Journal articles: 'RRNA Methyltransferase'

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Corrêa, Laís L., Marta A. Witek, Natalia Zelinskaya, Renata C. Picão, and Graeme L. Conn. "Heterologous Expression and Functional Characterization of the Exogenously Acquired Aminoglycoside Resistance Methyltransferases RmtD, RmtD2, and RmtG." Antimicrobial Agents and Chemotherapy 60, no. 1 (November 9, 2015): 699–702. http://dx.doi.org/10.1128/aac.02482-15.

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ABSTRACTThe exogenously acquired 16S rRNA methyltransferases RmtD, RmtD2, and RmtG were cloned and heterologously expressed inEscherichia coli, and the recombinant proteins were purified to near homogeneity. Each methyltransferase conferred an aminoglycoside resistance profile consistent with m7G1405 modification, and this activity was confirmed byinvitro30S methylation assays. Analyses of protein structure and interaction withS-adenosyl-l-methionine suggest that the molecular mechanisms of substrate recognition and catalysis are conserved across the 16S rRNA (m7G1405) methyltransferase family.

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Savic, Miloje, S. Sunita, Natalia Zelinskaya, Pooja M. Desai, Rachel Macmaster, Kellie Vinal, and Graeme L. Conn. "30S Subunit-Dependent Activation of the Sorangium cellulosum So ce56 Aminoglycoside Resistance-Conferring 16S rRNA Methyltransferase Kmr." Antimicrobial Agents and Chemotherapy 59, no. 5 (March 2, 2015): 2807–16. http://dx.doi.org/10.1128/aac.00056-15.

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ABSTRACTMethylation of bacterial 16S rRNA within the ribosomal decoding center confers exceptionally high resistance to aminoglycoside antibiotics. This resistance mechanism is exploited by aminoglycoside producers for self-protection while functionally equivalent methyltransferases have been acquired by human and animal pathogenic bacteria. Here, we report structural and functional analyses of theSorangium cellulosumSo ce56 aminoglycoside resistance-conferring methyltransferase Kmr. Our results demonstrate that Kmr is a 16S rRNA methyltransferase acting at residue A1408 to confer a canonical aminoglycoside resistance spectrum inEscherichia coli. Kmr possesses a class I methyltransferase core fold but with dramatic differences in the regions which augment this structure to confer substrate specificity in functionally related enzymes. Most strikingly, the region linking core β-strands 6 and 7, which forms part of theS-adenosyl-l-methionine (SAM) binding pocket and contributes to base flipping by the m1A1408 methyltransferase NpmA, is disordered in Kmr, correlating with an exceptionally weak affinity for SAM. Kmr is unexpectedly insensitive to substitutions of residues critical for activity of other 16S rRNA (A1408) methyltransferases and also to the effects of by-product inhibition byS-adenosylhomocysteine (SAH). Collectively, our results indicate that adoption of a catalytically competent Kmr conformation and binding of the obligatory cosubstrate SAM must be induced by interaction with the 30S subunit substrate.

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Nosrati, Meisam, Debayan Dey, Atousa Mehrani, Sarah E. Strassler, Natalia Zelinskaya, Eric D. Hoffer, Scott M. Stagg, Christine M. Dunham, and Graeme L. Conn. "Functionally critical residues in the aminoglycoside resistance-associated methyltransferase RmtC play distinct roles in 30S substrate recognition." Journal of Biological Chemistry 294, no. 46 (October 8, 2019): 17642–53. http://dx.doi.org/10.1074/jbc.ra119.011181.

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Methylation of the small ribosome subunit rRNA in the ribosomal decoding center results in exceptionally high-level aminoglycoside resistance in bacteria. Enzymes that methylate 16S rRNA on N7 of nucleotide G1405 (m7G1405) have been identified in both aminoglycoside-producing and clinically drug-resistant pathogenic bacteria. Using a fluorescence polarization 30S-binding assay and a new crystal structure of the methyltransferase RmtC at 3.14 Å resolution, here we report a structure-guided functional study of 30S substrate recognition by the aminoglycoside resistance-associated 16S rRNA (m7G1405) methyltransferases. We found that the binding site for these enzymes in the 30S subunit directly overlaps with that of a second family of aminoglycoside resistance-associated 16S rRNA (m1A1408) methyltransferases, suggesting that both groups of enzymes may exploit the same conserved rRNA tertiary surface for docking to the 30S. Within RmtC, we defined an N-terminal domain surface, comprising basic residues from both the N1 and N2 subdomains, that directly contributes to 30S-binding affinity. In contrast, additional residues lining a contiguous adjacent surface on the C-terminal domain were critical for 16S rRNA modification but did not directly contribute to the binding affinity. The results from our experiments define the critical features of m7G1405 methyltransferase–substrate recognition and distinguish at least two distinct, functionally critical contributions of the tested enzyme residues: 30S-binding affinity and stabilizing a binding-induced 16S rRNA conformation necessary for G1405 modification. Our study sets the scene for future high-resolution structural studies of the 30S-methyltransferase complex and for potential exploitation of unique aspects of substrate recognition in future therapeutic strategies.

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Chen, Hao, Zhennan Shi, Jiaojiao Guo, Kao-jung Chang, Qianqian Chen, Cong-Hui Yao, Marcia C. Haigis, and Yang Shi. "The human mitochondrial 12S rRNA m4C methyltransferase METTL15 is required for mitochondrial function." Journal of Biological Chemistry 295, no. 25 (May 5, 2020): 8505–13. http://dx.doi.org/10.1074/jbc.ra119.012127.

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Mitochondrial DNA gene expression is coordinately regulated both pre- and post-transcriptionally, and its perturbation can lead to human pathologies. Mitochondrial rRNAs (mt-rRNAs) undergo a series of nucleotide modifications after release from polycistronic mitochondrial RNA precursors, which is essential for mitochondrial ribosomal biogenesis. Cytosine N4-methylation (m4C) at position 839 (m4C839) of the 12S small subunit mt-rRNA was identified decades ago; however, its biogenesis and function have not been elucidated in detail. Here, using several approaches, including immunofluorescence, RNA immunoprecipitation and methylation assays, and bisulfite mapping, we demonstrate that human methyltransferase-like 15 (METTL15), encoded by a nuclear gene, is responsible for 12S mt-rRNA methylation at m4C839 both in vivo and in vitro. We tracked the evolutionary history of RNA m4C methyltransferases and identified a difference in substrate preference between METTL15 and its bacterial ortholog rsmH. Additionally, unlike the very modest impact of a loss of m4C methylation in bacterial small subunit rRNA on the ribosome, we found that METTL15 depletion results in impaired translation of mitochondrial protein-coding mRNAs and decreases mitochondrial respiration capacity. Our findings reveal that human METTL15 is required for mitochondrial function, delineate the evolution of methyltransferase substrate specificities and modification patterns in rRNA, and highlight a differential impact of m4C methylation on prokaryotic ribosomes and eukaryotic mitochondrial ribosomes.

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Rowe, Sebastian J., Ryan J. Mecaskey, Mohamed Nasef, Rachel C. Talton, Rory E. Sharkey, Joshua C. Halliday, and Jack A. Dunkle. "Shared requirements for key residues in the antibiotic resistance enzymes ErmC and ErmE suggest a common mode of RNA recognition." Journal of Biological Chemistry 295, no. 51 (October 5, 2020): 17476–85. http://dx.doi.org/10.1074/jbc.ra120.014280.

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Erythromycin-resistance methyltransferases are SAM dependent Rossmann fold methyltransferases that convert A2058 of 23S rRNA to m62A2058. This modification sterically blocks binding of several classes of antibiotics to 23S rRNA, resulting in a multidrug-resistant phenotype in bacteria expressing the enzyme. ErmC is an erythromycin resistance methyltransferase found in many Gram-positive pathogens, whereas ErmE is found in the soil bacterium that biosynthesizes erythromycin. Whether ErmC and ErmE, which possess only 24% sequence identity, use similar structural elements for rRNA substrate recognition and positioning is not known. To investigate this question, we used structural data from related proteins to guide site-saturation mutagenesis of key residues and characterized selected variants by antibiotic susceptibility testing, single turnover kinetics, and RNA affinity–binding assays. We demonstrate that residues in α4, α5, and the α5-α6 linker are essential for methyltransferase function, including an aromatic residue on α4 that likely forms stacking interactions with the substrate adenosine and basic residues in α5 and the α5-α6 linker that likely mediate conformational rearrangements in the protein and cognate rRNA upon interaction. The functional studies led us to a new structural model for the ErmC or ErmE-rRNA complex.

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McGann, Patrick, Sarah Chahine, Darius Okafor, Ana C. Ong, Rosslyn Maybank, Yoon I. Kwak, Kerry Wilson, Michael Zapor, Emil Lesho, and Mary Hinkle. "Detecting 16S rRNA Methyltransferases in Enterobacteriaceae by Use of Arbekacin." Journal of Clinical Microbiology 54, no. 1 (November 4, 2015): 208–11. http://dx.doi.org/10.1128/jcm.02642-15.

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16S rRNA methyltransferases confer resistance to most aminoglycosides, but discriminating their activity from that of aminoglycoside-modifying enzymes (AMEs) is challenging using phenotypic methods. We demonstrate that arbekacin, an aminoglycoside refractory to most AMEs, can rapidly detect 16S methyltransferase activity inEnterobacteriaceaewith high specificity using the standard disk susceptibility test.

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van Tran, Nhan, Felix G. M. Ernst, Ben R. Hawley, Christiane Zorbas, Nathalie Ulryck, Philipp Hackert, Katherine E. Bohnsack, et al. "The human 18S rRNA m6A methyltransferase METTL5 is stabilized by TRMT112." Nucleic Acids Research 47, no. 15 (July 22, 2019): 7719–33. http://dx.doi.org/10.1093/nar/gkz619.

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Abstract N6-methyladenosine (m6A) has recently been found abundantly on messenger RNA and shown to regulate most steps of mRNA metabolism. Several important m6A methyltransferases have been described functionally and structurally, but the enzymes responsible for installing one m6A residue on each subunit of human ribosomes at functionally important sites have eluded identification for over 30 years. Here, we identify METTL5 as the enzyme responsible for 18S rRNA m6A modification and confirm ZCCHC4 as the 28S rRNA modification enzyme. We show that METTL5 must form a heterodimeric complex with TRMT112, a known methyltransferase activator, to gain metabolic stability in cells. We provide the first atomic resolution structure of METTL5–TRMT112, supporting that its RNA-binding mode differs distinctly from that of other m6A RNA methyltransferases. On the basis of similarities with a DNA methyltransferase, we propose that METTL5–TRMT112 acts by extruding the adenosine to be modified from a double-stranded nucleic acid.

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White, Joshua, Zhihua Li, Richa Sardana, Janusz M. Bujnicki, Edward M. Marcotte, and Arlen W. Johnson. "Bud23 Methylates G1575 of 18S rRNA and Is Required for Efficient Nuclear Export of Pre-40S Subunits." Molecular and Cellular Biology 28, no. 10 (March 10, 2008): 3151–61. http://dx.doi.org/10.1128/mcb.01674-07.

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ABSTRACT BUD23 was identified from a bioinformatics analysis of Saccharomyces cerevisiae genes involved in ribosome biogenesis. Deletion of BUD23 leads to severely impaired growth, reduced levels of the small (40S) ribosomal subunit, and a block in processing 20S rRNA to 18S rRNA, a late step in 40S maturation. Bud23 belongs to the S-adenosylmethionine-dependent Rossmann-fold methyltransferase superfamily and is related to small-molecule methyltransferases. Nevertheless, we considered that Bud23 methylates rRNA. Methylation of G1575 is the only mapped modification for which the methylase has not been assigned. Here, we show that this modification is lost in bud23 mutants. The nuclear accumulation of the small-subunit reporters Rps2-green fluorescent protein (GFP) and Rps3-GFP, as well as the rRNA processing intermediate, the 5′ internal transcribed spacer 1, indicate that bud23 mutants are defective for small-subunit export. Mutations in Bud23 that inactivated its methyltransferase activity complemented a bud23Δ mutant. In addition, mutant ribosomes in which G1575 was changed to adenosine supported growth comparable to that of cells with wild-type ribosomes. Thus, Bud23 protein, but not its methyltransferase activity, is important for biogenesis and export of the 40S subunit in yeast.

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Ruszkowska, Agnieszka. "METTL16, Methyltransferase-Like Protein 16: Current Insights into Structure and Function." International Journal of Molecular Sciences 22, no. 4 (February 22, 2021): 2176. http://dx.doi.org/10.3390/ijms22042176.

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Methyltransferase-like protein 16 (METTL16) is a human RNA methyltransferase that installs m6A marks on U6 small nuclear RNA (U6 snRNA) and S-adenosylmethionine (SAM) synthetase pre-mRNA. METTL16 also controls a significant portion of m6A epitranscriptome by regulating SAM homeostasis. Multiple molecular structures of the N-terminal methyltransferase domain of METTL16, including apo forms and complexes with S-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 m6A 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 m6A RNA methyltransferases.

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L. Aishwarya, K. V., P. V. Geetha, M. Shanthi, and S. Uma. "Co occurrence of two 16S rRNA methyltrasferases along with NDM and OXA 48 like carbapenamases on a single plasmid in Klebsiella pneumoniae." Journal of Laboratory Physicians 11, no. 04 (October 2019): 305–11. http://dx.doi.org/10.4103/jlp.jlp_59_19.

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Abstract BACKGROUND: The carbapenemase-encoding genes, bla NDM- and bla OXA-48 - like , confer resistance to all the known beta-lactams and are encountered along with other beta-lactamase-encoding genes and/or 16S ribosomal RNA (rRNA)-methylating genes. The co-occurrence of bla NDM and bla OXA-48 - like on a single plasmid is a rare occurrence. AIM AND OBJECTIVE: The purpose of the study was to characterize the plasmids in Klebsiella pneumoniae isolates producing 16S rRNA methyltransferase along with bla NDM , bla OXA-48-like , and other resistance encoding genes. MATERIALS AND METHODS: One-hundred and seventeen K. pneumoniae clinical isolates which were resistant to aminoglycosides were collected. Polymerase chain reaction-based screening for 16S rRNA methyltransferase genes armA, rmtB, and rmtC; carbapenamase genes bla NDM , bla OXA-48-like , bla IMP, bla VIM, and bla KPC ; and other resistance genes such as bla TEM, bla SHV, bla CTX-M , and qnr (A, B, and S) determinants acc (6') Ib-cr was performed. Conjugation experiment was carried out for seven isolates that anchored bla NDM and bla OXA-48-like along with any one of the 16S rRNA methyltransferases. The plasmid-based replicon typing for different plasmid-incompatible (Inc) group was performed on the conjugatively transferable plasmids. RESULTS: Among the 16S rRNA methyltransferases, armA was more predominant. bla NDM and bla OXA-48 -like were present in 56 (47.86%) and 22 (18.80%) isolates, respectively. Out of seven isolates which were conjugatively transferable, only four had bla NDM and bla OXA-48 - like on the same plasmid and they belonged to Inc N and A/C replicon. Three isolates co-harbored 16S rRNA methyltransferases armA, rmtB, and rmtC, and out of the them, one isolate harbored two 16S rRNA methyltransferases armA and rmtB, on the single-plasmid replicon A/C. CONCLUSION: This is the first report revealing the coexistence of bla NDM and bla OXA-48 - like co-harboring two 16S rRNA methylases on a single conjugative plasmid replicon belonging to incompatibility group A/C.

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Zong, Zhiyong, Sally R. Partridge, and Jonathan R. Iredell. "RmtC 16S rRNA Methyltransferase in Australia." Antimicrobial Agents and Chemotherapy 52, no. 2 (November 19, 2007): 794–95. http://dx.doi.org/10.1128/aac.01399-07.

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Zhu, Chengming, Qi Yan, Chenchun Weng, Xinhao Hou, Hui Mao, Dun Liu, Xuezhu Feng, and Shouhong Guang. "Erroneous ribosomal RNAs promote the generation of antisense ribosomal siRNA." Proceedings of the National Academy of Sciences 115, no. 40 (September 17, 2018): 10082–87. http://dx.doi.org/10.1073/pnas.1800974115.

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Ribosome biogenesis is a multistep process, during which mistakes can occur at any step of pre-rRNA processing, modification, and ribosome assembly. Misprocessed rRNAs are usually detected and degraded by surveillance machineries. Recently, we identified a class of antisense ribosomal siRNAs (risiRNAs) that down-regulate pre-rRNAs through the nuclear RNAi pathway. To further understand the biological roles of risiRNAs, we conducted both forward and reverse genetic screens to search for more suppressor of siRNA (susi) mutants. We isolated a number of genes that are broadly conserved from yeast to humans and are involved in pre-rRNA modification and processing. Among them, SUSI-2(ceRRP8) is homologous to human RRP8 and engages in m1A methylation of the 26S rRNA. C27F2.4(ceBUD23) is an m7G-methyltransferase of the 18S rRNA. E02H1.1(ceDIMT1L) is a predicted m6(2)Am6(2)A-methyltransferase of the 18S rRNA. Mutation of these genes led to a deficiency in modification of rRNAs and elicited accumulation of risiRNAs, which further triggered the cytoplasmic-to-nuclear and cytoplasmic-to-nucleolar translocations of the Argonaute protein NRDE-3. The rRNA processing deficiency also resulted in accumulation of risiRNAs. We also isolated SUSI-3(RIOK-1), which is similar to human RIOK1, that cleaves the 20S rRNA to 18S. We further utilized RNAi and CRISPR-Cas9 technologies to perform candidate-based reverse genetic screens and identified additional pre-rRNA processing factors that suppressed risiRNA production. Therefore, we concluded that erroneous rRNAs can trigger risiRNA generation and subsequently, turn on the nuclear RNAi-mediated gene silencing pathway to inhibit pre-rRNA expression, which may provide a quality control mechanism to maintain homeostasis of rRNAs.

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Gutierrez, Belen, Jose A. Escudero, Alvaro San Millan, Laura Hidalgo, Laura Carrilero, Cristina M. Ovejero, Alfonso Santos-Lopez, Daniel Thomas-Lopez, and Bruno Gonzalez-Zorn. "Fitness Cost and Interference of Arm/Rmt Aminoglycoside Resistance with the RsmF Housekeeping Methyltransferases." Antimicrobial Agents and Chemotherapy 56, no. 5 (February 13, 2012): 2335–41. http://dx.doi.org/10.1128/aac.06066-11.

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ABSTRACTArm/Rmt methyltransferases have emerged recently in pathogenic bacteria as enzymes that confer high-level resistance to 4,6-disubstituted aminoglycosides through methylation of the G1405 residue in the 16S rRNA (like ArmA and RmtA to -E). In prokaryotes, nucleotide methylations are the most common type of rRNA modification, and they are introduced posttranscriptionally by a variety of site-specific housekeeping enzymes to optimize ribosomal function. Here we show that while the aminoglycoside resistance methyltransferase RmtC methylates G1405, it impedes methylation of the housekeeping methyltransferase RsmF at position C1407, a nucleotide that, like G1405, forms part of the aminoglycoside binding pocket of the 16S rRNA. To understand the origin and consequences of this phenomenon, we constructed a series of in-frame knockout and knock-in mutants ofEscherichia coli, corresponding to the genotypesrsmF+, ΔrsmF,rsmF+rmtC+, and ΔrsmF rmtC+. When analyzed for the antimicrobial resistance pattern, the ΔrsmFbacteria had a decreased susceptibility to aminoglycosides, including 4,6- and 4,5-deoxystreptamine aminoglycosides, showing that the housekeeping methylation at C1407 is involved in intrinsic aminoglycoside susceptibility inE. coli. Competition experiments between the isogenicE. colistrains showed that, contrary to expectation, acquisition ofrmtCdoes not entail a fitness cost for the bacterium. Finally, matrix-assisted laser desorption ionization (MALDI) mass spectrometry allowed us to determine that RmtC methylates the G1405 residue not only in presence but also in the absence of aminoglycoside antibiotics. Thus, the coupling between housekeeping and acquired methyltransferases subverts the methylation architecture of the 16S rRNA but elicits Arm/Rmt methyltransferases to be selected and retained, posing an important threat to the usefulness of aminoglycosides worldwide.

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Wachino, Jun-ichi, Keigo Shibayama, Hiroshi Kurokawa, Kouji Kimura, Kunikazu Yamane, Satowa Suzuki, Naohiro Shibata, Yasuyoshi Ike, and Yoshichika Arakawa. "Novel Plasmid-Mediated 16S rRNA m1A1408 Methyltransferase, NpmA, Found in a Clinically Isolated Escherichia coli Strain Resistant to Structurally Diverse Aminoglycosides." Antimicrobial Agents and Chemotherapy 51, no. 12 (September 17, 2007): 4401–9. http://dx.doi.org/10.1128/aac.00926-07.

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ABSTRACT We have isolated a multiple-aminoglycoside-resistant Escherichia coli strain, strain ARS3, and have been the first to identify a novel plasmid-mediated 16S rRNA methyltransferase, NpmA. This new enzyme shared a relatively low level of identity (30%) to the chromosomally encoded 16S rRNA methyltransferase (KamA) of Streptomyces tenjimariensis, an actinomycete aminoglycoside producer. The introduction of a recombinant plasmid carrying npmA could confer on E. coli consistent resistance to both 4,6-disubstituted 2-deoxystreptamines, such as amikacin and gentamicin, and 4,5-disubstituted 2-deoxystreptamines, including neomycin and ribostamycin. The histidine-tagged NpmA elucidated methyltransferase activity against 30S ribosomal subunits but not against 50S subunits and the naked 16S rRNA molecule in vitro. We further confirmed that NpmA is an adenine N-1 methyltransferase specific for the A1408 position at the A site of 16S rRNA. Drug footprinting data indicated that binding of aminoglycosides to the target site was apparently interrupted by methylation at the A1408 position. These observations demonstrate that NpmA is a novel plasmid-mediated 16S rRNA methyltransferase that provides a panaminoglycoside-resistant nature through interference with the binding of aminoglycosides toward the A site of 16S rRNA through N-1 methylation at position A1408.

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Husain, Nilofer, Karolina L. Tkaczuk, Rajesh T. Shenoy, Katarzyna H. Kaminska, Sonja Čubrilo, Gordana Maravić-Vlahoviček, Janusz M. Bujnicki, and J. Sivaraman. "Structural basis for the methylation of G1405 in 16S rRNA by aminoglycoside resistance methyltransferase Sgm from an antibiotic producer: a diversity of active sites in m 7 G methyltransferases." Nucleic Acids Research 38, no. 12 (February 27, 2010): 4120–32. http://dx.doi.org/10.1093/nar/gkq122.

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Abstract Sgm (Sisomicin-gentamicin methyltransferase) from antibiotic-producing bacterium Micromonospora zionensis is an enzyme that confers resistance to aminoglycosides like gentamicin and sisomicin by specifically methylating G1405 in bacterial 16S rRNA. Sgm belongs to the aminoglycoside resistance methyltransferase (Arm) family of enzymes that have been recently found to spread by horizontal gene transfer among disease-causing bacteria. Structural characterization of Arm enzymes is the key to understand their mechanism of action and to develop inhibitors that would block their activity. Here we report the structure of Sgm in complex with cofactors S-adenosylmethionine (AdoMet) and S-adenosylhomocysteine (AdoHcy) at 2.0 and 2.1 Å resolution, respectively, and results of mutagenesis and rRNA footprinting, and protein-substrate docking. We propose the mechanism of methylation of G1405 by Sgm and compare it with other m 7 G methyltransferases, revealing a surprising diversity of active sites and binding modes for the same basic reaction of RNA modification. This analysis can serve as a stepping stone towards developing drugs that would specifically block the activity of Arm methyltransferases and thereby re-sensitize pathogenic bacteria to aminoglycoside antibiotics.

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Zou, Meijuan, Ying Mu, Xin Chai, Min Ouyang, Long-Jiang Yu, Lixin Zhang, Jörg Meurer, and Wei Chi. "The critical function of the plastid rRNA methyltransferase, CMAL, in ribosome biogenesis and plant development." Nucleic Acids Research 48, no. 6 (February 25, 2020): 3195–210. http://dx.doi.org/10.1093/nar/gkaa129.

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Abstract Methylation of nucleotides in ribosomal RNAs (rRNAs) is a ubiquitous feature that occurs in all living organisms. The formation of methylated nucleotides is performed by a variety of RNA-methyltransferases. Chloroplasts of plant cells result from an endosymbiotic event and possess their own genome and ribosomes. However, enzymes responsible for rRNA methylation and the function of modified nucleotides in chloroplasts remain to be determined. Here, we identified an rRNA methyltransferase, CMAL (Chloroplast MraW-Like), in the Arabidopsis chloroplast and investigated its function. CMAL is the Arabidopsis ortholog of bacterial MraW/ RsmH proteins and accounts to the N4-methylation of C1352 in chloroplast 16S rRNA, indicating that CMAL orthologs and this methyl-modification nucleotide is conserved between bacteria and the endosymbiont-derived eukaryotic organelle. The knockout of CMAL in Arabidopsis impairs the chloroplast ribosome accumulation and accordingly reduced the efficiency of mRNA translation. Interestingly, the loss of CMAL leads not only to defects in chloroplast function, but also to abnormal leaf and root development and overall plant morphology. Further investigation showed that CMAL is involved in the plant development probably by modulating auxin derived signaling pathways. This study uncovered the important role of 16S rRNA methylation mediated by CMAL in chloroplast ribosome biogenesis and plant development.

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Granier, Sophie A., Laura Hidalgo, Alvaro San Millan, Jose Antonio Escudero, Belen Gutierrez, Anne Brisabois, and Bruno Gonzalez-Zorn. "ArmA Methyltransferase in a Monophasic Salmonella enterica Isolate from Food." Antimicrobial Agents and Chemotherapy 55, no. 11 (August 22, 2011): 5262–66. http://dx.doi.org/10.1128/aac.00308-11.

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ABSTRACTThe 16S rRNA methyltransferase ArmA is a worldwide emerging determinant that confers high-level resistance to most clinically relevant aminoglycosides. We report here the identification and characterization of a multidrug-resistantSalmonella entericasubspecies I.4,12:i:− isolate recovered from chicken meat sampled in a supermarket on February 2009 in La Reunion, a French island in the Indian Ocean. Susceptibility testing showed an unusually high-level resistance to gentamicin, as well as to ampicillin, expanded-spectrum cephalosporins and amoxicillin-clavulanate. Molecular analysis of the 16S rRNA methyltransferases revealed presence of thearmAgene, together withblaTEM-1,blaCMY-2, andblaCTX-M-3. All of these genes could be transferreden blocthrough conjugation intoEscherichia coliat a frequency of 10−5CFU/donor. Replicon typing and S1 pulsed-field gel electrophoresis revealed that thearmAgene was borne on an ∼150-kb broad-host-range IncP plasmid, pB1010. To elucidate howarmAhad integrated in pB1010, a PCR mapping strategy was developed for Tn1548, the genetic platform forarmA.The gene was embedded in a Tn1548-like structure, albeit with a deletion of the macrolide resistance genes, and an IS26was inserted within themelgene. To our knowledge, this is the first report of ArmA methyltransferase in food, showing a novel route of transmission for this resistance determinant. Further surveillance in food-borne bacteria will be crucial to determine the role of food in the spread of 16S rRNA methyltransferase genes worldwide.

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Hopkins, Katie L., Jose A. Escudero, Laura Hidalgo, and Bruno Gonzalez-Zorn. "16S rRNA Methyltransferase RmtC inSalmonella entericaSerovar Virchow." Emerging Infectious Diseases 16, no. 4 (April 2010): 712–15. http://dx.doi.org/10.3201/eid1604.090736.

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Richter, Uwe, Kristina Kühn, Sachiko Okada, Axel Brennicke, Andreas Weihe, and Thomas Börner. "A mitochondrial rRNA dimethyladenosine methyltransferase in Arabidopsis." Plant Journal 61, no. 4 (February 2010): 558–69. http://dx.doi.org/10.1111/j.1365-313x.2009.04079.x.

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Gupta, Kirti, Ankit Gupta, and Saman Habib. "Characterization of a Plasmodium falciparum rRNA methyltransferase." Molecular and Biochemical Parasitology 223 (July 2018): 13–18. http://dx.doi.org/10.1016/j.molbiopara.2018.06.001.

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Xu, Zhili, Heather C. O'Farrell, Jason P. Rife, and Gloria M. Culver. "A conserved rRNA methyltransferase regulates ribosome biogenesis." Nature Structural & Molecular Biology 15, no. 5 (April 6, 2008): 534–36. http://dx.doi.org/10.1038/nsmb.1408.

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Tomikawa, Chie. "7-Methylguanosine Modifications in Transfer RNA (tRNA)." International Journal of Molecular Sciences 19, no. 12 (December 17, 2018): 4080. http://dx.doi.org/10.3390/ijms19124080.

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More than 90 different modified nucleosides have been identified in tRNA. Among the tRNA modifications, the 7-methylguanosine (m7G) modification is found widely in eubacteria, eukaryotes, and a few archaea. In most cases, the m7G modification occurs at position 46 in the variable region and is a product of tRNA (m7G46) methyltransferase. The m7G46 modification forms a tertiary base pair with C13-G22, and stabilizes the tRNA structure. A reaction mechanism for eubacterial tRNA m7G methyltransferase has been proposed based on the results of biochemical, bioinformatic, and structural studies. However, an experimentally determined mechanism of methyl-transfer remains to be ascertained. The physiological functions of m7G46 in tRNA have started to be determined over the past decade. For example, tRNA m7G46 or tRNA (m7G46) methyltransferase controls the amount of other tRNA modifications in thermophilic bacteria, contributes to the pathogenic infectivity, and is also associated with several diseases. In this review, information of tRNA m7G modifications and tRNA m7G methyltransferases is summarized and the differences in reaction mechanism between tRNA m7G methyltransferase and rRNA or mRNA m7G methylation enzyme are discussed.

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Abedeera, Sudeshi M., Caitlin M. Hawkins, and Sanjaya C. Abeysirigunawardena. "RsmG forms stable complexes with premature small subunit rRNA during bacterial ribosome biogenesis." RSC Advances 10, no. 38 (2020): 22361–69. http://dx.doi.org/10.1039/d0ra02732d.

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RsmG is the methyltransferase responsible for the N7 methylation of G527 of 16S rRNA. Here we show that RsmG binds preferably to premature bacterial small subunit rRNA. The presence of ribosomal proteins also influences the stability of RsmG–rRNA complexes.

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Inoue, Koichi, Soumit Basu, and Masayori Inouye. "Dissection of 16S rRNA Methyltransferase (KsgA) Function in Escherichia coli." Journal of Bacteriology 189, no. 23 (September 21, 2007): 8510–18. http://dx.doi.org/10.1128/jb.01259-07.

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ABSTRACT A 16S rRNA methyltransferase, KsgA, identified originally in Escherichia coli is highly conserved in all living cells, from bacteria to humans. KsgA orthologs in eukaryotes possess functions in addition to their rRNA methyltransferase activity. E. coli Era is an essential GTP-binding protein. We recently observed that KsgA functions as a multicopy suppressor for the cold-sensitive cell growth of an era mutant [Era(E200K)] strain (Q. Lu and M. Inouye, J. Bacteriol. 180:5243-5246, 1998). Here we observed that although KsgA(E43A), KsgA(G47A), and KsgA(E66A) mutations located in the S-adenosylmethionine-binding motifs severely reduced its methyltransferase activity, these mutations retained the ability to suppress the growth defect of the Era(E200K) strain at a low temperature. On the other hand, a KsgA(R248A) mutation at the C-terminal domain that does not affect the methyltransferase activity failed to suppress the growth defect. Surprisingly, E. coli cells overexpressing wild-type KsgA, but not KsgA(R248A), were found to be highly sensitive to acetate even at neutral pH. Such growth inhibition also was observed in the presence of other weak organic acids, such as propionate and benzoate. These chemicals are known to be highly toxic at acidic pH by lowering the intracellular pH. We found that KsgA-induced cells had increased sensitivity to extreme acid conditions (pH 3.0) compared to that of noninduced cells. These results suggest that E. coli KsgA, in addition to its methyltransferase activity, has another unidentified function that plays a role in the suppression of the cold-sensitive phenotype of the Era(E200K) strain and that the additional function may be involved in the acid shock response. We discuss a possible mechanism of the KsgA-induced acid-sensitive phenotype.

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Atkinson, Gemma C., Lykke H. Hansen, Tanel Tenson, Anette Rasmussen, Finn Kirpekar, and Birte Vester. "Distinction between the Cfr Methyltransferase Conferring Antibiotic Resistance and the Housekeeping RlmN Methyltransferase." Antimicrobial Agents and Chemotherapy 57, no. 8 (June 10, 2013): 4019–26. http://dx.doi.org/10.1128/aac.00448-13.

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ABSTRACTThecfrgene encodes the Cfr methyltransferase that primarily methylates C-8 in A2503 of 23S rRNA in the peptidyl transferase region of bacterial ribosomes. The methylation provides resistance to six classes of antibiotics of clinical and veterinary importance. TherlmNgene encodes the RlmN methyltransferase that methylates C-2 in A2503 in 23S rRNA and A37 in tRNA, but RlmN does not significantly influence antibiotic resistance. The enzymes are homologous and use the same mechanism involving radicalS-adenosyl methionine to methylate RNA via an intermediate involving a methylated cysteine in the enzyme and a transient cross-linking to the RNA, but they differ in which carbon atom in the adenine they methylate. Comparative sequence analysis identifies differentially conserved residues that indicate functional sequence divergence between the two classes of Cfr- and RlmN-like sequences. The differentiation between the two classes is supported by previous and new experimental evidence from antibiotic resistance, primer extensions, and mass spectrometry. Finally, evolutionary aspects of the distribution of Cfr- and RlmN-like enzymes are discussed.

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Sergeeva, Olga, Philipp Sergeev, Pavel Melnikov, Tatiana Prikazchikova, Olga Dontsova, and Timofei Zatsepin. "Modification of Adenosine196 by Mettl3 Methyltransferase in the 5’-External Transcribed Spacer of 47S Pre-rRNA Affects rRNA Maturation." Cells 9, no. 4 (April 24, 2020): 1061. http://dx.doi.org/10.3390/cells9041061.

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Ribosome biogenesis is among the founding processes in the cell. During the first stages of ribosome biogenesis, polycistronic precursor of ribosomal RNA passes complex multistage maturation after transcription. Quality control of preribosomal RNA (pre-rRNA) processing is precisely regulated by non-ribosomal proteins and structural features of pre-rRNA molecules, including modified nucleotides. However, many participants of rRNA maturation are still unknown or poorly characterized. We report that RNA m6A methyltransferase Mettl3 interacts with the 5′ external transcribed spacer (5′ETS) of the 47S rRNA precursor and modifies adenosine 196. We demonstrated that Mettl3 knockdown results in the increase of pre-rRNA processing rates, while intracellular amounts of rRNA processing machinery components (U3, U8, U13, U14, and U17 small nucleolar RNA (snoRNA)and fibrillarin, nucleolin, Xrn2, and rrp9 proteins), rRNA degradation rates, and total amount of mature rRNA in the cell stay unchanged. Increased efficacy of pre-rRNA cleavage at A’ and A0 positions led to the decrease of 47S and 45S pre-rRNAs in the cell and increase of mature rRNA amount in the cytoplasm. The newly identified conserved motif DRACH sequence modified by Mettl3 in the 5′-ETS region is found and conserved only in primates, which may suggest participation of m6A196 in quality control of pre-rRNA processing at initial stages demanded by increased complexity of ribosome biogenesis.

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Hager, Jutta, Bart L. Staker, and Ursula Jakob. "Substrate Binding Analysis of the 23S rRNA Methyltransferase RrmJ." Journal of Bacteriology 186, no. 19 (October 1, 2004): 6634–42. http://dx.doi.org/10.1128/jb.186.19.6634-6642.2004.

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ABSTRACT The 23S rRNA methyltransferase RrmJ (FtsJ) is responsible for the 2′-O methylation of the universally conserved U2552 in the A loop of 23S rRNA. This 23S rRNA modification appears to be critical for ribosome stability, because the absence of functional RrmJ causes the cellular accumulation of the individual ribosomal subunits at the expense of the functional 70S ribosomes. To gain insight into the mechanism of substrate recognition for RrmJ, we performed extensive site-directed mutagenesis of the residues conserved in RrmJ and characterized the mutant proteins both in vivo and in vitro. We identified a positively charged, highly conserved ridge in RrmJ that appears to play a significant role in 23S rRNA binding and methylation. We provide a structural model of how the A loop of the 23S rRNA binds to RrmJ. Based on these modeling studies and the structure of the 50S ribosome, we propose a two-step model where the A loop undocks from the tightly packed 50S ribosomal subunit, allowing RrmJ to gain access to the substrate nucleotide U2552, and where U2552 undergoes base flipping, allowing the enzyme to methylate the 2′-O position of the ribose.

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Dunn, Sianadh, Olivia Lombardi, and Victoria H. Cowling. "c-Myc co-ordinates mRNA cap methylation and ribosomal RNA production." Biochemical Journal 474, no. 3 (January 20, 2017): 377–84. http://dx.doi.org/10.1042/bcj20160930.

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The mRNA cap is a structure added to RNA pol II transcripts in eukaryotes, which recruits factors involved in RNA processing, nuclear export and translation initiation. RNA guanine-7 methyltransferase (RNMT)–RNA-activating miniprotein (RAM), the mRNA cap methyltransferase complex, completes the basic functional mRNA cap structure, cap 0, by methylating the cap guanosine. Here, we report that RNMT–RAM co-ordinates mRNA processing with ribosome production. Suppression of RNMT–RAM reduces synthesis of the 45S ribosomal RNA (rRNA) precursor. RNMT–RAM is required for c-Myc expression, a major regulator of RNA pol I, which synthesises 45S rRNA. Constitutive expression of c-Myc restores rRNA synthesis when RNMT–RAM is suppressed, indicating that RNMT–RAM controls rRNA production predominantly by controlling c-Myc expression. We report that RNMT–RAM is recruited to the ribosomal DNA locus, which may contribute to rRNA synthesis in certain contexts.

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Bueno, Maria Fernanda C., Gabriela R. Francisco, Jessica A. O'Hara, Doroti de Oliveira Garcia, and Yohei Doi. "Coproduction of 16S rRNA Methyltransferase RmtD or RmtG with KPC-2 and CTX-M Group Extended-Spectrum β-Lactamases in Klebsiella pneumoniae." Antimicrobial Agents and Chemotherapy 57, no. 5 (March 4, 2013): 2397–400. http://dx.doi.org/10.1128/aac.02108-12.

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ABSTRACTEightKlebsiella pneumoniaeclinical strains with high-level aminoglycoside resistance were collected from eight hospitals in São Paulo State, Brazil, in 2010 and 2011. Three of them produced an RmtD group 16S rRNA methyltransferase, RmtD1 or RmtD2. Five strains were found to produce a novel 16S rRNA methyltransferase, designated RmtG, which shared 57 to 58% amino acid identity with RmtD1 and RmtD2. Seven strains coproduced KPC-2 with or without various CTX-M group extended-spectrum β-lactamases, while the remaining strain coproduced CTX-M-2.

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McCulloch, Vicki, and Gerald S. Shadel. "Human Mitochondrial Transcription Factor B1 Interacts with the C-Terminal Activation Region of h-mtTFA and Stimulates Transcription Independently of Its RNA Methyltransferase Activity." Molecular and Cellular Biology 23, no. 16 (August 15, 2003): 5816–24. http://dx.doi.org/10.1128/mcb.23.16.5816-5824.2003.

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ABSTRACT A significant advancement in understanding mitochondrial gene expression is the recent identification of two new human mitochondrial transcription factors, h-mtTFB1 and h-mtTFB2. Both proteins stimulate transcription in collaboration with the high-mobility group box transcription factor, h-mtTFA, and are homologous to rRNA methyltransferases. In fact, the dual-function nature of h-mtTFB1 was recently demonstrated by its ability to methylate a conserved rRNA substrate. Here, we demonstrate that h-mtTFB1 binds h-mtTFA both in HeLa cell mitochondrial extracts and in direct-binding assays via an interaction that requires the C-terminal tail of h-mtTFA, a region necessary for transcriptional activation. In addition, point mutations in conserved methyltransferase motifs of h-mtTFB1 revealed that it stimulates transcription in vitro independently of S-adenosylmethionine binding and rRNA methyltransferase activity. Furthermore, one mutation (G65A) eliminated the ability of h-mtTFB1 to bind DNA yet did not affect transcriptional activation. These results, coupled with the observation that h-mtTFB1 and human mitochondrial RNA (h-mtRNA) polymerase can also be coimmunoprecipitated, lead us to propose a model in which h-mtTFA demarcates mitochondrial promoter locations and where h-mtTFB proteins bridge an interaction between the C-terminal tail of h-mtTFA and mtRNA polymerase to facilitate specific initiation of transcription. Altogether, these data provide important new insight into the mechanism of transcription initiation in human mitochondria and indicate that the dual functions of h-mtTFB1 can be separated.

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Sharkey, Rory E., Johnny B. Herbert, Danielle A. McGaha, Vy Nguyen, Allyn J. Schoeffler, and Jack A. Dunkle. "Three critical regions of the erythromycin resistance methyltransferase, ErmE, are required for function supporting a model for the interaction of Erm family enzymes with substrate rRNA." RNA 28, no. 2 (November 18, 2021): 210–26. http://dx.doi.org/10.1261/rna.078946.121.

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6-Methyladenosine modification of DNA and RNA is widespread throughout the three domains of life and often accomplished by a Rossmann-fold methyltransferase domain which contains conserved sequence elements directing S-adenosylmethionine cofactor binding and placement of the target adenosine residue into the active site. Elaborations to the conserved Rossman-fold and appended domains direct methylation to diverse DNA and RNA sequences and structures. Recently, the first atomic-resolution structure of a ribosomal RNA adenine dimethylase (RRAD) family member bound to rRNA was solved, TFB1M bound to helix 45 of 12S rRNA. Since erythromycin resistance methyltransferases are also members of the RRAD family, and understanding how these enzymes recognize rRNA could be used to combat their role in antibiotic resistance, we constructed a model of ErmE bound to a 23S rRNA fragment based on the TFB1M–rRNA structure. We designed site-directed mutants of ErmE based on this model and assayed the mutants by in vivo phenotypic assays and in vitro assays with purified protein. Our results and additional bioinformatic analyses suggest our structural model captures key ErmE–rRNA interactions and indicate three regions of Erm proteins play a critical role in methylation: the target adenosine binding pocket, the basic ridge, and the α4-cleft.

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32

Lövgren, J. Mattias, and P. Mikael Wikström. "The rlmB Gene Is Essential for Formation of Gm2251 in 23S rRNA but Not for Ribosome Maturation inEscherichia coli." Journal of Bacteriology 183, no. 23 (December 1, 2001): 6957–60. http://dx.doi.org/10.1128/jb.183.23.6957-6960.2001.

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ABSTRACT In Saccharomyces cerevisiae, the rRNA Gm2270 methyltransferase, Pet56p, has an essential role in the maturation of the mitochondrial large ribosomal subunit that is independent of its methyltransferase activity. Here we show that the proposedEscherichia coli ortholog, RlmB (formerly YjfH), indeed is essential for the formation of Gm in position 2251 of 23S rRNA. However, a ΔrlmB mutant did not show any ribosome assembly defects and was not outgrown by a wild-type strain even after 120 cell mass doublings. Thus, RlmB has no important role in ribosome assembly or function in E. coli.

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33

Farrow, Kylie A., Dena Lyras, Galina Polekhina, Katerina Koutsis, Michael W. Parker, and Julian I. Rood. "Identification of Essential Residues in the Erm(B) rRNA Methyltransferase of Clostridium perfringens." Antimicrobial Agents and Chemotherapy 46, no. 5 (May 2002): 1253–61. http://dx.doi.org/10.1128/aac.46.5.1253-1261.2002.

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ABSTRACT Macrolide-lincosamide-streptogramin B resistance is widespread, with the determinants encoding resistance to antibiotics such as erythromycin being detected in many bacterial pathogens. Resistance is most commonly mediated by the production of an Erm protein, a 23S rRNA methyltransferase. We have undertaken a mutational analysis of the Erm(B) protein from Clostridium perfringens with the objective of developing a greater understanding of the mechanism of action of this protein. A recombinant plasmid that carried the erm(B) gene was mutated by either in vitro hydroxylamine mutagenesis or passage through the mutator strain XL1-Red. Twenty-eight independently derived mutants were identified, nine of which had single point mutations in the erm(B) gene. These mutants produced stable but nonfunctional Erm(B) proteins, and all had amino acid changes within conserved methyltransferase motifs that were important for either substrate binding or catalysis. Modeling of the C. perfringens Erm(B) protein confirmed that the point mutations all involved residues important for the structure and/or function of this rRNA methyltransferase. These regions of the protein therefore represent potential targets for the rational development of methyltransferase inhibitors.

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Sergeeva, O. V., D. E. Burakovsky, P. V. Sergiev, T. S. Zatsepin, M. Tomkuviene, S. Klimasauskas, and O. A. Dontsova. "Usage of rRNA-methyltransferase for site-specific fluorescent labeling." Moscow University Chemistry Bulletin 67, no. 2 (March 2012): 88–93. http://dx.doi.org/10.3103/s0027131412020058.

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Kita, S., I. Tanaka, M. Yao, and Y. Tanaka. "Structural and functional analysis of rRNA methyltransferase fromStaphylococcus aureus." Acta Crystallographica Section A Foundations of Crystallography 67, a1 (August 22, 2011): C435—C436. http://dx.doi.org/10.1107/s0108767311089069.

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Mann, Paul A., Liqun Xiong, Alexander S. Mankin, Andrew S. Chau, Cara A. Mendrick, David J. Najarian, Christina A. Cramer, et al. "EmtA, a rRNA methyltransferase conferring high-level evernimicin resistance." Molecular Microbiology 41, no. 6 (September 2001): 1349–56. http://dx.doi.org/10.1046/j.1365-2958.2001.02602.x.

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Pintard, L. "MRM2 encodes a novel yeast mitochondrial 21S rRNA methyltransferase." EMBO Journal 21, no. 5 (March 1, 2002): 1139–47. http://dx.doi.org/10.1093/emboj/21.5.1139.

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Gu, Xiang Rong, Claes Gustafsson, Jung Ku, Ming Yu, and Daniel V. Santi. "Identification of the 16S rRNA m5C967 Methyltransferase fromEscherichia coli†." Biochemistry 38, no. 13 (March 1999): 4053–57. http://dx.doi.org/10.1021/bi982364y.

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39

Su, Sai L., and David Dubnau. "Binding of Bacillus subtilis ermC' methyltransferase to 23S rRNA." Biochemistry 29, no. 25 (June 26, 1990): 6033–42. http://dx.doi.org/10.1021/bi00477a022.

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40

Kumar, Atul, Santosh Kumar, and Bhupesh Taneja. "The structure of Rv2372c identifies an RsmE-like methyltransferase fromMycobacterium tuberculosis." Acta Crystallographica Section D Biological Crystallography 70, no. 3 (February 22, 2014): 821–32. http://dx.doi.org/10.1107/s1399004713033555.

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U1498 of 16S rRNA plays an important role in translation fidelity as well as in antibiotic response. U1498 is present in a methylated form in the decoding centre of the ribosome. In this study, Rv2372c fromMycobacterium tuberculosishas been identified as an RsmE-like methyltransferase which specifically methylates U1498 of 16S rRNA at the N3 position and can complement RsmE-deletedEscherichia coli. The crystal structure of Rv2372c has been determined, and reveals that the protein belongs to a distinct class in the SPOUT superfamily and exists as a dimer. The deletion of critical residues at the C-terminus of Rv2372c leads to an inability of the protein to form stable dimers and to abolition of the methyltransferase activity. A ternary model of Rv2372c with its cofactorS-adenosylmethionine (SAM) and the 16S rRNA fragment148716S rRNA1510helps to identify binding pockets for SAM (in the deep trefoil knot) and substrate RNA (at the dimer interface) and suggests an SN2 mechanism for the methylation of N3 of U1498 in 16S rRNA.

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41

Fritsche, Thomas R., Mariana Castanheira, George H. Miller, Ronald N. Jones, and Eliana S. Armstrong. "Detection of Methyltransferases Conferring High-Level Resistance to Aminoglycosides in Enterobacteriaceae from Europe, North America, and Latin America." Antimicrobial Agents and Chemotherapy 52, no. 5 (March 17, 2008): 1843–45. http://dx.doi.org/10.1128/aac.01477-07.

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ABSTRACT The alteration of ribosomal targets by recently described 16S rRNA methyltransferases confers resistance to most aminoglycosides, including arbekacin. Enterobacteriaceae and nonfermentative bacilli acquired through global surveillance programs were screened for the presence of these enzymes on the basis of phenotypes that were resistant to nine tested aminoglycosides. Subsequent molecular studies determined that 20 of 21 (95.2%) methyltransferase-positive isolates consisted of novel species records or geographic occurrences (North America [armA and rmtB], Latin America [rmtD], and Europe [armA]; rmtA, rmtC, and npmA were not detected). The global emergence of high-level aminoglycoside resistance has become a rapidly changing event requiring careful monitoring.

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Weitnauer, Gabriele, Sibylle Gaisser, Axel Trefzer, Sigrid Stockert, Lucy Westrich, Luis M. Quiros, Carmen Mendez, Jose A. Salas, and Andreas Bechthold. "An ATP-Binding Cassette Transporter and Two rRNA Methyltransferases Are Involved in Resistance to Avilamycin in the Producer Organism Streptomyces viridochromogenesTü57." Antimicrobial Agents and Chemotherapy 45, no. 3 (March 1, 2001): 690–95. http://dx.doi.org/10.1128/aac.45.3.690-695.2001.

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ABSTRACT Three different resistance factors from the avilamycin biosynthetic gene cluster of Streptomyces viridochromogenes Tü57, which confer avilamycin resistance when expressed in Streptomyces lividans TK66, were isolated. Analysis of the deduced amino acid sequences showed that AviABC1 is similar to a large family of ATP-binding transporter proteins and that AviABC2 resembles hydrophobic transmembrane proteins known to act jointly with the ATP-binding proteins. The deduced amino acid sequence of aviRb showed similarity to those of other rRNA methyltransferases, and AviRa did not resemble any protein in the databases. Independent expression inS. lividans TK66 of aviABC1 plus aviABC2, aviRa, or aviRb conferred different levels of resistance to avilamycin: 5, 10, or 250 μg/ml, respectively. When either aviRa plus aviRb or aviRaplus aviRb plus aviABC1 plusaviABC2 was coexpressed in S. lividans TK66, avilamycin resistance levels reached more than 250 μg/ml. Avilamycin A inhibited poly(U)-directed polyphenylalanine synthesis in an in vitro system using ribosomes of S. lividans TK66(pUWL201) (GWO),S. lividans TK66(pUWL201-Ra) (GWRa), or S. lividans TK66(pUWL201-Rb) (GWRb), whereas ribosomes of S. lividans TK66 containing pUWL201-Ra+Rb (GWRaRb) were highly resistant. aviRa and aviRb were expressed inEscherichia coli, and both enzymes were purified as fusion proteins to near homogeneity. Both enzymes showed rRNA methyltransferase activity using a mixture of 16S and 23S rRNAs fromE. coli as the substrate. Coincubation experiments revealed that the enzymes methylate different positions of rRNA.

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43

Lyu, Guoliang, Le Zong, Chao Zhang, Xiaoke Huang, Wenbing Xie, Junnan Fang, Yiting Guan, et al. "Metastasis-related methyltransferase 1 (Merm1) represses the methyltransferase activity of Dnmt3a and facilitates RNA polymerase I transcriptional elongation." Journal of Molecular Cell Biology 11, no. 1 (March 21, 2018): 78–90. http://dx.doi.org/10.1093/jmcb/mjy023.

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Abstract 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. Functional analysis of gene regulation revealed that Merm1 is capable of maintaining hypomethylated rRNA gene bodies and co-localizes with RNA polymerase I in the nucleolus. Dnmt3a recruits Merm1, and in return, Merm1 ensures the binding of Dnmt3a to hypomethylated gene bodies. Such interplay between Dnmt3a and Merm1 facilitates transcriptional elongation by RNA polymerase I. Our findings reveal a repressive factor for Dnmt3a and uncover a molecular mechanism underlying transcriptional elongation of rRNA genes.

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44

Long, Katherine S., Jacob Poehlsgaard, Corinna Kehrenberg, Stefan Schwarz, and Birte Vester. "The Cfr rRNA Methyltransferase Confers Resistance to Phenicols, Lincosamides, Oxazolidinones, Pleuromutilins, and Streptogramin A Antibiotics." Antimicrobial Agents and Chemotherapy 50, no. 7 (July 2006): 2500–2505. http://dx.doi.org/10.1128/aac.00131-06.

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ABSTRACT A novel multidrug resistance phenotype mediated by the Cfr rRNA methyltransferase is observed in Staphylococcus aureus and Escherichia coli. The cfr gene has previously been identified as a phenicol and lincosamide resistance gene on plasmids isolated from Staphylococcus spp. of animal origin and recently shown to encode a methyltransferase that modifies 23S rRNA at A2503. Antimicrobial susceptibility testing shows that S. aureus and E. coli strains expressing the cfr gene exhibit elevated MICs to a number of chemically unrelated drugs. The phenotype is named PhLOPSA for resistance to the following drug classes: Phenicols, Lincosamides, Oxazolidinones, Pleuromutilins, and Streptogramin A antibiotics. Each of these five drug classes contains important antimicrobial agents that are currently used in human and/or veterinary medicine. We find that binding of the PhLOPSA drugs, which bind to overlapping sites at the peptidyl transferase center that abut nucleotide A2503, is perturbed upon Cfr-mediated methylation. Decreased drug binding to Cfr-methylated ribosomes has been confirmed by footprinting analysis. No other rRNA methyltransferase is known to confer resistance to five chemically distinct classes of antimicrobials. In addition, the findings described in this study represent the first report of a gene conferring transferable resistance to pleuromutilins and oxazolidinones.

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45

Gustafsson, Claes, and Britt C. Persson. "Identification of the rrmA Gene Encoding the 23S rRNA m1G745 Methyltransferase in Escherichia coli and Characterization of an m1G745-Deficient Mutant." Journal of Bacteriology 180, no. 2 (January 15, 1998): 359–65. http://dx.doi.org/10.1128/jb.180.2.359-365.1998.

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ABSTRACT An Escherichia coli mutant lacking the modified nucleotide m1G in rRNA has previously been isolated (G. R. Björk and L. A. Isaksson, J. Mol. Biol. 51:83–100, 1970). In this study, we localize the position of the m1G to nucleotide 745 in 23S rRNA and characterize a mutant deficient in this modification. This mutant shows a 40% decreased growth rate in rich media, a drastic reduction in loosely coupled ribosomes, a 20% decreased polypeptide chain elongation rate, and increased resistance to the ribosome binding antibiotic viomycin. TherrmA gene encoding 23S rRNA m1G745 methyltransferase was mapped to bp 1904000 on the E. colichromosome and identified to be identical to the previously sequenced gene yebH.

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46

Yang, Weiwei, and Fupin Hu. "Research Updates of Plasmid-Mediated Aminoglycoside Resistance 16S rRNA Methyltransferase." Antibiotics 11, no. 7 (July 7, 2022): 906. http://dx.doi.org/10.3390/antibiotics11070906.

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With the wide spread of multidrug-resistant bacteria, a variety of aminoglycosides have been used in clinical practice as one of the effective options for antimicrobial combinations. However, in recent years, the emergence of high-level resistance against pan-aminoglycosides has worsened the status of antimicrobial resistance, so the production of 16S rRNA methyltransferase (16S-RMTase) should not be ignored as one of the most important resistance mechanisms. What is more, on account of transferable plasmids, the horizontal transfer of resistance genes between pathogens becomes easier and more widespread, which brings challenges to the treatment of infectious diseases and infection control of drug-resistant bacteria. In this review, we will make a presentation on the prevalence and genetic environment of 16S-RMTase encoding genes that lead to high-level resistance to aminoglycosides.

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47

Sergeeva, O. V., I. V. Prokhorova, Y. Ordabaev, P. O. Tsvetkov, P. V. Sergiev, A. A. Bogdanov, A. A. Makarov, and O. A. Dontsova. "Properties of small rRNA methyltransferase RsmD: Mutational and kinetic study." RNA 18, no. 6 (April 25, 2012): 1178–85. http://dx.doi.org/10.1261/rna.032763.112.

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48

Demirci, H., L. H. G. Larsen, T. Hansen, A. Rasmussen, A. Cadambi, S. T. Gregory, F. Kirpekar, and G. Jogl. "Multi-site-specific 16S rRNA methyltransferase RsmF from Thermus thermophilus." RNA 16, no. 8 (June 17, 2010): 1584–96. http://dx.doi.org/10.1261/rna.2088310.

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49

Lesnyak, Dmitry V., Jerzy Osipiuk, Tatiana Skarina, Petr V. Sergiev, Alexey A. Bogdanov, Aled Edwards, Alexei Savchenko, Andrzej Joachimiak, and Olga A. Dontsova. "Methyltransferase That Modifies Guanine 966 of the 16 S rRNA." Journal of Biological Chemistry 282, no. 8 (December 21, 2006): 5880–87. http://dx.doi.org/10.1074/jbc.m608214200.

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50

Denoya, C. D., and D. Dubnau. "Site and substrate specificity of the ermC 23S rRNA methyltransferase." Journal of Bacteriology 169, no. 8 (1987): 3857–60. http://dx.doi.org/10.1128/jb.169.8.3857-3860.1987.

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Journal articles on the topic 'RRNA Methyltransferase'

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