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Wenhe Zhong, Ann Koay, Anna Ngo, Yan Li, Qianhui Nah, Yee Hwa Wong, Yok Hian Chionh, Hui Qi Ng, Xiaoying Koh-Stenta, Anders Poulsen, Klement Foo, Megan McBee, Meng Ling Choong, Abbas El Sahili, Congbao Kang, Alex Matter, Julien Lescar, Jeffrey Hill, Peter C Dedon
Bacterial tRNA modification synthesis pathways are critical to cell survival under stress and thus represent ideal mechanism-based targets for antibiotic development. One such target is the tRNA-(N1 G37) methyltransferase (TrmD), which is conserved and essential in many bacterial pathogens. Here we developed and applied a widely applicable, radioactivity-free, bioluminescence-based high-throughput screen (HTS) against 116,350 compounds from structurally diverse small-molecule libraries to identify inhibitors of Pseudomonas aeruginosa TrmD ( PaTrmD)...
January 25, 2019: ACS Infectious Diseases
Richiro Ushimaru, Hung-Wen Liu
Albomycins are peptidyl thionucleoside natural products that display antimicrobial activity against clinically important patho-gens. Their structures are characterized by a thioheptose with atypical stereochemistry including a D-xylofuranose ring modified with a D-amino acid moiety. Herein it is demonstrated that AbmH is a pyridoxal 5'-phosphate (PLP)-dependent transal-dolase that catalyzes a threo-selective aldol-type reaction to gener-ate the thioheptose core with a D-ribofuranose ring and an L-amino acid moiety...
January 23, 2019: Journal of the American Chemical Society
Gustavo C Román, Oscar Mancera-Páez, Camilo Bernal
DNA methylation and other epigenetic factors are important in the pathogenesis of late-onset Alzheimer's disease (LOAD). Methylenetetrahydrofolate reductase ( MTHFR ) gene mutations occur in most elderly patients with memory loss. MTHFR is critical for production of S-adenosyl-l-methionine (SAM), the principal methyl donor. A common mutation (1364T/T) of the cystathionine-γ-lyase ( CTH ) gene affects the enzyme that converts cystathionine to cysteine in the transsulfuration pathway causing plasma elevation of total homocysteine (tHcy) or hyperhomocysteinemia-a strong and independent risk factor for cognitive loss and AD...
January 14, 2019: International Journal of Molecular Sciences
Hui Liu, Rui-Xue Xu, Xiao-Shuang Zhang, Ting-Ting Zhu, Hong-Xiang Lou, Ai-Xia Cheng
Previously it has been shown that the caffeoyl coenzyme A O-methyltransferase (CCoAOMT) type enzyme PaF6OMT, synthesized by the liverwort Plagiochasma appendiculatum Lehm. & Lindenb., (Aytoniaceae), interacts preferentially with 6-OH flavones. To clarify the biochemistry and evolution of liverwort OMTs, a comparison was made between the nucleotide sequence and biological activity of PaF6OMT and those of three of its homologs MpOMT1 (from Marchantia paleacea Bertol., (Marchantiaceae)), MeOMT1 (Marchantia emarginata Reinw et al...
January 6, 2019: Phytochemistry
Mosaab Yahyaa, Anna Berim, Bhagwat Nawade, Muhammad Ibdah, Natalia Dudareva, Mwafaq Ibdah
Carrot (Daucus carota subsp. sativus) is a widely cultivated root vegetable of high economic importance. The aroma of carrot roots and aboveground organs is mainly defined by terpenes. We found that leaves of orange carrot cultivar also produce considerable amounts of the phenylpropenes methyleugenol and methylisoeugenol. Notably, methyleugenol is most abundant in young leaves, while methylisoeugenol is the dominant phenylpropene in mature leaf tissue. The goal of the present study was to shed light on the biochemistry and molecular biology of these compounds' biosynthesis and accumulation...
March 2019: Phytochemistry
Jorge Ripoll-Rozada, Mafalda Costa, José A Manso, Ana Maranha, Vanessa Miranda, André Sequeira, M Rita Ventura, Sandra Macedo-Ribeiro, Pedro José Barbosa Pereira, Nuno Empadinhas
Mycobacteria are a wide group of organisms that includes strict pathogens, such as Mycobacterium tuberculosis , as well as environmental species known as nontuberculous mycobacteria (NTM), some of which-namely Mycobacterium avium -are important opportunistic pathogens. In addition to a distinctive cell envelope mediating critical interactions with the host immune system and largely responsible for their formidable resistance to antimicrobials, mycobacteria synthesize rare intracellular polymethylated polysaccharides implicated in the modulation of fatty acid metabolism, thus critical players in cell envelope assembly...
January 3, 2019: Proceedings of the National Academy of Sciences of the United States of America
Peter Dome, Laszlo Tombor, Judit Lazary, Xenia Gonda, Zoltan Rihmer
Given the moderate efficacy of the currently available antidepressants (ADs) in the treatment of major depressive disorder (MDD), the identification of agents that are both able to enhance the effectiveness of ADs and have a good safety profile is a reasonable task for current psychopharmacology. In addition to the well-known drugs (second-generation antipsychotics, levothyroxine, dopaminergic agents, etc.) for augmentation, investigations suggest that several nutraceuticals and over-the-counter (OTC) drugs may be effective and safe as adjunct therapeutic agents to conventional ADs...
December 29, 2018: Brain Research Bulletin
Laura Mosca, Martina Pagano, Concetta Paola Ilisso, Donatella Delle Cave, Vincenzo Desiderio, Luigi Mele, Michele Caraglia, Giovanna Cacciapuoti, Marina Porcelli
S-Adenosyl-l-methionine (AdoMet) is a naturally and widely occurring sulfonium compound that plays a primary role in cell metabolism and acts as the principal methyl donor in many methylation reactions. AdoMet also exhibits antiproliferative and proapoptotic activities in different cancer cells. However, the molecular mechanisms underlying the effects exerted by AdoMet have only been partially studied. In the current study, we evaluated the antiproliferative effect of AdoMet on Cal-33 oral and JHU-SCC-011 laryngeal squamous cancer cells to define the underlying mechanisms...
December 21, 2018: Journal of Cellular Physiology
Shaifali Pal, Shubhra Rastogi, Dinesh A Nagegowda, Madan Mohan Gupta, Ajit Kumar Shasany, Chandan Singh Chanotiya
The medicinal properties of Ashwagandha (Withania somnifera) are accredited to a group of compounds called as withanolides. 24-methylene cholesterol is the intermediate for sterol biosynthesis and a proposed precursor of withanolides biogenesis. But, conversion of 24-methylene cholesterol to withaferin A and other withanolides has not yet been biochemically dissected. Hence, in an effort to fill this gap, an important gene S-adenosyl L-methionine-dependent sterol-C24-methyltransferase type 1 (SMT1), involved in the first committed step for sterol biosynthesis, from W...
December 12, 2018: Plant & Cell Physiology
Guoliang Lyu, Le Zong, Chao Zhang, Xiaoke Huang, Wenbing Xie, Junnan Fang, Yiting Guan, Lijun Zhang, Ting Ni, Jun Gu, Wei Tao
Stimulatory regulators for DNA methyltransferase activity, such as Dnmt3L and some Dnmt3b isoforms, affect DNA methylation patterns, thereby maintaining gene body methylation and maternal methylation imprinting, as well as the methylation landscape of pluripotent cells. Here we show that metastasis-related methyltransferase 1 (Merm1), a protein deleted in individuals with Williams-Beuren syndrome, acts as a repressive regulator of Dnmt3a. Merm1 interacts with Dnmt3a and represses its methyltransferase activity with the requirement of the binding motif for S-adenosyl-L-methionine...
March 21, 2018: Journal of Molecular Cell Biology
Concetta Paola Ilisso, Donatella Delle Cave, Laura Mosca, Martina Pagano, Alessandra Coppola, Luigi Mele, Michele Caraglia, Giovanna Cacciapuoti, Marina Porcelli
Background: To get insight into the molecular mechanisms underlying the anti-tumor activity of S-adenosyl-l-methionine (AdoMet), we analyzed AdoMet-induced modulation of microRNAs (miRNAs) expression profile in MCF-7 breast cell line and its correlation with cancer-related biological pathways. Methods: MiRNA expression profiling was performed using a TaqMan MiRNA Array, following 500 µM AdoMet-treatment. The results were confirmed by Quantitative real-time PCR analysis...
2018: Cancer Cell International
M D Neranjan Tharuka, Thanthrige Thiunuwan Priyathilaka, Hyerim Yang, Amirthalingam Pavithiran, Jehee Lee
Viperin is recognized as an antiviral protein that is stimulated by interferon, viral exposures, and other pathogenic molecules in vertebrate. In this study, a viperin homolog in the Big-belly seahorse (Hippocampus abdominalis; HaVip) was functionally characterized to determine its subcellular localization, expression pattern, and antiviral activity in vitro. The HaVip coding sequence encodes a 348 amino acid polypeptide with predicted molecular weight of 38.48 kDa. Sequence analysis revealed that HaVip comprises three main domains: the N-terminal amphipathic α-helix, a radical S-adenosyl-L-methionine (SAM) domain, and a conserved C-terminal domain...
December 5, 2018: Fish & Shellfish Immunology
Roee Birnbaum, Naama Yosha-Orpaz, Miri Yanoov-Sharav, Dvora Kidron, Hila Gur, Keren Yosovich, Tally Lerman-Sagie, Gustavo Malinger, Dorit Lev
Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyze the transfer of methyl groups from S-adenosyl-l-methionine to nitrogen atoms on arginine residues. Arginine methylation is involved in multiple biological processes, such as signal transduction, mRNA splicing, transcriptional control, DNA repair, and protein translocation. Currently, 10 patients have been described with mutations in PRMT7. The shared findings include: hypotonia, intellectual disability, short stature, brachydactyly, and mild dysmorphic features...
December 4, 2018: American Journal of Medical Genetics. Part A
Romana Bacova, Borivoj Klejdus, Pavel Ryant, Natalia Cernei, Vojtech Adam, Dalibor Huska
Epigenetic changes are important mechanisms in the regulation of chromatin structure and gene expression. Cytosine methylation is one of the major epigenetic modifications, mediated by DNA methyltransferases, which transfer methyl groups from S-adenosyl-L-methionine (SAM) to the fifth carbon of cytosine. Various external environmental conditions can change the global hypo/hypermethylation pattern of DNA. These alterations may affect the organism's response to stress conditions. In this study, for the first time, we investigated the effects of 5-azacytidine, a DNA methyltransferase inhibitor, and cadmium, a toxic metal and environmental pollutant, on the growth, biosynthesis of secondary metabolites (phenols, flavonoids, carotenoids), SAM, S-adenosylhomocysteine, 5'-methylthioadenosine and global 5-methylcytosine (5-mC) in the green microalgae Chlamydomonas reinhardtii and Scenedesmus quadricauda...
December 2, 2018: Journal of Phycology
Sarah Hymbaugh, Lindsay Pecor, Christoper M Tracy, Lindsay R Comstock
Histones, the fundamental building blocks of nucleosomes, undergo post-translational modifications and play a major role in the regulation of transcriptional processes. While the significance of these modifications, including methylation, is widely recognized, little is known about the mechanisms that link such events. To improve our understanding of how protein methylation is intricately linked, we have developed novel N-mustard analogs of S-adenosyl-L-methionine (SAM) functionalized with azides and alkynes to serve as probes of biological methylation...
November 14, 2018: Chembiochem: a European Journal of Chemical Biology
Patricia Amara, Jean-Marie Mouesca, Maxime Bella, Lydie Martin, Claire Saragaglia, Serge Gambarelli, Yvain Nicolet
The radical S-adenosyl-l-methionine tryptophan lyase uses radical-based chemistry to convert l-tryptophan into 3-methyl-2-indolic acid, a fragment in the biosynthesis of the thiopeptide antibiotic nosiheptide. This complex reaction involves several successive steps corresponding to (i) the activation by a specific hydrogen-atom abstraction, (ii) an unprecedented •CO2 - radical migration, (iii) a cyanide fragment release, and (iv) the termination of the radical-based reaction. In vitro study of this reaction is made more difficult because the enzyme produces a significant amount of a shunt product instead of the natural product...
November 16, 2018: Journal of the American Chemical Society
Cheng Dong, Guangping Dong, Li Li, Licheng Zhu, Wolfram Tempel, Yanli Liu, Rong Huang, Jinrong Min
α-N-terminal methylation of proteins is an important post-translational modification that is catalyzed by two different N-terminal methyltransferases, namely NTMT1 and NTMT2. Previous studies have suggested that NTMT1 is a tri-methyltransferase, whereas NTMT2 is a mono-methyltransferase. Here, we report the first crystal structures, to our knowledge, of NTMT2 in binary complex with S-adenosyl-L-methionine as well as in ternary complex with S-adenosyl-L-homocysteine and a substrate peptide. Our structural observations combined with biochemical studies reveal that NTMT2 is also able to di-/tri-methylate the GPKRIA peptide and di-methylate the PPKRIA peptide, otherwise it is predominantly a mono-methyltransferase...
2018: Communications biology
Dhanaraju Mandalapu, Xinjian Ji, Qi Zhang
Sulfoxides and sulfones are commonly found in nature as a result of thioether oxidation, whereas only a very few enzymes have been found to metabolize these compounds. Utilizing the strong reduction potential of the [4Fe-4S] cluster of radical S-adenosyl-l-methionine (SAM) enzymes, we herein report the first enzyme-catalyzed reductive cleavage of sulfoxide and sulfone. We show two radical SAM enzymes, tryptophan lyase NosL and the class C radical SAM methyltransferase NosN, are able to act on a sulfoxide SAHO and a sulfone SAHO2 , both of which are structurally similar to SAM...
November 12, 2018: Biochemistry
William E Broderick, Brian M Hoffman, Joan B Broderick
The seeds for recognition of the vast superfamily of radical S-adenosyl-l-methionine (SAM) enzymes were sown in the 1960s, when Joachim Knappe found that the dissimilation of pyruvate was dependent on SAM and Fe(II), and Barker and co-workers made similar observations for lysine 2,3-aminomutase. These intriguing observations, coupled with the evidence that SAM and Fe were cofactors in radical catalysis by these enzyme systems, drew us in the 1990s to explore how Fe(II) and SAM initiate radical reactions. Our early work focused on the same enzyme Knappe had originally characterized: the pyruvate formate-lyase activating enzyme (PFL-AE)...
October 15, 2018: Accounts of Chemical Research
Adam Frankel, Jennifer I Brown
Protein arginine N-methyltransferase (PRMT) kinetic parameters have been catalogued over the past fifteen years for eight of the nine mammalian enzyme family members. Like the majority of methyltransferases, these enzymes employ the highly ubiquitous cofactor S-adenosyl-l-methionine as a co-substrate to methylate arginine residues in peptidic substrates with an approximately 4-μM median KM . The median values for PRMT turnover number (kcat ) and catalytic efficiency (kcat /KM ) are 0.0051 s-1 and 708 M-1  s-1 , respectively...
October 17, 2018: Biochimica et biophysica acta. Proteins and proteomics
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