Leloir glycosyltransferases of natural product C-glycosylation: structure, mechanism and specificity

2020 ◽  
Vol 48 (4) ◽  
pp. 1583-1598 ◽  
Author(s):  
Gregor Tegl ◽  
Bernd Nidetzky
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Chemical Structure ◽  
Binding Pocket ◽  
Structural Features ◽  
Structural Studies ◽  
Acceptor Atom ◽  
Nucleophilic Reactivity ◽  
Insight Into ◽  
Significant Attention

A prominent attribute of chemical structure in microbial and plant natural products is aromatic C-glycosylation. In plants, various flavonoid natural products have a β-C-d-glucosyl moiety attached to their core structure. Natural product C-glycosides have attracted significant attention for their own unique bioactivity as well as for representing non-hydrolysable analogs of the canonical O-glycosides. The biosynthesis of natural product C-glycosides is accomplished by sugar nucleotide-dependent (Leloir) glycosyltransferases. Here, we provide an overview on the C-glycosyltransferases of microbial, plant and insect origin that have been biochemically characterized. Despite sharing basic evolutionary relationships, as evidenced by their common membership to glycosyltransferase family GT-1 and conserved GT-B structural fold, the known C-glycosyltransferases are diverse in the structural features that govern their reactivity, selectivity and specificity. Bifunctional glycosyltransferases can form C- and O-glycosides dependent on the structure of the aglycon acceptor. Recent crystal structures of plant C-glycosyltransferases and di-C-glycosyltransferases complement earlier structural studies of bacterial enzymes and provide important molecular insight into the enzymatic discrimination between C- and O-glycosylation. Studies of enzyme structure and mechanism converge on the view of a single displacement (SN2)-like mechanism of enzymatic C-glycosyl transfer, largely analogous to O-glycosyl transfer. The distinction between reactions at the O- or C-acceptor atom is achieved through the precise positioning of the acceptor relative to the donor substrate in the binding pocket. Nonetheless, C-glycosyltransferases may differ in the catalytic strategy applied to induce nucleophilic reactivity at the acceptor carbon. Evidence from the mutagenesis of C-glycosyltransferases may become useful in engineering these enzymes for tailored reactivity.

scholarly journals Cheminformatics Analysis of Natural Product Scaffolds: Comparison of Scaffolds Produced by Animals, Plants, Fungi and Bacteria

2020 ◽  
Author(s):  
Peter Ertl ◽  
Tim Schuhmann
Keyword(s):  
Natural Products ◽  
Natural Selection ◽  
Natural Product ◽  
Selection Process ◽  
Structural Features ◽  
New Drugs ◽  
Large Database ◽  
Biologically Relevant ◽  
Different Types ◽  
Selection Of

AbstractNatural products (NPs) have evolved over a very long natural selection process to form optimal interactions with biologically relevant macromolecules. NPs are therefore an extremely useful source of inspiration for the design of new drugs. In the present study we report the results of a cheminformatics analysis of a large database of NP structures focusing on their scaffolds. First, general differences between NP scaffolds and scaffolds from synthetic molecules are discussed, followed by a comparison of the properties of scaffolds produced by different types of organisms. Scaffolds produced by plants are the most complex and those produced by bacteria differ in many structural features from scaffolds produced by other organisms. The results presented here may be used as a guidance in selection of scaffolds for the design of novel NP-like bioactive structures or NP-inspired libraries.

scholarly journals All-carbon [3 + 2] cycloaddition in natural product synthesis

2020 ◽  
Vol 16 ◽  
pp. 3015-3031
Author(s):  
Zhuo Wang ◽  
Junyang Liu
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Structural Features ◽  
Single Step ◽  
Natural Product Synthesis ◽  
Synthetic Chemistry ◽  
Quaternary Centers ◽  
Chemical Structures ◽  
Quaternary Center ◽  
Medicinal Properties

Many natural products possess interesting medicinal properties that arise from their intriguing chemical structures. The highly-substituted carbocycle is one of the most common structural features in many structurally complicated natural products. However, the construction of highly-substituted, stereo-congested, five-membered carbocycles containing all-carbon quaternary center(s) is, at present, a distinct challenge in modern synthetic chemistry, which can be accessed through the all-carbon [3 + 2] cycloaddition. More importantly, the all-carbon [3 + 2] cycloaddition can forge vicinal all-carbon quaternary centers in a single step and has been demonstrated in the synthesis of complex natural products. In this review, we present the development of all-carbon [3 + 2] cycloadditions and illustrate their application in natural product synthesis reported in the last decade covering 2011–2020 (inclusive).

Considerations on Structure of Natural Rubber Vulcanizates

1968 ◽  
Vol 41 (3) ◽  
pp. 659-668 ◽  
Author(s):  
H. Westlinning ◽  
S. Wolff
Keyword(s):  
Chain Length ◽  
Crosslink Density ◽  
Chemical Structure ◽  
Structural Features ◽  
Polymer Modification ◽  
Kinetic Measurements ◽  
Secondary Reactions ◽  
Ring Structures ◽  
Natural Rubber Vulcanizates ◽  
Insight Into

Abstract Deep insight into the chemistry of vulcanization, its kinetics, and network structures have been provided by the elucidation of reactions of mono and diolefins with sulfur and accelerators, primarily at NRPRA, and the kinetic measurements of transformation of vulcanizing agents with 1,5-polyenes by Scheele and co-workers at the Kautschuk Institute der Technischen Hochschule, Hannover. It is now established that both accelerated and unaccelerated vulcanization of 1,5-polyenes with sulfur begins with formation of polysulfide crosslinks. As sulfur disappearance and formation of polysulfide proceed, secondary reactions participate increasingly. These involve a series of transformations of the crosslinks originally formed. This leads to a continual change in chain length of crosslinks, in their chemical constitution, and in structural features of the polymer. Figure 1 shows schematically the results of sulfur vulcanization. Crosslinks consist of mono, di, or polysulfide structures, depending on vulcanization time and temperature. As polysulfide bonds disappear, the polymer is modified by the appearance of monosulfidic ring structures and conjugated double bonds in the chain. Secondary reactions may change the crosslink density of the vulcanizate. There are three possibilities: shortening of the crosslink chain length can proceed (a) without change in, (b) with decreasing, or (c) with increasing, crosslink density. Which occurs must be determined for each system. For each polymer the density of crosslinking, its chemical structure, and the extent of polymer modification determine physical, chemical, and technological properties of the vulcanizate.

scholarly journals Cytostatic and Cytotoxic Natural Products against Cancer Cell Models

Molecules ◽  
2019 ◽  
Vol 24 (10) ◽  
pp. 2012 ◽  
Author(s):  
Taotao Ling ◽  
Walter H. Lang ◽  
Julie Maier ◽  
Marizza Quintana Centurion ◽  
Fatima Rivas
Keyword(s):  
Natural Products ◽  
Protein Synthesis ◽  
Natural Product ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Drug Resistant ◽  
Cell Models ◽  
Cellular Models ◽  
Insight Into

The increasing prevalence of drug resistant and/or high-risk cancers indicate further drug discovery research is required to improve patient outcome. This study outlines a simplified approach to identify lead compounds from natural products against several cancer cell lines, and provides the basis to better understand structure activity relationship of the natural product cephalotaxine. Using high-throughput screening, a natural product library containing fractions and pure compounds was interrogated for proliferation inhibition in acute lymphoblastic leukemia cellular models (SUP-B15 and KOPN-8). Initial hits were verified in control and counter screens, and those with EC50 values ranging from nanomolar to low micromolar were further characterized via mass spectrometry, NMR, and cytotoxicity measurements. Most of the active compounds were alkaloid natural products including cephalotaxine and homoharringtonine, which were validated as protein synthesis inhibitors with significant potency against several cancer cell lines. A generated BODIPY-cephalotaxine probe provides insight into the mode of action of cephalotaxine and further rationale for its weaker potency when compared to homoharringtonine. The steroidal natural products (ecdysone and muristerone A) also showed modest biological activity and protein synthesis inhibition. Altogether, these findings demonstrate that natural products continue to provide insight into structure and function of molecules with therapeutic potential against drug resistant cancer cell models.

scholarly journals NPBS database: a chemical data resource with relational data between natural products and biological sources

Database ◽  
2020 ◽  
Vol 2020 ◽  
Author(s):  
Tingjun Xu ◽  
Weiming Chen ◽  
Junhong Zhou ◽  
Jingfang Dai ◽  
Yingyong Li ◽  
...  
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Chemical Structure ◽  
Chemical Data ◽  
Relational Data ◽  
Data Link ◽  
Data Resource ◽  
Biological Sources ◽  
Specific Species

Abstract NPBS (Natural Products & Biological Sources) database is a chemical data resource with relational data between natural products and biological sources, manually curated from literatures of natural product researches. The relational data link a specific species and all the natural products derived from it and contrarily link a specific natural product and all the biological sources. The biological sources cover diverse species of plant, bacterial, fungal and marine organisms; the natural molecules have proper chemical structure data and computable molecular properties and all the relational data have corresponding references. NPBS database provides a wider choice of biological sources and can be used for dereplication to prevent re-isolation and re-characterization of already known natural products. Database URL: http://www.organchem.csdb.cn/scdb/NPBS

scholarly journals Structural Insights for Core Scaffold and Substrate Specificity of B1, B2, and B3 Metallo-β-Lactamases

2022 ◽  
Vol 12 ◽  
Author(s):  
Yeongjin Yun ◽  
Sangjun Han ◽  
Yoon Sik Park ◽  
Hyunjae Park ◽  
Dogyeong Kim ◽  
...  
Keyword(s):  
Substrate Specificity ◽  
Active Site ◽  
Chemical Structure ◽  
Substrate Binding ◽  
Binding Pocket ◽  
Structural Features ◽  
Amino Acid Sequences ◽  
Zinc Ions ◽  
Substrate Binding Pocket ◽  
Inhibitory Spectrum

Metallo-β-lactamases (MBLs) hydrolyze almost all β-lactam antibiotics, including penicillins, cephalosporins, and carbapenems; however, no effective inhibitors are currently clinically available. MBLs are classified into three subclasses: B1, B2, and B3. Although the amino acid sequences of MBLs are varied, their overall scaffold is well conserved. In this study, we systematically studied the primary sequences and crystal structures of all subclasses of MBLs, especially the core scaffold, the zinc-coordinating residues in the active site, and the substrate-binding pocket. We presented the conserved structural features of MBLs in the same subclass and the characteristics of MBLs of each subclass. The catalytic zinc ions are bound with four loops from the two central β-sheets in the conserved αβ/βα sandwich fold of MBLs. The three external loops cover the zinc site(s) from the outside and simultaneously form a substrate-binding pocket. In the overall structure, B1 and B2 MBLs are more closely related to each other than they are to B3 MBLs. However, B1 and B3 MBLs have two zinc ions in the active site, while B2 MBLs have one. The substrate-binding pocket is different among all three subclasses, which is especially important for substrate specificity and drug resistance. Thus far, various classes of β-lactam antibiotics have been developed to have modified ring structures and substituted R groups. Currently available structures of β-lactam-bound MBLs show that the binding of β-lactams is well conserved according to the overall chemical structure in the substrate-binding pocket. Besides β-lactam substrates, B1 and cross-class MBL inhibitors also have distinguished differences in the chemical structure, which fit well to the substrate-binding pocket of MBLs within their inhibitory spectrum. The systematic structural comparison among B1, B2, and B3 MBLs provides in-depth insight into their substrate specificity, which will be useful for developing a clinical inhibitor targeting MBLs.

scholarly journals Four-Step Access to the Sesquiterpene Natural Product Presilphiperfolan-1β-ol and Unnatural Derivatives via Supramolecular Catalysis

2019 ◽  
Author(s):  
Leonidas-Dimitrios Syntrivanis ◽  
Shani Levi ◽  
Alessandro Prescimone ◽  
Dan Thomas Major ◽  
Konrad Tiefenbacher
Keyword(s):  
Natural Products ◽  
Experimental Evidence ◽  
Natural Product ◽  
Synthetic Approach ◽  
Supramolecular Catalysis ◽  
Direct Experimental Evidence ◽  
Derivatives Of ◽  
Biosynthetic Machinery ◽  
Insight Into

Herein we report the shortest synthesis of the tricyclic sesquiterpene presilphiperfolan-1β-ol to date, utilizing the supramolecular resorcinarene capsule as catalyst for the key step. This synthetic approach also allows access to unnatural derivatives of the natural product, which would not be accessible through the biosynthetic machinery. Additionally, this study provides useful insight into the biosynthesis of the presilphiperfolanol natural products, including the first direct experimental evidence for the proposed biosynthetic connection between caryophyllene and the presilphiperfolanols.

scholarly journals Structural Searching of Biosynthetic Enzymes to Predict Protein Targets of Natural Products

Planta Medica ◽  
2017 ◽  
Vol 84 (05) ◽  
pp. 304-310 ◽  
Author(s):  
Noé Sturm ◽  
Ronald Quinn ◽  
Esther Kellenberger
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Structural Features ◽  
Biosynthetic Enzymes ◽  
Protein Targets ◽  
Putative Protein ◽  
Structural Relationships ◽  
Full Analysis ◽  
Crystallographic Structures ◽  
Novel Targets

AbstractRecently, we have demonstrated that site comparison methodology using flavonoid biosynthetic enzymes as the query could automatically identify structural features common to different flavonoid-binding proteins, allowing for the identification of flavonoid targets such as protein kinases. With the aim of further validating the hypothesis that biosynthetic enzymes and therapeutic targets can contain a similar natural product imprint, we collected a set of 159 crystallographic structures representing 38 natural product biosynthetic enzymes by searching the Protein Databank. Each enzyme structure was used as a query to screen a repository of approximately 10 000 ligandable sites by active site similarity. We report a full analysis of the screening results and highlight three retrospective examples where the natural product validates the method, thereby revealing novel structural relationships between natural product biosynthetic enzymes and putative protein targets of the natural product. From a prospective perspective, our work provides a list of up to 64 potential novel targets for 25 well-characterized natural products.

scholarly journals Four-Step Access to the Sesquiterpene Natural Product Presilphiperfolan-1β-ol and Unnatural Derivatives via Supramolecular Catalysis

2019 ◽  
Author(s):  
Leonidas-Dimitrios Syntrivanis ◽  
Shani Levi ◽  
Alessandro Prescimone ◽  
Dan Thomas Major ◽  
Konrad Tiefenbacher
Keyword(s):  
Natural Products ◽  
Experimental Evidence ◽  
Natural Product ◽  
Synthetic Approach ◽  
Supramolecular Catalysis ◽  
Direct Experimental Evidence ◽  
Derivatives Of ◽  
Biosynthetic Machinery ◽  
Insight Into

Herein we report the shortest synthesis of the tricyclic sesquiterpene presilphiperfolan-1β-ol to date, utilizing the supramolecular resorcinarene capsule as catalyst for the key step. This synthetic approach also allows access to unnatural derivatives of the natural product, which would not be accessible through the biosynthetic machinery. Additionally, this study provides useful insight into the biosynthesis of the presilphiperfolanol natural products, including the first direct experimental evidence for the proposed biosynthetic connection between caryophyllene and the presilphiperfolanols.

scholarly journals Natural Product-Inspired Pyranonaphthoquinone Inhibitors of Indoleamine 2,3-Dioxygenase-1 (IDO-1)

2013 ◽  
Vol 66 (1) ◽  
pp. 40 ◽  
Author(s):  
David J. A. Bridewell ◽  
Jonathan Sperry ◽  
Jason R. Smith ◽  
Priambudi Kosim-Satyaputra ◽  
Lai-Ming Ching ◽  
...  
Keyword(s):  
Natural Products ◽  
Cell Viability ◽  
Natural Product ◽  
Structural Features ◽  
Lead Compounds ◽  
Indoleamine 2,3 Dioxygenase ◽  
Drug Concentrations ◽  
Cellular Context ◽  
In Cells

A series of pyranonaphthoquinone derivatives possessing structural features present in both natural products annulin B and exiguamine A have been shown to exhibit low micromolar inhibition of indoleamine 2,3-dioxygenase-1 (IDO-1). These inhibitors retain activity against the enzyme in a cellular context with an approximate one-log loss of dose potency against IDO-1 in cells. One particular analogue, triazole 8 shows good inhibition of IDO-1 along with little loss of cell viability at low drug concentrations. These results have extended the naphthoquinone series of novel IDO-1 inhibitors based on lead compounds from nature.

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