scholarly journals The expanding field of non-canonical RNA capping: new enzymes and mechanisms

2021 ◽  
Vol 8 (5) ◽  
pp. 201979
Author(s):  
Jana Wiedermannová ◽  
Christina Julius ◽  
Yulia Yuzenkova
Keyword(s):  
Cell Wall ◽  
Small Molecules ◽  
Rna Metabolism ◽  
Human Cells ◽  
Rna Polymerases ◽  
Nucleotide Analogues ◽  
Trna Synthetases ◽  
Rich Variety ◽  
Rna Capping

Recent years witnessed the discovery of ubiquitous and diverse 5′-end RNA cap-like modifications in prokaryotes as well as in eukaryotes. These non-canonical caps include metabolic cofactors, such as NAD + /NADH, FAD, cell wall precursors UDP-GlcNAc, alarmones, e.g. dinucleotides polyphosphates, ADP-ribose and potentially other nucleoside derivatives. They are installed at the 5′ position of RNA via template-dependent incorporation of nucleotide analogues as an initiation substrate by RNA polymerases. However, the discovery of NAD-capped processed RNAs in human cells suggests the existence of alternative post-transcriptional NC capping pathways. In this review, we compiled growing evidence for a number of these other mechanisms which produce various non-canonically capped RNAs and a growing repertoire of capping small molecules. Enzymes shown to be involved are ADP-ribose polymerases, glycohydrolases and tRNA synthetases, and may potentially include RNA 3′-phosphate cyclases, tRNA guanylyl transferases, RNA ligases and ribozymes. An emerging rich variety of capping molecules and enzymes suggests an unrecognized level of complexity of RNA metabolism.

Potent Chitin Synthase Inhibitors from Plants

2020 ◽  
Vol 16 (1) ◽  
pp. 58-63
Author(s):  
Amrutha Vijayakumar ◽  
Ajith Madhavan ◽  
Chinchu Bose ◽  
Pandurangan Nanjan ◽  
Sindhu S. Kokkal ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Caenorhabditis Elegans ◽  
Aspergillus Niger ◽  
Small Molecules ◽  
Tip Growth ◽  
Chitin Synthase ◽  
Chitin Synthesis ◽  
Hyphal Tip Growth ◽  
Hyphal Tip

Background: Chitin is the main component of fungal, protozoan and helminth cell wall. They help to maintain the structural and functional characteristics of these organisms. The chitin wall is dynamic and is repaired, rearranged and synthesized as the cells develop. Active synthesis can be noticed during cytokinesis, laying of primary septum, maintenance of lateral cell wall integrity and hyphal tip growth. Chitin synthesis involves coordinated action of two enzymes namely, chitin synthase (that lays new cell wall) and chitinase (that removes the older ones). Since chitin synthase is conserved in different eukaryotic microorganisms that can be a ‘soft target’ for inhibition with small molecules. When chitin synthase is inhibited, it leads to the loss of viability of cells owing to the self- disruption of the cell wall by existing chitinase. Methods: In the described study, small molecules from plant sources were screened for their ability to interfere with hyphal tip growth, by employing Hyphal Tip Burst assay (HTB). Aspergillus niger was used as the model organism. The specific role of these small molecules in interfering with chitin synthesis was established with an in-vitro method. The enzyme required was isolated from Aspergillus niger and its activity was deduced through a novel method involving non-radioactively labelled substrate. The activity of the potential lead molecules were also checked against Candida albicans and Caenorhabditis elegans. The latter was adopted as a surrogate for the pathogenic helminths as it shares similarity with regard to cell wall structure and biochemistry. Moreover, it is widely studied and the methodologies are well established. Results: Out of the 11 compounds and extracts screened, 8 were found to be prospective. They were also found to be effective against Candida albicans and Caenorhabditis elegans. Conclusion: Purified Methyl Ethyl Ketone (MEK) Fraction1 (F1) of Coconut (Cocos nucifera) Shell Extract (COSE) was found to be more effective against Candida albicans with an IC50 value of 3.04 μg/mL and on L4 stage of Caenorhabditis elegans with an IC50 of 77.8 μg/mL.

scholarly journals In VitroEffect ofCinnamomum zeylanicumBlume Essential Oil onCandidaspp. Involved in Oral Infections

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Marianne de Lucena Rangel ◽  
Sabrina Garcia de Aquino ◽  
Jefferson Muniz de Lima ◽  
Lúcio Roberto Castellano ◽  
Ricardo Dias de Castro
Keyword(s):  
Cell Wall ◽  
Essential Oil ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Fungal Growth ◽  
Human Cells ◽  
Phytochemical Analysis ◽  
Oral Infections ◽  
Human Red Blood Cells ◽  
Main Component

The present study demonstrates the antifungal potential of chemically characterized essential oil (EO) ofCinnamomum zeylanicumBlume onCandidaspp. biofilm and establishes its mode of action, effect on fungal growth kinetics, and cytotoxicity to human cells. The minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC) values varied from 62.5 to 1,000μg/mL, and the effect seems to be due to interference with cell wall biosynthesis. The kinetics assay showed that EO at MICx2 (500μg/mL) induced a significant (p < 0.05) reduction of the fungal growth after exposure for 8 h. At this concentration, the EO was also able to hinder biofilm formation and reduceCandidaspp. monospecies and multispecies in mature biofilm at 24 h and 48 h (p < 0.05). A protective effect on human red blood cells was detected with the EO at concentrations up to 750μg/mL, as well as an absence of a significant reduction (p > 0.05) in the viability of human red blood cells at concentrations up to 1,000μg/mL. Phytochemical analysis identified eugenol as the main component (68.96%) of the EO.C. zeylanicumBlume EO shows antifungal activity, action on the yeast cell wall, and a deleterious effect onCandidaspp. biofilms. This natural product did not show evidence of cytotoxicity toward human cells.

scholarly journals Correction to A Biosynthetic Strategy for Re-engineering the Staphylococcus aureus Cell Wall with Non-native Small Molecules

2011 ◽  
Vol 6 (9) ◽  
pp. 971-971 ◽  
Author(s):  
James W. Nelson ◽  
Alexander G. Chamessian ◽  
Patrick J. McEnaney ◽  
Ryan P. Murelli ◽  
Barbara I. Kazmierczak ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Small Molecules

The NTP pyrophosphatase DCTPP1 contributes to the homoeostasis and cleansing of the dNTP pool in human cells

2014 ◽  
Vol 459 (1) ◽  
pp. 171-180 ◽  
Author(s):  
Cristina E. Requena ◽  
Guiomar Pérez-Moreno ◽  
Luis M. Ruiz-Pérez ◽  
Antonio E. Vidal ◽  
Dolores González-Pacanowska
Keyword(s):  
Human Cells ◽  
Nucleotide Analogues ◽  
Dntp Pool

Human DCTPP1 is an all-α nucleotidohydrolase which hydrolyses intracellular dCTP and genotoxic nucleotide analogues, thus preventing their incorporation into DNA. DCTPP1 localizes in the nucleus, cytosol and mitochondria where it contributes to the homoeostasis and cleansing of dNTP pools.

scholarly journals High-Throughput Screening for Protein Synthesis Inhibitors Targeting Aminoacyl-tRNA Synthetases

2017 ◽  
Vol 23 (2) ◽  
pp. 174-182 ◽  
Author(s):  
Jiwon Kong ◽  
Pengfei Fang ◽  
Franck Madoux ◽  
Timothy P. Spicer ◽  
Louis Scampavia ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Small Molecules ◽  
High Throughput ◽  
High Throughput Screening ◽  
Protein Synthesis Inhibitors ◽  
Chemical Libraries ◽  
Trna Synthetases ◽  
Aminoacyl Trna Synthetases ◽  
Reticulocyte Lysate ◽  
The Individual

Aminoacylation has been implicated in a wide variety of cancers. Aminoacyl-tRNA synthetases (ARSs) exist in large excess in tumor cells due to their increased demand for translation, whereas most other protein-synthesis apparatuses are quantitatively limited. Among other components that constitute the translation machinery—namely, tRNA, amino acid, ATP, and ARS—ARS is the only target that can be blocked by small molecules. No constitutively active ARSs have been reported, and mutations of ARS can cause inaccurate substrate recognition and malformation of the multi-ARS complex (MSC). Hence, interference of the activity is expected to be independent of genotype without developing resistance. Here, we report a high-throughput screening (HTS) system to find mammalian ARS inhibitors. The rabbit–reticulocyte lysate we used closely resembles both the individual and complexed structures of human ARSs, and it may predispose active compounds that are readily applicable for humankind. This assay was further validated because it identified familiar translational inhibitors from a pilot screen, such as emetine, proving its suitability for our purpose. The assay demonstrated excellent quality control (QC) parameters and reproducibility, and is proven ready for further HTS campaigns with large chemical libraries.

scholarly journals Structural insights into plasticity and discovery of remdesivir metabolite GS-441524 binding in SARS-CoV-2 macrodomain

2021 ◽  
Author(s):  
Xiaomin Ni ◽  
Martin Schröder ◽  
Vincent Olieric ◽  
May E. Sharpe ◽  
Victor Olmos ◽  
...  
Keyword(s):  
Immune Response ◽  
Small Molecules ◽  
Protein Interaction ◽  
Therapeutic Strategy ◽  
Protein Domain ◽  
Active Metabolites ◽  
Nucleotide Analogues ◽  
Inhibitor Development ◽  
Naturally Occurring ◽  
Structural Insights

ABSTRACTThe nsP3 macrodomain is a conserved protein interaction module that plays essential regulatory roles in host immune response by recognizing and removing posttranslational ADP-ribosylation sites during SARS-CoV-2 infection. Thus, targeting this protein domain may offer a therapeutic strategy to combat the current and future virus pandemics. To assist inhibitor development efforts, we report here a comprehensive set of macrodomain crystal structures complexed with diverse naturally-occurring nucleotides, small molecules as well as nucleotide analogues including GS-441524 and its phosphorylated analogue, active metabolites of remdesivir. The presented data strengthen our understanding of the SARS-CoV-2 macrodomain structural plasticity and it provides chemical starting points for future inhibitor development.

scholarly journals HP1 Proteins Are Essential for a Dynamic Nuclear Response That Rescues the Function of Perturbed Heterochromatin in Primary Human Cells

2006 ◽  
Vol 27 (3) ◽  
pp. 949-962 ◽  
Author(s):  
Rugang Zhang ◽  
Song-tao Liu ◽  
Wei Chen ◽  
Michael Bonner ◽  
John Pehrson ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Nucleotide Sequence ◽  
Small Molecules ◽  
Histone Modifications ◽  
Human Cells ◽  
Pericentromeric Heterochromatin ◽  
Dna Nucleotide Sequence ◽  
Nuclear Response ◽  
Hp1 Proteins ◽  
Primary Human Cells

ABSTRACT Cellular information is encoded genetically in the DNA nucleotide sequence and epigenetically by the “histone code,” DNA methylation, and higher-order packaging of DNA into chromatin. Cells possess intricate mechanisms to sense and repair damage to DNA and the genetic code. However, nothing is known of the mechanisms, if any, that repair and/or compensate for damage to epigenetically encoded information, predicted to result from perturbation of DNA and histone modifications or other changes in chromatin structure. Here we show that primary human cells respond to a variety of small molecules that perturb DNA and histone modifications by recruiting HP1 proteins to sites of altered pericentromeric heterochromatin. This response is essential to maintain the HP1-binding kinetochore protein hMis12 at kinetochores and to suppress catastrophic mitotic defects. Recruitment of HP1 proteins to pericentromeres depends on histone H3.3 variant deposition, mediated by the HIRA histone chaperone. These data indicate that defects in pericentromeric epigenetic heterochromatin modifications initiate a dynamic HP1-dependent response that rescues pericentromeric heterochromatin function and is essential for viable progression through mitosis.

The Small Molecules of Life

2014 ◽  
Author(s):  
Eugene H. Cordes
Keyword(s):  
Cell Wall ◽  
Protein Structure ◽  
Drug Discovery ◽  
Nucleic Acids ◽  
Small Molecules ◽  
Protein Function ◽  
Mammalian Cells ◽  
Living Organism ◽  
Living Organisms ◽  
Life On Earth

All life on Earth is unified. Life may have flickered into being, only to be subsequently extinguished, many times during the early days of our planet’s evolution. But on exactly one occasion, life on Earth did arise and persist. Every living organism is a descendent of that life. We are all hatched from the same primeval egg. The universal roles of the big molecules of life—proteins and nucleic acids—reflect this unique origin. The genetic code that links the language of nucleic acids to that of proteins is universal throughout the amazing diversity of living organisms. Protein relatives serve the same or similar functions in living organisms from wheat to humans. We are going to have a closer look at the proteins as we move forward: protein structure in chapter 3, protein function in chapter 4, and proteins as targets for drug discovery in chapters 6 through 12. This is not to argue that there are no differences among the molecules of life. Clearly, there are. For example, bacteria are isolated from their environment by a surrounding cell wall. There is no related structure in mammalian cells. We take advantage of these differences to sustain and restore human health. For example, many antibiotics act by preventing construction of bacterial cell walls. We will see two examples in what follows: Primaxin and fludalanine. The unity of life extends to the small molecules of life as well. There is compelling similarity among the small molecules that carry out critical functions of life. Adenosine triphosphate (ATP) is the universal energy currency of life; molecules that transmit messages from one nerve cell to another are shared between sea snails and humans. Molecules on the routes of metabolic pathways are much the same in fruit flies and flying bats, and on and on.

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