 -
Biochimica Et Biophysica Acta Sep 1997Phosphatidylethanolamine N-methyltransferase (PEMT) converts phosphatidylethanolamine to phosphatidylcholine. Most PEMT activity (PEMT1) is associated with endoplasmic... (Review)
Review
Phosphatidylethanolamine N-methyltransferase (PEMT) converts phosphatidylethanolamine to phosphatidylcholine. Most PEMT activity (PEMT1) is associated with endoplasmic reticulum. A second form of the enzyme (PEMT2) has been localized to the mitochondria-associated membrane. PEMT2 is a 22.5-kDa protein that has been purified from rat liver. The rat liver PEMT2 cDNA and the murine PEMT gene have been cloned and characterized. The PEMT gene encodes both forms of the enzyme. Deletion of the PEMT gene eliminates all activity in liver that converts phosphatidylethanolamine to phosphatidylcholine. The activity of PEMT is regulated by supply of the substrates, phosphatidylethanolamine and S-adenosylmethionine, and by the product S-adenosylhomocysteine. The expression of the gene is regulated during development and by the supply of choline in the diet. There is reciprocal regulation of the Kennedy pathway for phosphatidylcholine biosynthesis (via CDP-choline) and phosphatidylethanolamine N-methyltransferase. Several experimental approaches suggest that this enzyme might play a role in regulation of hepatocyte growth and cell division.
Topics: Animals; Cloning, Molecular; DNA, Complementary; Liver; Methyltransferases; Phosphatidylethanolamine N-Methyltransferase; Substrate Specificity
PubMed: 9370326
DOI: 10.1016/s0005-2760(97)00108-2 -
Cells Oct 2023DNA methylation is an epigenetic mechanism that regulates gene expression without altering gene sequences in health and disease. DNA methyltransferases (DNMTs) are... (Review)
Review
The Role of Clonal Hematopoiesis of Indeterminant Potential and DNA (Cytosine-5)-Methyltransferase Dysregulation in Pulmonary Arterial Hypertension and Other Cardiovascular Diseases.
DNA methylation is an epigenetic mechanism that regulates gene expression without altering gene sequences in health and disease. DNA methyltransferases (DNMTs) are enzymes responsible for DNA methylation, and their dysregulation is both a pathogenic mechanism of disease and a therapeutic target. DNMTs change gene expression by methylating CpG islands within exonic and intergenic DNA regions, which typically reduces gene transcription. Initially, mutations in the genes and pathologic DNMT protein expression were found to cause hematologic diseases, like myeloproliferative disease and acute myeloid leukemia, but recently they have been shown to promote cardiovascular diseases, including coronary artery disease and pulmonary hypertension. We reviewed the regulation and functions of DNMTs, with an emphasis on somatic mutations in , a common cause of clonal hematopoiesis of indeterminant potential (CHIP) that may also be involved in the development of pulmonary arterial hypertension (PAH). Accumulation of somatic mutations in and other CHIP genes in hematopoietic cells and cardiovascular tissues creates an inflammatory environment that promotes cardiopulmonary diseases, even in the absence of hematologic disease. This review summarized the current understanding of the roles of DNMTs in maintenance and de novo methylation that contribute to the pathogenesis of cardiovascular diseases, including PAH.
Topics: Humans; DNA (Cytosine-5-)-Methyltransferases; DNA Methyltransferase 3A; Methyltransferases; Clonal Hematopoiesis; Pulmonary Arterial Hypertension; Cardiovascular Diseases; DNA; DNA, Intergenic
PubMed: 37947606
DOI: 10.3390/cells12212528 -
Annual Review of Pharmacology and... 1999Methyl conjugation is an important pathway in the biotransformation of many exogenous and endogenous compounds. Pharmacogenetic studies of methyltransferase enzymes have... (Review)
Review
Methyl conjugation is an important pathway in the biotransformation of many exogenous and endogenous compounds. Pharmacogenetic studies of methyltransferase enzymes have resulted in the identification and characterization of functionally important common genetic polymorphisms for catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. In recent years, characterization of these genetic polymorphisms has been extended to include the cloning of cDNAs and genes, as well as a determination of the molecular basis for the effects of inheritance on these methyltransferase enzymes. The thiopurine methyltransferase genetic polymorphism is responsible for clinically significant individual variations in the toxicity and therapeutic efficacy of thiopurine drugs such as 6-mercaptopurine. Phenotyping for the thiopurine methyltransferase genetic polymorphism represents one of the first examples in which testing for a pharmacogenetic variant has entered standard clinical practice. The full functional implications of pharmacogenetic variation in the activities of catechol O-methyltransferase and histamine N-methyltransferase remain to be determined. Finally, experimental strategies used to study methylation pharmacogenetics illustrate the rapid evolution of biochemical, pharmacologic, molecular, and genomic approaches that have been used to determine the role of inheritance in variation in drug metabolism, effect, and toxicity.
Topics: Animals; Catechol O-Methyltransferase; Histamine N-Methyltransferase; Humans; Methylation; Methyltransferases; Pharmaceutical Preparations
PubMed: 10331075
DOI: 10.1146/annurev.pharmtox.39.1.19 -
Journal of Translational Medicine May 2022In recent years, 5-methylcytosine (mC) RNA modification has emerged as a key player in regulating RNA metabolism and function through coding as well as non-coding RNAs.... (Review)
Review
In recent years, 5-methylcytosine (mC) RNA modification has emerged as a key player in regulating RNA metabolism and function through coding as well as non-coding RNAs. Accumulating evidence has shown that mC modulates the stability, translation, transcription, nuclear export, and cleavage of RNAs to mediate cell proliferation, differentiation, apoptosis, stress responses, and other biological functions. In humans, mC RNA modification is catalyzed by the NOL1/NOP2/sun (NSUN) family and DNA methyltransferase 2 (DNMT2). These RNA modifiers regulate the expression of multiple oncogenes such as fizzy-related-1, forkhead box protein C2, Grb associated-binding protein 2, and TEA domain transcription factor 1, facilitating the pathogenesis and progression of cancers. Furthermore, the aberrant expression of methyltransferases have been identified in various cancers and used to predict the prognosis of patients. In this review, we present a comprehensive overview of mC RNA methyltransferases. We specifically highlight the potential mechanism of action of mC in cancer. Finally, we discuss the prospect of mC-relative studies.
Topics: 5-Methylcytosine; Humans; Methyltransferases; Neoplasms; RNA; RNA Processing, Post-Transcriptional
PubMed: 35562754
DOI: 10.1186/s12967-022-03427-2