scholarly journals Promiscuity and specificity of eukaryotic glycosyltransferases

2020 ◽  
Vol 48 (3) ◽  
pp. 891-900 ◽  
Author(s):  
Ansuman Biswas ◽  
Mukund Thattai
Keyword(s):  
Small Molecule ◽  
Large Family ◽  
Organic Substrates ◽  
Cellular Interactions ◽  
Structural Studies ◽  
Glycosidic Linkage ◽  
Enzyme Promiscuity ◽  
Acceptor Substrate ◽  
Wide Range ◽  
Recognition Motifs

Glycosyltransferases are a large family of enzymes responsible for covalently linking sugar monosaccharides to a variety of organic substrates. These enzymes drive the synthesis of complex oligosaccharides known as glycans, which play key roles in inter-cellular interactions across all the kingdoms of life; they also catalyze sugar attachment during the synthesis of small-molecule metabolites such as plant flavonoids. A given glycosyltransferase enzyme is typically responsible for attaching a specific donor monosaccharide, via a specific glycosidic linkage, to a specific moiety on the acceptor substrate. However these enzymes are often promiscuous, able catalyze linkages between a variety of donors and acceptors. In this review we discuss distinct classes of glycosyltransferase promiscuity, each illustrated by enzymatic examples from small-molecule or glycan synthesis. We highlight the physical causes of promiscuity, and its biochemical consequences. Structural studies of glycosyltransferases involved in glycan synthesis show that they make specific contacts with ‘recognition motifs’ that are much smaller than the full oligosaccharide substrate. There is a wide range in the sizes of glycosyltransferase recognition motifs: highly promiscuous enzymes recognize monosaccharide or disaccharide motifs across multiple oligosaccharides, while highly specific enzymes recognize large, complex motifs found on few oligosaccharides. In eukaryotes, the localization of glycosyltransferases within compartments of the Golgi apparatus may play a role in mitigating the glycan variability caused by enzyme promiscuity.

scholarly journals Small Molecule Inhibitors in the Treatment of Rheumatoid Arthritis and Beyond: Latest Updates and Potential Strategy for Fighting COVID-19

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1876
Author(s):  
Magdalena Massalska ◽  
Wlodzimierz Maslinski ◽  
Marzena Ciechomska
Keyword(s):  
Rheumatoid Arthritis ◽  
Small Molecule ◽  
Viral Entry ◽  
Small Molecule Inhibitors ◽  
Large Family ◽  
Downstream Signaling ◽  
Wide Range ◽  
Synthetic Dmards ◽  
Potential Strategy ◽  
Inflammatory Molecules

The development of biological disease-modifying antirheumatic drugs (bDMARDs) and target synthetic DMARDs (tsDMARDs), also known as small molecule inhibitors, represent a breakthrough in rheumatoid arthritis (RA) treatment. The tsDMARDs are a large family of small molecules targeting mostly the several types of kinases, which are essential in downstream signaling of pro-inflammatory molecules. This review highlights current challenges associated with the treatment of RA using small molecule inhibitors targeting intracellular JAKs/MAPKs/NF-κB/SYK-BTK signaling pathways. Indeed, we have provided the latest update on development of small molecule inhibitors, their clinical efficacy and safety as a strategy for RA treatment. On the other hand, we have highlighted the risk and adverse effects of tsDMARDs administration including, among others, infections and thromboembolism. Therefore, performance of blood tests or viral infection screening should be recommended before the tsDMARDs administration. Interestingly, recent events of SARS-CoV-2 outbreak have demonstrated the potential use of small molecule inhibitors not only in RA treatment, but also in fighting COVID-19 via blocking the viral entry, preventing of hyperimmune activation and reducing cytokine storm. Thus, small molecule inhibitors, targeting wide range of pro-inflammatory singling pathways, may find wider implications not only for the management of RA but also in the controlling of COVID-19.

Synthesis of Elaborate Benzofuran-2-Carboxamide Derivatives Through a Combination of 8-Aminoquinoline Directed C–H Arylations and Transamidations

2019 ◽  
Author(s):  
Michael Oschmann ◽  
Linus Johansson Holm ◽  
Oscar Verho
Keyword(s):  
Small Molecule ◽  
High Efficiency ◽  
Synthetic Strategy ◽  
Small Molecule Screening ◽  
Physiological Properties ◽  
Wide Range ◽  
Directing Group ◽  
Synthetic Sequence

Benzofurans are everywhere in nature and they have been extensively studied by medicinal chemists over the years because of their chemotherapeutic and physiological properties. Herein, we describe a strategy that can be used to access elaborate benzo-2-carboxamide derivatives, which involves a synthetic sequence of 8-aminoquinoline directed C–H arylations followed by transamidations. For the directed C–H arylations, Pd catalysis was used to install a wide range of aryl and heteroaryl substituents at the C3 position of the benzofuran scaffold in high efficiency. Directing group cleavage and further diversification of the C3-arylated benzofuran products were then achieved in a single synthetic operation through the utilization of a two-step transamidation protocol. By bocylating the 8-aminoquinoline amide moiety of these products, it proved possible to activate them towards aminolysis with different amine nucleophiles. Interestingly, this aminolysis reaction was found to proceed efficiently without the need of any additional catalyst or additive. Given the high efficiency and modularity of this synthetic strategy, it constitute a very attractive approach for generating structurally-diverse collections of benzofuran derivatives for small molecule screening.

scholarly journals Responses to Ecopollutants and Pathogenization Risks of Saprotrophic Rhodococcus Species

Pathogens ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 974
Author(s):  
Irina B. Ivshina ◽  
Maria S. Kuyukina ◽  
Anastasiia V. Krivoruchko ◽  
Elena A. Tyumina
Keyword(s):  
Survival Strategies ◽  
Complex Life Cycle ◽  
Anthropogenic Pressure ◽  
Resting Cells ◽  
Organic Substrates ◽  
Negative Effects ◽  
Anthropogenic Pollutants ◽  
Rhodococcus Species ◽  
Wide Range ◽  
Rigid Cell Wall

Under conditions of increasing environmental pollution, true saprophytes are capable of changing their survival strategies and demonstrating certain pathogenicity factors. Actinobacteria of the genus Rhodococcus, typical soil and aquatic biotope inhabitants, are characterized by high ecological plasticity and a wide range of oxidized organic substrates, including hydrocarbons and their derivatives. Their cell adaptations, such as the ability of adhering and colonizing surfaces, a complex life cycle, formation of resting cells and capsule-like structures, diauxotrophy, and a rigid cell wall, developed against the negative effects of anthropogenic pollutants are discussed and the risks of possible pathogenization of free-living saprotrophic Rhodococcus species are proposed. Due to universal adaptation features, Rhodococcus species are among the candidates, if further anthropogenic pressure increases, to move into the group of potentially pathogenic organisms with “unprofessional” parasitism, and to join an expanding list of infectious agents as facultative or occasional parasites.

scholarly journals Glossary and tutorial of xenobiotic metabolism terms used during small molecule drug discovery and development (IUPAC Technical Report)

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Paul Erhardt ◽  
Kenneth Bachmann ◽  
Donald Birkett ◽  
Michael Boberg ◽  
Nicholas Bodor ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecule ◽  
Chemical Structure ◽  
Early Stage ◽  
Xenobiotic Metabolism ◽  
Drug Discovery And Development ◽  
Small Molecule Drug ◽  
Technical Report ◽  
Wide Range ◽  
Draft Version

Abstract This project originated more than 15 years ago with the intent to produce a glossary of drug metabolism terms having definitions especially applicable for use by practicing medicinal chemists. A first-draft version underwent extensive beta-testing that, fortuitously, engaged international audiences in a wide range of disciplines involved in drug discovery and development. It became clear that the inclusion of information to enhance discussions among this mix of participants would be even more valuable. The present version retains a chemical structure theme while expanding tutorial comments that aim to bridge the various perspectives that may arise during interdisciplinary communications about a given term. This glossary is intended to be educational for early stage researchers, as well as useful for investigators at various levels who participate on today’s highly multidisciplinary, collaborative small molecule drug discovery teams.

The chemistry of stabilized clusters

1982 ◽  
Vol 308 (1501) ◽  
pp. 27-34 ◽  
Keyword(s):  
Electron Donor ◽  
Organic Molecules ◽  
Metal Cluster ◽  
Organic Substrates ◽  
Insertion Reactions ◽  
Donor Ligand ◽  
Small Organic Molecules ◽  
Wide Range ◽  
Metal Metal ◽  
High Yields

Studies of the chemistry of metal cluster complexes and, in particular, their reactions with small organic molecules, have been confined to relatively few systems. Among the reasons for this are: (i) not many clusters are easily synthesized in high yields; (ii) their reactions often give a multitude of products that are difficult to separate and characterize; (iii) the conditions required to bring about reactions often lead to fragmentation of the cluster into lower nuclearity (often mononuclear) species. One cluster whose chemistry has been extensively studied is [Os 3 H 2 (CO) 10 ]. This can be synthesized in high yields from [Os 3 (CO) 12 ] + H 2 (Knox et al. 1975) and reacts readily under mild conditions with a wide range of electron-donor molecules by virtue of its coordinative unsaturation (Shapley et al. 1975; Deeming & Hasso 1976; Adams & Golembeski 1979). Formally, one may consider that a metal—metal double bond is present, which is reduced to a single bond on coordination of an additional two-electron donor ligand such as an organophosphine. The presence of metal—hydrogen bonds in this cluster and the cluster’s ability to coordinate organic substrates enable it to undergo a wide variety of insertion reactions, leading to products that may be regarded as intermediates in the reduction of organic molecules by clusters (Deeming & Hasso 1975; Keister & Shapley 1975).

scholarly journals Newly discovered Asgard archaea Hermodarchaeota potentially degrade alkanes and aromatics via alkyl/benzyl-succinate synthase and benzoyl-CoA pathway

2021 ◽  
Author(s):  
Jia-Wei Zhang ◽  
Hong-Po Dong ◽  
Li-Jun Hou ◽  
Yang Liu ◽  
Ya-Fei Ou ◽  
...  
Keyword(s):  
Nitrate Reduction ◽  
Coenzyme A ◽  
Organic Substrates ◽  
Mangrove Sediments ◽  
Sulfate Reducing ◽  
Sequence Read Archive ◽  
Wide Range ◽  
Genes Encoding ◽  
Sediment Carbon ◽  
Reducing Bacteria

AbstractAsgard archaea are widely distributed in anaerobic environments. Previous studies revealed the potential capability of Asgard archaea to utilize various organic substrates including proteins, carbohydrates, fatty acids, amino acids and hydrocarbons, suggesting that Asgard archaea play an important role in sediment carbon cycling. Here, we describe a previously unrecognized archaeal phylum, Hermodarchaeota, affiliated with the Asgard superphylum. The genomes of these archaea were recovered from metagenomes generated from mangrove sediments, and were found to encode alkyl/benzyl-succinate synthases and their activating enzymes that are similar to those identified in alkane-degrading sulfate-reducing bacteria. Hermodarchaeota also encode enzymes potentially involved in alkyl-coenzyme A and benzoyl-coenzyme A oxidation, the Wood–Ljungdahl pathway and nitrate reduction. These results indicate that members of this phylum have the potential to strictly anaerobically degrade alkanes and aromatic compounds, coupling the reduction of nitrate. By screening Sequence Read Archive, additional genes encoding 16S rRNA and alkyl/benzyl-succinate synthases analogous to those in Hermodarchaeota were identified in metagenomic datasets from a wide range of marine and freshwater sediments. These findings suggest that Asgard archaea capable of degrading alkanes and aromatics via formation of alkyl/benzyl-substituted succinates are ubiquitous in sediments.

Model Child Care Health Policies

2013 ◽  
Author(s):  
Keyword(s):  
Child Care ◽  
Early Education ◽  
Health And Safety ◽  
Large Family ◽  
Health Policies ◽  
After School ◽  
Wide Range ◽  
Before And After ◽  
Care Health ◽  
Child Care Facilities

Significantly revised and updated, the new Model Child Care Health Policies, 5th Edition is a must-have tool to foster adoption and implemenation of best practices for health and safety in group care settings for young children. These settings include early care and education as well as before and after school child care programs. These model policies are intended to ease the burden of writing site-specific health and safety policies from scratch. They cover a wide range of aspects of operation of early education and child care programs. Child care programs of any type can use Model Child Care Health Policies by selecting relevant issues for their operation and modifying the wording to make selected policies appropriate to the specific settings. These settings include early education and child care centers, small and large family child care homes, part day-programs for ill children, facilities that serve children with special needs, school-age child care facilities, and drop-in facilities. The model policies can be adapted for public, private, Head Start, and tuition-funded facilities. All of the most commonly covered health and safety topics the National Association of Child Care Resource and Referral Agencies found in state regulations are included in this guide.

Elucidating Protein-protein Interactions Through Computational Approaches and Designing Small Molecule Inhibitors Against them for Various Diseases

2018 ◽  
Vol 18 (20) ◽  
pp. 1719-1736 ◽  
Author(s):  
Sharanya Sarkar ◽  
Khushboo Gulati ◽  
Manikyaprabhu Kairamkonda ◽  
Amit Mishra ◽  
Krishna Mohan Poluri
Keyword(s):  
Small Molecule ◽  
Protein Interactions ◽  
Small Molecule Inhibitors ◽  
Computational Techniques ◽  
Protein Protein Interactions ◽  
Computational Tools ◽  
Computational Approaches ◽  
Protein Protein Interaction ◽  
Wide Range ◽  
Therapeutic Measures

Background: To carry out wide range of cellular functionalities, proteins often associate with one or more proteins in a phenomenon known as Protein-Protein Interaction (PPI). Experimental and computational approaches were applied on PPIs in order to determine the interacting partners, and also to understand how an abnormality in such interactions can become the principle cause of a disease. Objective: This review aims to elucidate the case studies where PPIs involved in various human diseases have been proven or validated with computational techniques, and also to elucidate how small molecule inhibitors of PPIs have been designed computationally to act as effective therapeutic measures against certain diseases. Results: Computational techniques to predict PPIs are emerging rapidly in the modern day. They not only help in predicting new PPIs, but also generate outputs that substantiate the experimentally determined results. Moreover, computation has aided in the designing of novel inhibitor molecules disrupting the PPIs. Some of them are already being tested in the clinical trials. Conclusion: This review delineated the classification of computational tools that are essential to investigate PPIs. Furthermore, the review shed light on how indispensable computational tools have become in the field of medicine to analyze the interaction networks and to design novel inhibitors efficiently against dreadful diseases in a shorter time span.

scholarly journals A new lead to NLRP3 inhibition

2017 ◽  
Vol 214 (11) ◽  
pp. 3147-3149 ◽  
Author(s):  
Mohamed Lamkanfi ◽  
Vishva M. Dixit
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Therapeutic Benefit ◽  
Human Diseases ◽  
Molecule Inhibitor ◽  
Wide Range ◽  
Potential Therapeutic Benefit

The discovery of a small molecule inhibitor that targets the inflammasome sensor NLRP3 offers a new path for the development of selective inflammasome blockers with potential therapeutic benefit in a wide range of human diseases (in this issue, see Jiang et al., https://doi.org/10.1084/jem.20171419).

Establishment of the symbiosis in Convoluta roscoffensis

1983 ◽  
Vol 63 (2) ◽  
pp. 419-434 ◽  
Author(s):  
A. E. Douglas
Keyword(s):  
Central Region ◽  
Related Species ◽  
Initial Contact ◽  
Structural Studies ◽  
Algal Population ◽  
Recognition Mechanism ◽  
Wide Range ◽  
Algal Photosynthesis ◽  
Convoluta Roscoffensis

Of a wide range of algae tested, juvenile Convoluta roscoffensis ingested only Platymonas convolutae, the natural symbiont; related species of the genera Platymonas, Prasinocladus and Tetraselmis; and Chlamydomonas coccoides. Platymonas convolutae was not ingested to a greater extent than Prasinocladus marinus, Tetraselmis tetrathele and Tetraselmis verrucosa, or taken up in preference to T. verrucosa when animals were exposed to a choice between the two species. Convoluta ingested fewer cells of C. coccoides than P. convolutae and related species. Uptake of P. convolutae was not affected by pretreatment of the cells with lectins or proteases, incubation in media of pH 5·0–9·0 or inhibition of algal photosynthesis, but was substantially reduced if the algae were killed.Cells of P. convolutae, Pr. marinus, T. tetrathele and T. verrucosa persisted and divided in juvenile Convoluta. The algal population in the worms started to increase 2–3 d after ingestion and within 15–20 d the animals were uniformly green. These algae formed a viable symbiosis with Convoluta and promoted the growth of the animals. In contrast, C. coccoides cells did not persist in Convoluta for more than 12–24 h a nd were probably disrupted.P. convolutae cells lost their thecae within a few days of ingestion and before migration from the central to sub-epidermal region of the animal. Animal vacuoles surrounded recently ingested thecate algae. Structural studies of the adult symbiosis suggest that the algae were also intracellular and enclosed in vacuoles.It is proposed that Convoluta discriminates against algae unrelated to P. convolutae on initial contact and in the central region of the host. The nature of the recognition mechanism(s) has not been established.

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