-
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 -
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 -
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 -
International Journal of Molecular... Feb 2021Methyltransferase-like protein 16 (METTL16) is a human RNA methyltransferase that installs mA marks on U6 small nuclear RNA (U6 snRNA) and -adenosylmethionine (SAM)... (Review)
Review
Methyltransferase-like protein 16 (METTL16) is a human RNA methyltransferase that installs mA marks on U6 small nuclear RNA (U6 snRNA) and -adenosylmethionine (SAM) synthetase pre-mRNA. METTL16 also controls a significant portion of mA epitranscriptome by regulating SAM homeostasis. Multiple molecular structures of the N-terminal methyltransferase domain of METTL16, including apo forms and complexes with -adenosylhomocysteine (SAH) or RNA, provided the structural basis of METTL16 interaction with the coenzyme and substrates, as well as indicated autoinhibitory mechanism of the enzyme activity regulation. Very recent structural and functional studies of vertebrate-conserved regions (VCRs) indicated their crucial role in the interaction with U6 snRNA. METTL16 remains an object of intense studies, as it has been associated with numerous RNA classes, including mRNA, non-coding RNA, long non-coding RNA (lncRNA), and rRNA. Moreover, the interaction between METTL16 and oncogenic lncRNA MALAT1 indicates the existence of METTL16 features specifically recognizing RNA triple helices. Overall, the number of known human mA methyltransferases has grown from one to five during the last five years. METTL16, CAPAM, and two rRNA methyltransferases, METTL5/TRMT112 and ZCCHC4, have joined the well-known METTL3/METTL14. This work summarizes current knowledge about METTL16 in the landscape of human mA RNA methyltransferases.
Topics: Binding Sites; Humans; Methylation; Methyltransferases; Neoplasms; Nucleic Acid Conformation; Protein Domains; RNA; RNA, Long Noncoding
PubMed: 33671635
DOI: 10.3390/ijms22042176 -
ACS Chemical Biology Jan 2015Growing evidence suggests that histone methyltransferases (HMTs, also known as protein methyltransferases (PMTs)) play an important role in diverse biological processes... (Review)
Review
Growing evidence suggests that histone methyltransferases (HMTs, also known as protein methyltransferases (PMTs)) play an important role in diverse biological processes and human diseases by regulating gene expression and the chromatin state. Therefore, HMTs have been increasingly recognized by the biomedical community as a class of potential therapeutic targets. High quality chemical probes of HMTs, as tools for deciphering their physiological functions and roles in human diseases and testing therapeutic hypotheses, are critical for advancing this promising field. In this review, we focus on the discovery, characterization, and biological applications of chemical probes for HMTs.
Topics: Animals; Drug Design; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Humans; Lysine; Models, Molecular; Protein Binding; Protein Processing, Post-Translational; Small Molecule Libraries; Structure-Activity Relationship
PubMed: 25423077
DOI: 10.1021/cb500785t -
Development (Cambridge, England) May 2023Histone modifications regulate chromatin remodeling and gene expression in development and diseases. DOT1L, the sole histone H3K79 methyltransferase, is essential for...
Histone modifications regulate chromatin remodeling and gene expression in development and diseases. DOT1L, the sole histone H3K79 methyltransferase, is essential for embryonic development. Here, we report that DOT1L regulates male fertility in mouse. DOT1L associates with MLLT10 in testis. DOT1L and MLLT10 localize to the sex chromatin in meiotic and post-meiotic germ cells in an inter-dependent manner. Loss of either DOT1L or MLLT10 leads to reduced testis weight, decreased sperm count and male subfertility. H3K79me2 is abundant in elongating spermatids, which undergo the dramatic histone-to-protamine transition. Both DOT1L and MLLT10 are essential for H3K79me2 modification in germ cells. Strikingly, histones are substantially retained in epididymal sperm from either DOT1L- or MLLT10-deficient mice. These results demonstrate that H3K79 methylation promotes histone replacement during spermiogenesis.
Topics: Animals; Male; Mice; Fertility; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Histones; Methylation; Methyltransferases; Semen; Spermatogenesis; Transcription Factors
PubMed: 37082953
DOI: 10.1242/dev.201501 -
Trends in Plant Science Mar 2012Arsenic (As) is a ubiquitous element that is widespread in the environment and causes numerous health problems. Biomethylation of As has implications for its mobility... (Review)
Review
Arsenic (As) is a ubiquitous element that is widespread in the environment and causes numerous health problems. Biomethylation of As has implications for its mobility and toxicity. Photosynthetic organisms may play a significant role in As geochemical cycling by methylating it to different As species, but little is known about the mechanisms of methylation. Methylated As species have been found in many photosynthetic organisms, and several arsenite S-adenosylmethionine (SAM) methyltransferases have been characterized in cyanobacteria and algae. However, higher plants may not have the ability to methylate As. Instead, methylated arsenicals in plants probably originate from microorganisms in soils and the rhizosphere. Here, we propose possible approaches for developing 'smart' photosynthetic organisms with an enhanced and sensitive biomethylation capacity for bioremediation and safer food.
Topics: Animals; Arsenic; Gene Expression Regulation, Enzymologic; Humans; Methylation; Methyltransferases; Photosynthesis; Phylogeny
PubMed: 22257759
DOI: 10.1016/j.tplants.2011.12.003 -
Protein & Cell Apr 2023Histone lysine methyltransferases (HKMTs) deposit methyl groups onto lysine residues on histones and play important roles in regulating chromatin structure and gene... (Review)
Review
Histone lysine methyltransferases (HKMTs) deposit methyl groups onto lysine residues on histones and play important roles in regulating chromatin structure and gene expression. The structures and functions of HKMTs have been extensively investigated in recent decades, significantly advancing our understanding of the dynamic regulation of histone methylation. Here, we review the recent progress in structural studies of representative HKMTs in complex with nucleosomes (H3K4, H3K27, H3K36, H3K79, and H4K20 methyltransferases), with emphasis on the molecular mechanisms of nucleosome recognition and trans-histone crosstalk by these HKMTs. These structural studies inform HKMTs' roles in tumorigenesis and provide the foundations for developing new therapeutic approaches targeting HKMTs in cancers.
Topics: Nucleosomes; Histones; Histone-Lysine N-Methyltransferase; Lysine; Methyltransferases; Methylation
PubMed: 37051671
DOI: 10.1093/procel/pwac032 -
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