scholarly journals 25 Years of Collaboration with A Genius: Deciphering Adenine Nucleotide Ca2+ Mobilizing Second Messengers Together with Professor Barry Potter

Molecules ◽  
2020 ◽  
Vol 25 (18) ◽  
pp. 4220
Author(s):  
Andreas H. Guse
Keyword(s):  
Cell Biology ◽  
Major Part ◽  
Adenine Nucleotide ◽  
Second Messengers ◽  
Disease Models ◽  
Tool Development ◽  
Proof Of Concept ◽  
Structure Activity ◽  
Acidic Organelles ◽  
Topical Area

Ca2+-mobilizing adenine nucleotide second messengers cyclic adenosine diphosphoribose, (cADPR), nicotinic acid adenine dinucleotide phosphate (NAADP), adenosine diphosphoribose (ADPR), and 2′deoxy-ADPR were discovered since the late 1980s. They either release Ca2+ from endogenous Ca2+ stores, e.g., endoplasmic reticulum or acidic organelles, or evoke Ca2+ entry by directly activating a Ca2+ channel in the plasma membrane. For 25 years, Professor Barry Potter has been one of the major medicinal chemists in this topical area, designing and contributing numerous analogues to develop structure–activity relationships (SAR) as a basis for tool development in biochemistry and cell biology and for lead development in proof-of-concept studies in disease models. With this review, I wish to acknowledge our 25-year-long collaboration on Ca2+-mobilizing adenine nucleotide second messengers as a major part of Professor Potter’s scientific lifetime achievements on the occasion of his retirement in 2020.

scholarly journals Publisher Correction: Genetic tool development in marine protists: emerging model organisms for experimental cell biology

2020 ◽  
Vol 17 (5) ◽  
pp. 551-551
Author(s):  
Drahomíra Faktorová ◽  
R. Ellen R. Nisbet ◽  
José A. Fernández Robledo ◽  
Elena Casacuberta ◽  
Lisa Sudek ◽  
...  
Keyword(s):  
Cell Biology ◽  
Model Organisms ◽  
Tool Development ◽  
Experimental Cell ◽  
Genetic Tool ◽  
Marine Protists

scholarly journals ‘The awesome power of yeast’ in Alzheimer’s disease research

2021 ◽  
Vol 42 (3) ◽  
pp. 130
Author(s):  
Sudip Dhakal
Keyword(s):  
Simple Model ◽  
Animal Models ◽  
Human Brain ◽  
Human Cell ◽  
Cell Biology ◽  
Experimental Studies ◽  
Disease Models ◽  
Disease Research ◽  
Research Findings ◽  
Technological Platforms

The difficulties in performing experimental studies related to diseases of the human brain have fostered a range of disease models from highly expensive and complex animal models to simple, robust, unicellular yeast models. Yeast models have been used in numerous studies to understand Alzheimer’s disease (AD) pathogenesis and to search for drugs targeting AD. Thanks to the conservation of fundamental eukaryotic processes including ageing and the availability of appropriate technological platforms, budding yeast are a simple model eukaryote to assist with understanding human cell biology, offering a platform to study human diseases. This article aims to provide insights from yeast models on the contributions of amyloid beta, a causative agent in AD, and recent research findings on AD chemoprevention.

Synthesis of 2′-/3′-O-Acylated Adenine Nucleotide Analogs and Their Interactions in Photophosphorylation

1983 ◽  
Vol 38 (1-2) ◽  
pp. 49-59 ◽  
Author(s):  
G. Onur ◽  
G. Schäfer ◽  
H. Strotmann
Keyword(s):  
Atp Hydrolysis ◽  
Competitive Inhibition ◽  
Adenine Nucleotide ◽  
Adenine Nucleotides ◽  
Acyl Migration ◽  
Specific Interaction ◽  
Nucleotide Analogs ◽  
Structure Activity ◽  
Atp Analogs ◽  
Inhibitory Activities

By mono esterification of 3′(2′)-hydroxyl residues of adenine nucleotides with various carboxylic acids a series of nucleotide analogs is available including fluorescent and photoaffinity labels. Their chemical synthesis is described. The equilibrium between 2′ and 3′ esters is determined by NMR spectroscopy, stability of the esters and their tendency of acyl migration is discussed. The interaction of the ADP derivatives with the chloroplast ATP synthesizing system is investigated. Actually, the analogs are typical energy transfer inhibitors, strongly inhibiting photophosphorylation and concomitant coupled electron transport (ci50 values ranging from 0.3 to 85 hm). On the basis of inhibitory activities of analogs bearing varying 3′-(2′)-substituents, structure-activity relationships are discussed. The inhibitory properties of the employed ADP analogs are based on their specific interaction with the catalytic ADP binding site of CF, and their extremely slow phosphorylation on the enzyme (rate 0.25% or less compared to ADP phosphorylation). Inhibition is competitive to ADP but non-competitive with regard to Pi. It is specific for the ADP derivatives, whereas the corresponding ATP analogs are only weak inhibitors in phosphorylation and the AMP derivatives are completely inactive. In light-triggered ATP hydrolysis, however, the ATP analogs exhibit an even stronger competitive inhibition than the ADP derivatives. The results suggest that a conformational change of ATPase takes place when the chloroplasts are transferred from energized to de-energized conditions which greatly affects the properties of the active site with respect to nucleotide binding.

scholarly journals Dissociating antibacterial from ototoxic effects of gentamicin C-subtypes

2020 ◽  
Vol 117 (51) ◽  
pp. 32423-32432
Author(s):  
Mary E. O’Sullivan ◽  
Yohan Song ◽  
Robert Greenhouse ◽  
Randy Lin ◽  
Adela Perez ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Side Effects ◽  
Hair Cell ◽  
Aminoglycoside Antibiotic ◽  
Antimicrobial Activities ◽  
Proof Of Concept ◽  
Cell Toxicity ◽  
Structure Activity ◽  
Future Drug

Gentamicin is a potent broad-spectrum aminoglycoside antibiotic whose use is hampered by ototoxic side-effects. Hospital gentamicin is a mixture of five gentamicin C-subtypes and several impurities of various ranges of nonexact concentrations. We developed a purification strategy enabling assaying of individual C-subtypes and impurities for ototoxicity and antimicrobial activity. We found that C-subtypes displayed broad and potent in vitro antimicrobial activities comparable to the hospital gentamicin mixture. In contrast, they showed different degrees of ototoxicity in cochlear explants, with gentamicin C2b being the least and gentamicin C2 the most ototoxic. Structure–activity relationships identified sites in the C4′-C6′ region on ring I that reduced ototoxicity while preserving antimicrobial activity, thus identifying targets for future drug design and mechanisms for hair cell toxicity. Structure–activity relationship data suggested and electrophysiological data showed that the C-subtypes both bind and permeate the hair cell mechanotransducer channel, with the stronger the binding the less ototoxic the compound. Finally, both individual and reformulated mixtures of C-subtypes demonstrated decreased ototoxicity while maintaining antimicrobial activity, thereby serving as a proof-of-concept of drug reformulation to minimizing ototoxicity of gentamicin in patients.

scholarly journals Meta!Blast: A Serious Game to Explore the Complexities of Structural and Metabolic Cell Biology

2010 ◽  
Author(s):  
Eve S. Wurtele ◽  
Diane C. Bassham ◽  
Julie Dickerson ◽  
David J. Kabala ◽  
William Schneller ◽  
...  
Keyword(s):  
Molecular Oxygen ◽  
Cell Biology ◽  
Cellular Structure ◽  
Electron Excitation ◽  
Structure And Function ◽  
Domain Expert ◽  
Proof Of Concept ◽  
Virtual Plant ◽  
And Function ◽  
Virtual Interactive

Knowledge of cellular structure and function has increased dramatically with the advent of modern molecular and computational technologies. Helping students to understand cellular dynamics is a major challenge to educators. To address this challenge, we have developed the Kabala Engine, an open source engine based on OpenSG (http://www.opensg.org) and VRJuggler (http://www.vrjuggler.org). This engine is designed to enable biologists, and indeed any domain expert — chemists, artists, psychologists — to create virtual interactive worlds for teaching or research. As a proof-of-concept, we have used this engine to create Meta!Blast, a virtual plant cell containing a prototype chloroplast in which students can enter, activate the light reactions, including electron excitation, and create molecular oxygen and ATP.

scholarly journals Selective Affimers Recognize BCL-2 Family Proteins Through Non-Canonical Structural Motifs

2019 ◽  
Author(s):  
Jennifer A. Miles ◽  
Fruzsina Hobor ◽  
James Taylor ◽  
Christian Tiede ◽  
Philip R. Rowell ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Cell Biology ◽  
Competitive Inhibition ◽  
Antibody Binding ◽  
Proof Of Concept ◽  
Protein Protein Interactions ◽  
The Family ◽  
Selective Ligands ◽  
Binding Cleft ◽  
Characterisation Methods

AbstractThe BCL-2 family is a challenging set of proteins to target selectively due to sequence and structural homologies across the family. Selective ligands for the BCL-2 family regulators of apoptosis are desirable as probes to understand cell biology and apoptotic signalling pathways, and as starting points for inhibitor design. We have used phage display to isolate Affimer reagents (non-antibody binding proteins based on a conserved scaffold) to identify ligands for MCL-1, BCL-xL, BCL-2, BAK and BAX, then used multiple biophysical characterisation methods to probe the interactions. We established that purified Affimers elicit selective and potent recognition of their target BCL-2 protein. For anti-apoptotic targets, competitive inhibition of their canonical protein-protein interactions is demonstrated. Co-crystal structures reveal an unprecedented mode of molecular recognition; where a BH3 helix is normally bound, flexible loops from the Affimer dock into the BH3 binding cleft. Moreover, the Affimers induce a change in the target proteins towards a desirable drug bound like conformation. These results indicate Affimers can be used as alternative templates to inspire design of selective BCL-2 family modulators, and provide proof-of-concept for the elaboration of selective non-antibody binding reagents for use in cell-biology applications.

scholarly journals Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane

2020 ◽  
Vol 64 (3) ◽  
pp. 513-531 ◽  
Author(s):  
Matilda Katan ◽  
Shamshad Cockcroft
Keyword(s):  
Plasma Membrane ◽  
Ion Channel ◽  
Tyrosine Kinases ◽  
Cell Biology ◽  
Second Messengers ◽  
Membrane Dynamics ◽  
Actin Dynamics ◽  
Ion Channel Regulation ◽  
Channel Regulation ◽  
Phosphoinositide 3 Kinase

Abstract Phosphatidylinositol(4,5) bisphosphate (PI(4,5)P2) has become a major focus in biochemistry, cell biology and physiology owing to its diverse functions at the plasma membrane. As a result, the functions of PI(4,5)P2 can be explored in two separate and distinct roles – as a substrate for phospholipase C (PLC) and phosphoinositide 3-kinase (PI3K) and as a primary messenger, each having unique properties. Thus PI(4,5)P2 makes contributions in both signal transduction and cellular processes including actin cytoskeleton dynamics, membrane dynamics and ion channel regulation. Signalling through plasma membrane G-protein coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and immune receptors all use PI(4,5)P2 as a substrate to make second messengers. Activation of PI3K generates PI(3,4,5)P3 (phosphatidylinositol(3,4,5)trisphosphate), a lipid that recruits a plethora of proteins with pleckstrin homology (PH) domains to the plasma membrane to regulate multiple aspects of cellular function. In contrast, PLC activation results in the hydrolysis of PI(4,5)P2 to generate the second messengers, diacylglycerol (DAG), an activator of protein kinase C and inositol(1,4,5)trisphosphate (IP3/I(1,4,5)P3) which facilitates an increase in intracellular Ca2+. Decreases in PI(4,5)P2 by PLC also impact on functions that are dependent on the intact lipid and therefore endocytosis, actin dynamics and ion channel regulation are subject to control. Spatial organisation of PI(4,5)P2 in nanodomains at the membrane allows for these multiple processes to occur concurrently.

Relationships of Adenine Nucleotide Metabolism to Platelet-Collagen Adhesion

1978 ◽  
Vol 39 (02) ◽  
pp. 366-378 ◽  
Author(s):  
Robert J Morin ◽  
Albert F T Chen
Keyword(s):  
Oxidative Phosphorylation ◽  
Major Part ◽  
Adenine Nucleotide ◽  
Nucleotide Metabolism ◽  
Collagen Fibrils ◽  
Metabolic Inhibitors ◽  
Adenine Nucleotide Metabolism ◽  
Energy Dependent ◽  
Adhesion Of Platelets ◽  
Adhesion Process

SummaryAdhesion of platelets to collagen fibrils in a stirred system was inhibited by preincubation of platelets with combinations of 2-deoxy-D-glucose and oligomycin or antimycin. The inhibition of adhesion was associated with a decrease in metabolic ATP to 6% of control levels. Without metabolic inhibitors, platelets adherent to collagen fibrils were found to have catabolized approximately 57% of their metabolic ATP, and converted a major part of this to IMP. Storage pool ATP and ADP contents were also diminished in the adherent platelets. Pretreatment with imipramine resulted in 76% inhibition of the release reaction, but only 5% inhibition of adhesion. Imipramine-treated platelets that were adherent to collagen showed significant depletion of metabolic ATP, but markedly diminished conversion of ATP to IMP as compared to control adherent platelets. Inhibition of deamination of platelet AMP by coformycin or erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) did not inhibit adhesion, although platelets adherent to collagen after treatment with these agents showed depletion of metabolic ATP. These studies suggest that adhesion is an energy dependent process, occurring independently of release, and not associated with conversion of ATP to IMP. The energy dependent portions of the adhesion process are probably disc to sphere transformation and pseudopod formation, the ATP threshold requirement is relatively low, and the ATP utilized can probably be regenerated during the adhesion process via glycolysis and oxidative phosphorylation.

scholarly journals Caspase-8 goes cardiolipin: a new platform to provide mitochondria with microdomains of apoptotic signals?

2008 ◽  
Vol 183 (4) ◽  
pp. 579-581 ◽  
Author(s):  
Luca Scorrano
Keyword(s):  
Cell Biology ◽  
Second Messengers ◽  
Cell Types ◽  
Caspase 8 ◽  
Mitochondrial Membranes ◽  
Close Proximity ◽  
Effector Caspases ◽  
Extracellular Stimuli ◽  
Intracellular Target ◽  
Specific Lipid

In certain cell types, apoptosis in response to extracellular stimuli like Fas depends on a mitochondrial amplificatory loop: the apical caspase-8 cleaves and activates the BH3-only member of the Bcl-2 family BID. In turn, BID induces the release of cytochrome c from mitochondria to the cytoplasm, where it is required to fully activate effector caspases. In this issue of The Journal of Cell Biology, Gonzalvez et al. (see p. 681) show that when caspase-8 activation and production of functional BID is required, it is performed on mitochondrial platforms provided by the mitochondrion-specific lipid cardiolipin. Cardiolipin anchors caspase-8 at contact sites between inner and outer mitochondrial membranes, facilitating its self activation. These findings suggests that like other second messengers such as Ca2+ and cAMP, production of apoptotic messengers can be compartmentalized in close proximity to their intracellular target.

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