Chemical biology studies on norrisolide.
Ontology highlight
ABSTRACT:
SUBMITTER: Guizzunti G
PROVIDER: S-EPMC2838712 | biostudies-literature | 2010 Mar
REPOSITORIES: biostudies-literature
Publications
Chemical biology studies on norrisolide.
Guizzunti Gianni G Brady Thomas P TP Fischer Derek D Malhotra Vivek V Theodorakis Emmanuel A EA
Bioorganic & medicinal chemistry 20100210 6
The cellular activity of norrisolide (7), a novel Golgi-vesiculating agent, was dissected as function of its chemical structure. This natural product induces irreversible vesiculation of the Golgi membranes and blocks protein transport at the level of the Golgi. The Golgi localization and fragmentation effects of 7 depend on the presence of the perhydroindane core, while the irreversibility of fragmentation depends on the acetyl group of 7. We show that fluorescent derivatives of norrisolide are ...[more]
Similar Datasets
Project description:There is a critical need for improving the level of chemistry awareness in systems biology. The data and information related to modulation of genes and proteins by small molecules continue to accumulate at the same time as simulation tools in systems biology and whole body physiologically based pharmacokinetics (PBPK) continue to evolve. We called this emerging area at the interface between chemical biology and systems biology systems chemical biology (SCB) (Nat Chem Biol 3: 447-450, 2007).The overarching goal of computational SCB is to develop tools for integrated chemical-biological data acquisition, filtering and processing, by taking into account relevant information related to interactions between proteins and small molecules, possible metabolic transformations of small molecules, as well as associated information related to genes, networks, small molecules, and, where applicable, mutants and variants of those proteins. There is yet an unmet need to develop an integrated in silico pharmacology/systems biology continuum that embeds drug-target-clinical outcome (DTCO) triplets, a capability that is vital to the future of chemical biology, pharmacology, and systems biology. Through the development of the SCB approach, scientists will be able to start addressing, in an integrated simulation environment, questions that make the best use of our ever-growing chemical and biological data repositories at the system-wide level. This chapter reviews some of the major research concepts and describes key components that constitute the emerging area of computational systems chemical biology.
| S-EPMC3547368 | biostudies-literature
Project description:Abnormal levels of DNA methylation and/or histone modifications are observed in patients with a wide variety of chronic diseases. Methylation of lysines within histone tails is a key modification that contributes to increased gene expression or repression depending on the specific residue and degree of methylation, which is in turn controlled by the interplay of lysine methyl transferases and demethylases. Drugs that target these and other enzymes controlling chromatin modifications can modulate the expression of clusters of genes, potentially offering higher therapeutic efficacy than classical agents acting on downstream biochemical pathways that are susceptible to degeneracy. Lysine demethylases, first discovered in 2004, are the subject of increasing interest as therapeutic targets. This review provides an overview of recent findings implicating lysine demethylases in a range of therapeutic areas including oncology, immunoinflammation, metabolic disorders, neuroscience, virology and regenerative medicine, together with a summary of recent advances in structural biology and small molecule inhibitor discovery, supporting the tractability of the protein family for the development of selective druglike inhibitors.
| S-EPMC3178875 | biostudies-literature
Project description:Chemical biology relies on effective synthetic chemistry for building molecules to probe and modulate biological function. Olefin metathesis in organic solvents is a valuable addition to this armamentarium, and developments during the previous decade are enabling metathesis in aqueous solvents for the manipulation of biomolecules. Functional group-tolerant ruthenium metathesis catalysts modified with charged moieties or hydrophilic polymers are soluble and active in water, enabling ring-opening metathesis polymerization, cross metathesis, and ring-closing metathesis. Alternatively, conventional hydrophobic ruthenium complexes catalyze a similar array of metathesis reactions in mixtures of water and organic solvents. This strategy has enabled cross metathesis on the surface of a protein. Continuing developments in catalyst design and methodology will popularize the bioorthogonal reactivity of metathesis.
| S-EPMC2628388 | biostudies-literature
Project description:Small-molecule fluorescent probes embody an essential facet of chemical biology. Although numerous compounds are known, the ensemble of fluorescent probes is based on a modest collection of modular "core" dyes. The elaboration of these dyes with diverse chemical moieties is enabling the precise interrogation of biochemical and biological systems. The importance of fluorescence-based technologies in chemical biology elicits a necessity to understand the major classes of small-molecule fluorophores. Here, we examine the chemical and photophysical properties of oft-used fluorophores and highlight classic and contemporary examples in which utility has been built upon these scaffolds.
| S-EPMC2802578 | biostudies-other
Project description:K(+) channels are revered for their universal action of suppressing electrical activity in nerve and muscle, as well as regulating salt and water transport in epithelial tissues involved in metabolism and digestion. These multisubunit membrane-embedded proteins carry out their physiological chore, selectively allowing the passage of potassium across the membrane, in response to changes in membrane voltage and ligand concentration. Elucidating the diverse gating properties of K(+) channels is of great biological interest since their molecular motions provide insight into how these structurally similar proteins function in a wide variety of tissues. Armed with patch clamps, chart recorders, and now high-resolution structures, electrophysiologists have been dipping into the top tray of the chemist's tool box: synthesizing cysteine-modifying agents and organic cations and grinding up insects, spiders, and other vermin to isolate natural products to poke, probe, and prod K(+) channels. Recently, there has been further cross-fertilization between chemists and K(+) channelologists, resulting in greater accessibility to more elaborate synthetic methodologies and screening approaches. In this review, we catalogue the evolution of chemical tools and approaches that have been utilized to elucidate the mechanistic underpinnings of K(+) channel biology.
| S-EPMC2629505 | biostudies-literature
Project description:Small-molecule fluorophores manifest the ability of chemistry to solve problems in biology. As we noted in a previous review (Lavis, L. D.; Raines, R. T. ACS Chem. Biol. 2008, 3, 142-155), the extant collection of fluorescent probes is built on a modest set of "core" scaffolds that evolved during a century of academic and industrial research. Here, we survey traditional and modern synthetic routes to small-molecule fluorophores and highlight recent biological insights attained with customized fluorescent probes. Our intent is to inspire the design and creation of new high-precision tools that empower chemical biologists.
| S-EPMC4006396 | biostudies-other
Project description:Academic screening centers across the world have endeavored to discover small molecules that can modulate biological systems. To increase the reach of functional-genomic and chemical screening programs, universities, research institutes, and governments have followed their industrial counterparts in adopting high-throughput paradigms. As academic screening efforts have steadily grown in scope and complexity, so have the ideas of what is possible with the union of technology and biology. This review addresses the recent conceptual and technological innovation that has been propelling academic screening into its own unique niche. In particular, high-content and whole-organism screening are changing how academics search for novel bioactive compounds. Importantly, we recognize examples of successful chemical probe development that have punctuated the changing technology landscape.
| S-EPMC3719966 | biostudies-literature
Project description:The presenilin proteins are the catalytic subunits of a tetrameric complex containing presenilin 1 or 2, anterior pharynx defective 1 (APH1), nicastrin, and PEN-2. Other components such as TMP21 may exist in a subset of specialized complexes. The presenilin complex is the founding member of a unique class of aspartyl proteases that catalyze the ?, ?, ? site cleavage of the transmembrane domains of Type I membrane proteins including amyloid precursor protein (APP) and Notch. Here, we detail the structural and chemical biology of this unusual enzyme. Taken together, these studies suggest that the complex exists in several conformations, and subtle long-range (allosteric) shifts in the conformation of the complex underpin substrate access to the catalytic site and the mechanism of action for allosteric inhibitors and modulators. Understanding the mechanics of these shifts will facilitate the design of ?-secretase modulator (GSM) compounds that modulate the relative efficiency of ?, ?, ? site cleavage and/or substrate specificity.
| S-EPMC5710098 | biostudies-literature
Project description:Inorganic nitrate (NO3 - ), nitrite (NO2 - ) and NO are nitrogenous species with a diverse and interconnected chemical biology. The formation of NO from nitrate and nitrite via a reductive 'nitrate-nitrite-NO' pathway and resulting in vasodilation is now an established complementary route to traditional NOS-derived vasodilation. Nitrate, found in our diet and abundant in mammalian tissues and circulation, is activated via reduction to nitrite predominantly by our commensal oral microbiome. The subsequent in vivo reduction of nitrite, a stable vascular reserve of NO, is facilitated by a number of haem-containing and molybdenum-cofactor proteins. NO generation from nitrite is enhanced during physiological and pathological hypoxia and in disease states involving ischaemia-reperfusion injury. As such, modulation of these NO vascular repositories via exogenously supplied nitrite and nitrate has been evaluated as a therapeutic approach in a number of diseases. Ultimately, the chemical biology of nitrate and nitrite is governed by local concentrations, reaction equilibrium constants, and the generation of transient intermediates, with kinetic rate constants modulated at differing physiological pH values and oxygen tensions. LINKED ARTICLES: This article is part of a themed section on Nitric Oxide 20 Years from the 1998 Nobel Prize. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.2/issuetoc.
| S-EPMC6295445 | biostudies-literature
Project description:Chemical physics as a discipline contributes many experimental tools, algorithms, and fundamental theoretical models that can be applied to biological problems. This is especially true now as the molecular level and the systems level descriptions begin to connect, and multi-scale approaches are being developed to solve cutting edge problems in biology. In some cases, the concepts and tools got their start in non-biological fields, and migrated over, such as the idea of glassy landscapes, fluorescence spectroscopy, or master equation approaches. In other cases, the tools were specifically developed with biological physics applications in mind, such as modeling of single molecule trajectories or super-resolution laser techniques. In this introduction to the special topic section on chemical physics of biological systems, we consider a wide range of contributions, all the way from the molecular level, to molecular assemblies, chemical physics of the cell, and finally systems-level approaches, based on the contributions to this special issue. Chemical physicists can look forward to an exciting future where computational tools, analytical models, and new instrumentation will push the boundaries of biological inquiry.
| S-EPMC5942441 | biostudies-literature