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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
Tsehai A J Grell, Benjamin N Bell, Chi Nguyen, Daniel P Dowling, Nathan A Bruender, Vahe Bandarian, Catherine L Drennan
7-carboxy-7-deazaguanine synthase, QueE, catalyzes the radical mediated ring contraction of 6-carboxy-5,6,7,8-tetrahydropterin, forming the characteristic pyrrolopyrimidine core of all 7-deazaguanine natural products. QueE is a member of the S-adenosyl-L-methionine (AdoMet) radical enzyme superfamily, which harnesses the reactivity of radical intermediates to perform challenging chemical reactions. Members of the AdoMet radical enzyme superfamily utilize a canonical binding motif, a CX3 CXφC motif, to bind a [4Fe-4S] cluster and a partial (β/α)6 TIM barrel fold for the arrangement of AdoMet and substrates for catalysis...
October 19, 2018: Protein Science: a Publication of the Protein Society
Yan Li, Wenhe Zhong, Ann Zhufang Koay, Hui Qi Ng, Xiaoying Koh-Stenta, Qianhui Nah, Siau Hoi Lim, Andreas Larsson, Julien Lescar, Jeffrey Hill, Peter C Dedon, CongBao Kang
Bacterial tRNA (guanine37 -N1 )-methyltransferase (TrmD) is an important antibacterial target due to its essential role in translation. TrmD has two domains connected with a flexible linker. The N-terminal domain (NTD) of TrmD contains the S-adenosyl-L-methionine (SAM) cofactor binding site and the C-terminal domain is critical for tRNA binding. Here we report the backbone NMR resonance assignments for NTD of Pseudomonas aeruginosa TrmD. Its secondary structure was determined based on the assigned resonances...
October 8, 2018: Biomolecular NMR Assignments
Xiao Liu, Chenghua Wei, Jing Luo, Yiping Wu, Xiaoyu Guo, Ye Ying, Ying Wen, Haifeng Yang
A photoelectrochemical (PEC) method is described for the determination of the activity of M.SssI methyltransferase (MTase). The assay relies on enzyme-linkage reactions and a DNA intercalator Ru(bpy)2 (dppz)2+ (where bpy is 2,2'-bipyridine, and dppz is dipyrido[3,2-a:2',3'-c]phenazine) which both serves as a PEC signal. The PEC electrode was obtained by immobilizing 5'-amino modified DNA strands (containing the methylation recognition site 5'-CCGG-3') on a polyethylenimine (PEI) coated ITO/SnO2 electrode with glutaraldehyde as crosslinking agent...
October 5, 2018: Mikrochimica Acta
Lindsey M Walker, William M Kincannon, Vahe Bandarian, Sean J Elliott
Enzymes in the S-adenosyl-l-methionine (AdoMet) radical enzyme superfamily are metalloenzymes that catalyze a wide variety of complex radical-mediated transformations with the aid of a [4Fe-4S] cluster, which is required for activation of AdoMet to generate the 5'-deoxyadenosyl radical to initiate the catalytic cycle. In addition to this cluster, some enzymes share an additional domain, the SPASM domain, that houses auxiliary FeS clusters whose functional significance is not clearly understood. The AdoMet radical enzyme Tte1186, which catalyzes a thioether cross-link in a cysteine rich peptide (SCIFF), has two auxiliary [4Fe-4S] clusters within a SPASM domain that are required for enzymatic activity but not for the generation of the 5'-deoxyadenosyl radical intermediate...
October 23, 2018: Biochemistry
Ewa Wunsch, Joanna Raszeja-Wyszomirska, Olivier Barbier, Malgorzata Milkiewicz, Marcin Krawczyk, Piotr Milkiewicz
BACKGROUND AND AIMS: Chronic liver disease induces an acquired deficiency of S-adenosyl-L-methionine (SAMe) leading to impairment of detoxifying processes in the liver. Ursodeoxycholic acid (UDCA) represents the standard treatment in primary biliary cholangitis (PBC). As both compounds exert their hepatoprotective effects by different mechanisms, it is conceivable that when used together their effect might be additive. The aim of this study was to analyse the effect of SAMe supplementation on liver biochemistry and health-related quality of life (HRQoL) in patients with PBC, treated with UDCA...
September 2018: Journal of Gastrointestinal and Liver Diseases: JGLD
Lizhi Tao, Troy A Stich, Corey J Fugate, Joseph T Jarrett, R David Britt
Biotin (vitamin B7 ) is an enzyme cofactor required by organisms from all branches of life but synthesized only in microbes and plants. In the final step of biotin biosynthesis, a radical S-adenosyl-l-methionine (SAM) enzyme, biotin synthase (BioB), converts the substrate dethiobiotin to biotin through the stepwise formation of two C-S bonds. Previous electron paramagnetic resonance (EPR) spectroscopic studies identified a semistable intermediate in the formation of the first C-S bond as 9-mercaptodethiobiotin linked to a paramagnetic [2Fe-2S] cluster through one of its bridging sulfides...
September 28, 2018: Journal of the American Chemical Society
Derek M Gagnon, Troy A Stich, Angad P Mehta, Sameh H Abdelwahed, Tadhg P Begley, R David Britt
Organisms that perform the de novo biosynthesis of cobalamin (vitamin B12) do so via unique pathways depending on the presence of oxygen in the environment. The anaerobic biosynthesis pathway of 5,6-dimethylbenzimidazole, the so-called "lower ligand" to the cobalt center, has been recently identified. This process begins with the conversion of 5-aminoimidazole ribotide (AIR) to 5-hydroxybenzimidazole (HBI) by the radical S-adenosyl-l-methionine (SAM) enzyme BzaF, also known as HBI synthase. In this work we report the characterization of a radical intermediate in the reaction of BzaF using electron paramagnetic resonance spectroscopy...
September 27, 2018: Journal of the American Chemical Society
Yajun Tao, Jun Wang, Jun Miao, Jie Chen, Shujun Wu, Jinyan Zhu, Dongping Zhang, Houwen Gu, Huan Cui, Shuangyue Shi, Mingyue Xu, Youli Yao, Zhiyun Gong, Zefeng Yang, Minghong Gu, Yong Zhou, Guohua Liang
Polyamines, including putrescine (Put), spermidine (Spd), and spermine (Spm), play essential roles in a wide variety of prokaryotic and eukaryotic organisms. Rice (Oryza sativa) contains four putative spermidine/spermine synthase (SPMS)-encoding genes (OsSPMS1, OsSPMS2, OsSPMS3, and OsACAULIS5), but none have been functionally characterized. In this study, we used a reverse genetic strategy to investigate the biological function of OsSPMS1. We generated several homozygous RNA interference (RNAi) and overexpression (OE) lines of OsSPMS1...
September 6, 2018: Plant Physiology
Lital Estrella Weil, Yulia Shmidov, Margarita Kublanovsky, David Morgenstern, Michal Feldman, Ronit Bitton, Dan Levy
Signaling via lysine methylation by protein lysine methyltransferases (PKMTs), has been linked to diverse biological and disease processes. The mono-methyltransferase SETD6 (SET-domain-containing protein 6) is a member of the PKMT family and was previously shown to regulate essential cellular processes such as the NF-κB, WNT and the oxidative stress pathways. However, on the biochemical level, little is known about the enzymatic mode of action of SETD6. Here we provide evidence that SETD6 forms high-molecular-weight structures...
October 19, 2018: Journal of Molecular Biology
Ekaterina Yu Bezsudnova, Tatiana N Stekhanova, Anna V Popinako, Tatiana V Rakitina, Alena Yu Nikolaeva, Konstantin M Boyko, Vladimir O Popov
Substrate and reaction promiscuity is a remarkable property of some enzymes and facilitates the adaptation to new metabolic demands in the evolutionary process. Substrate promiscuity is also a basis for protein engineering for biocatalysis. However, molecular principles of enzyme promiscuity are not well understood. Even for the widely studied PLP-dependent transaminases of class III, the reliable prediction of the biocatalytically important amine transaminase activity is still difficult if the desired activity is unrelated to the natural activity...
November 2018: Applied Microbiology and Biotechnology
David Mischoulon, Mark Hyman Rapaport
Depression remains difficult to manage, despite the many registered treatments available. For many depressed individuals, particularly those who have not responded to and/or had adverse effects from standard therapies, herbal and natural medications represent a potentially valuable alternative. This chapter will review several natural remedies used in the treatment of depression. Specific remedies covered include St. John's wort (SJW), S-adenosyl-L-methionine (SAMe), omega-3 fatty acids, rhodiola, and others...
August 24, 2018: Handbook of Experimental Pharmacology
Yu Zhao, Yu-Feng Mao, Yi-Shuang Tang, Ming-Zhu Ni, Qiao-Hong Liu, Yan Wang, Qin Feng, Jing-Hua Peng, Yi-Yang Hu
AIM: To elucidate tongue coating microbiota and metabolic differences in chronic hepatitis B (CHB) patients with yellow or white tongue coatings. METHODS: Tongue coating samples were collected from 53 CHB patients (28 CHB yellow tongue coating patients and 25 CHB white tongue coating patients) and 22 healthy controls. Microbial DNA was extracted from the tongue samples, and the bacterial 16S ribosomal RNA gene V3 region was amplified from all samples and sequenced with the Ion Torrent PGM™ sequencing platform according to the standard protocols...
August 14, 2018: World Journal of Gastroenterology: WJG
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