Search Results (47)

Myo-inositol-1,2,3,4,5,6-hexakisphosphate (IP6) is commonly found in plant-derived foods and has important pharmacological properties against many pathologies. One of them appears to be neurodegeneration, which is notably stimulated by dysregulated metal metabolism. Consequently, we explore the role of IP6 in mitigating neurodegenerative events catalyzed by dysregulated free iron. More precisely, we performed spectrophotometric measurements in aqueous solutions to investigate the ability of IP6 to chelate Fe³⁺ and inhibit its role in catalyzing the oxidative degradation of dopamine and ascorbic acid, two key molecules in neuronal redox systems. Our results demonstrate that IP6 effectively prevents the formation of harmful intermediates, such as neuromelanin and reactive oxygen species, which are linked to neuronal damage. Additionally, we assessed the effect of IP6 on Fe³⁺-induced protein aggregation, focusing on α-synuclein, which is closely associated with Parkinson’s disease. Our data reveal that IP6 accelerates the conversion of toxic α-synuclein oligomers into less harmful amyloid fibrils, thereby reducing their neurotoxic potential. Our findings highlight the dual function of IP6 as a potent Fe³⁺ chelator and modulator of protein aggregation pathways, reinforcing its potential as a neuroprotective agent. Consequently, IP6 offers promising therapeutic potential for mitigating the progression of neurodegenerative disorders such as Parkinson’s and Alzheimer’s diseases. Full article

The HIV-1 capsid is one of virology’s most iconic structures, yet how it assembles has long remained elusive. Remarkably, the capsid is made from just a single protein, CA, which forms a lattice of ~250 hexamers and exactly 12 pentamers. Conical capsids form inside budded virions during maturation, but early efforts to reproduce this in vitro resulted instead in open-ended tubes with a purely hexameric lattice. The missing component in capsid assembly was finally identified as the metabolite inositol hexakisphosphate (IP6). Simply mixing soluble CA protein with IP6 is sufficient to drive the spontaneous assembly of conical capsids with a similar size and shape to those inside of infectious virions. Equally important, IP6 stabilises capsids once formed, increasing their stability from minutes to hours. Indeed, such is the dependence of HIV-1 on IP6 that the virus actively packages it into virions during production. These discoveries have stimulated work from multiple labs into the role and importance of IP6 in HIV-1 replication, and is the subject of this review. Full article

Background/Objectives: Ectopic calcification is a pathological condition characterized by the mineralization of soft tissues due to the deposition of calcium phosphate crystals. Hexasodium fytate (CSL525, previously known as SNF472) is a crystallization inhibitor being developed for the treatment of ectopic calcification-related disorders. Our aim was to investigate CSL525 for the treatment of soft-tissue calcification disorders in animal models of pseudoxanthoma elasticum and calcinosis cutis. Methods: In a first study, abcc6^-/- zebrafish larvae were exposed to 1 mM CSL525 for 7 days or kept under the same conditions without CSL525, and spinal mineralization was quantified. In a second study, abcc6^-/- mice were administered subcutaneously with CSL525 at 15 mg/kg thrice weekly for eight weeks. Vehicle-treated WT (C57BL/6J) and abcc6^-/- mice served as controls, and muzzle skin calcification was quantified. In a third study, calcinosis cutis was induced in rats through subcutaneous administration of 0.15 mg FeCl₃ at two sites in the thorax. Rats were administered either subcutaneous CSL525 (60 mg/kg) or vehicle (0.9% NaCl), and calcium content was measured in the skin. Results: CSL525 significantly reduced the calcified area (~40%) in abcc6a^-/- zebrafish larvae. The abcc6^-/- mice receiving CSL525 showed a 57% inhibition of muzzle calcification compared to vehicle-treated abcc6^-/- mice. CSL525 inhibited skin calcification development by 60% in the calcinosis cutis rat model. Conclusions: CSL525 may prove beneficial not only in preventing the progression of cardiovascular calcification but also in treating other ectopic calcification conditions, including skin calcification associated with genetic disorders such as PXE. Full article

Gle1 functions as a regulator of Dbp5, a DEAD-box-containing RNA helicase that is a component of the nuclear pore complex. In association with Gle1 and inositol hexakisphosphate (IP6), ADP-bound Dbp5 facilitates the release of RNA. The RNA-bound Dbp5 undergoes ATP hydrolysis and is activated by Gle1 in the presence of IP6. The formation of a ternary complex involving Dbp5, Gle1, and the nucleoporin Nup159 promotes ADP secretion and prevents RNA recombination. To date, several complex structures of Gle1 with its binding partners have been described; however, the structure of unbound Gle1 remains elusive. To investigate the structural features associated with complex formation, the crystal structure of N-terminally truncated Gle1 from Debaryomyces hansenii (DhGle1ΔN) was determined at a resolution of 1.5 Å. The DhGle1ΔN protein comprises 13 α-helices. Structural comparisons with homologs, all of which have been characterized in various complexes, revealed no significant conformational changes. However, several distinct secondary structural elements were identified in α1, α3, α4, and α8. This study may provide valuable insights into the architecture of yeast Gle1 proteins and their interactions with Dbp5, which is crucial for understanding the regulation of mRNA export. Full article

Cereals are among the foods rich in myo-inositol hexakisphosphate (phytic acid, IP6), lower myo-inositol phosphates (IPx), a wide range of phenolic compounds, as well as vitamins, minerals, oligosaccharides, phytosterols and para-aminobenzoic acid, and are attributed with multiple bioactivities, particularly associated with the prevention of metabolic syndrome and colon cancer. The bran fraction of wheat, maize, brown rice and other cereals contains high levels of phytate, free and total phenolics, and endogenous enzymes such as amylases, phytase, xylanase, β-glucanase and feruloyl esterase, whose activities can be increased by germination. The preliminary steps of digestion begin in the oral cavity where substrates for the action of endogenous cereal and salivary enzymes start to be released from the food matrix. IP6 released from phytate complexes with arabinoxylans, starch and protein bodies would eventually enhance the absorption of nutrients, including phenolics, by regulating tight junctions and, together with ferulic acid (FA), would maintain cell barrier integrity and epithelial antibacterial immunity. In addition, both IP6 and FA exert potent and complementary antioxidant effects, while FA together with IPx generated through advanced hydrolysis of IP6 by endogenous and microbial phytases may affect digestive enzyme activity and incretin secretion, resulting in modulated insulin and glucagon release and prevention of various diabetic complications. Contrary to widespread negative attitudes towards phytate, in this review, we present the strategy of selecting cereals with high phytate and phenolic content, as well as high endogenous phytase, feruloyl esterase and endoxylanase activities, to produce value-added health-promoting foods. The advanced hydrolysis of phytate and phenolic compounds by cereal and/or microbial enzymes would generate substantial amounts of “enzymatically generated inositol” (EGI), including IP6, IPx and myo-inositol, the compounds that, together with free FA, provide enhanced bioavailability of cereal nutrients through multiple synergistic effects not previously realised. Full article

Inositol hexakisphosphate (InsP₆) is the most abundant inositol polyphosphate both in plant and animal cells. Exogenous InsP₆ is known to inhibit cell proliferation and induce apoptosis in cancerous cells. However, cellular entry of exogenous InsP₆ is hindered due to the presence of highly negative charge on this molecule. Therefore, to enhance the cellular delivery of InsP₆ in cancerous cells, InsP₆ was encapsulated by chitosan (CS), a natural polysaccharide, via the ionic gelation method. Our hypothesis is that encapsulated InsP₆ will enter the cell more efficiently to trigger its apoptotic effects. The incorporation of InsP₆ into CS was optimized by varying the ratios of the two and confirmed by InsP₆ analysis via polyacrylamide gel electrophoresis (PAGE) and atomic absorption spectrophotometry (AAS). The complex was further characterized by Scanning Electron Microscopy (SEM) and Fourier Transform Infrared Spectroscopy (FTIR) for physicochemical changes. The data indicated morphological changes and changes in the spectral properties of the complex upon encapsulation. The encapsulated InsP₆ enters human breast cancer MCF-7 cells more efficiently than free InsP₆ and triggers apoptosis via a mechanism involving the production of reactive oxygen species (ROS). This work has potential for developing cancer therapeutic applications utilizing natural compounds that are likely to overcome the severe toxic effects associated with synthetic chemotherapeutic drugs. Full article

Inositols have demonstrated a role in cancer prevention and treatment in many kinds of neoplasms. Their molecular mechanisms vary from the regulation of survival and proliferative pathways to the modulation of immunity and oxidative stress. The dysregulation of many pathways and mechanisms regulated by inositols has been demonstrated in endocrine and neuroendocrine tumors but the role of inositol supplementation in this context has not been clarified. The aim of this review is to summarize the molecular basis of the possible role of inositols in endocrine and neuroendocrine tumors, proposing it as an adjuvant therapy. Full article

In the fullerene cone HIV-1 capsid, the central channels of the hexameric and pentameric capsomers each contain a ring of arginine (Arg18) residues that perform essential roles in capsid assembly and function. In both the hexamer and pentamer, the Arg18 rings coordinate inositol hexakisphosphate, an assembly and stability factor for the capsid. Previously, it was shown that amino-acid substitutions of Arg18 can promote pentamer incorporation into capsid-like particles (CLPs) that spontaneously assemble in vitro under high-salt conditions. Here, we show that these Arg18 mutant CLPs contain a non-canonical pentamer conformation and distinct lattice characteristics that do not follow the fullerene geometry of retroviral capsids. The Arg18 mutant pentamers resemble the hexamer in intra-oligomeric contacts and form a unique tetramer-of-pentamers that allows for incorporation of an octahedral vertex with a cross-shaped opening in the hexagonal capsid lattice. Our findings highlight an unexpected degree of structural plasticity in HIV-1 capsid assembly. Full article

Recent research has uncovered a promising approach to addressing the growing global health concern of obesity and related disorders. The inhibition of inositol hexakisphosphate kinase 1 (IP6K1) has emerged as a potential therapeutic strategy. This study employs multiple ligand-based in silico modeling techniques to investigate the structural requirements for benzisoxazole derivatives as IP6K1 inhibitors. Firstly, we developed linear 2D Quantitative Structure–Activity Relationship (2D-QSAR) models to ensure both their mechanistic interpretability and predictive accuracy. Then, ligand-based pharmacophore modeling was performed to identify the essential features responsible for the compounds’ high activity. To gain insights into the 3D requirements for enhanced potency against the IP6K1 enzyme, we employed multiple alignment techniques to set up 3D-QSAR models. Given the absence of an available X-ray crystal structure for IP6K1, a reliable homology model for the enzyme was developed and structurally validated in order to perform structure-based analyses on the selected dataset compounds. Finally, molecular dynamic simulations, using the docked poses of these compounds, provided further insights. Our findings consistently supported the mechanistic interpretations derived from both ligand-based and structure-based analyses. This study offers valuable guidance on the design of novel IP6K1 inhibitors. Importantly, our work exclusively relies on non-commercial software packages, ensuring accessibility for reproducing the reported models. Full article

The inositol pyrophosphate pathway, a complex cell signaling network, plays a pivotal role in orchestrating vital cellular processes in the budding yeast, where it regulates cell cycle progression, growth, endocytosis, exocytosis, apoptosis, telomere elongation, ribosome biogenesis, and stress responses. This pathway has gained significant attention in pharmacology and medicine due to its role in generating inositol pyrophosphates, which serve as crucial signaling molecules not only in yeast, but also in higher eukaryotes. As targets for therapeutic development, genetic modifications within this pathway hold promise for disease treatment strategies, offering practical applications in biotechnology. The model organism Saccharomyces cerevisiae, renowned for its genetic tractability, has been instrumental in various studies related to the inositol pyrophosphate pathway. This review is focused on the Kcs1 and Vip1, the two enzymes involved in the biosynthesis of inositol pyrophosphate in S. cerevisiae, highlighting their roles in various cell processes, and providing an up-to-date overview of their relationship with phosphate homeostasis. Moreover, the review underscores the potential applications of these findings in the realms of medicine and biotechnology, highlighting the profound implications of comprehending this intricate signaling network. Full article

The YopJ group of acetylating effectors from phytopathogens of the genera Pseudomonas and Ralstonia have been widely studied to understand how they modify and suppress their host defence targets. In contrast, studies on a related group of effectors, the Eop1 group, lag far behind. Members of the Eop1 group are widely present in the Erwinia-Pantoea clade of Gram-negative bacteria, which contains phytopathogens, non-pathogens and potential biocontrol agents, implying that they may play an important role in agroecological or pathological adaptations. The lack of research in this group of YopJ effectors has left a significant knowledge gap in their functioning and role. For the first time, we perform a comparative analysis combining AlphaFold modelling, in planta transient expressions and targeted mutational analyses of the Eop1 group effectors from the Erwinia-Pantoea clade, to help elucidate their likely activity and mechanism(s). This integrated study revealed several new findings, including putative binding sites for inositol hexakisphosphate and acetyl coenzyme A and newly postulated target-binding domains, and raises questions about whether these effectors function through a catalytic triad mechanism. The results imply that some Eop1s may use a catalytic dyad acetylation mechanism that we found could be promoted by the electronegative environment around the active site. Full article

Inositol is a unique biological small molecule that can be phosphorylated or even further pyrophosphorylated on each of its six hydroxyl groups. These numerous phosphorylation states of inositol along with the kinases and phosphatases that interconvert them comprise the inositol phosphate signaling pathway. Inositol hexakisphosphate kinases, or IP6Ks, convert the fully mono-phosphorylated inositol to the pyrophosphate 5-IP7 (also denoted IP7). There are three isoforms of IP6K: IP6K1, 2, and 3. Decades of work have established a central role for IP6Ks in cell signaling. Genetic and pharmacologic manipulation of IP6Ks in vivo and in vitro has shown their importance in metabolic disease, chronic kidney disease, insulin signaling, phosphate homeostasis, and numerous other cellular and physiologic processes. In addition to these peripheral processes, a growing body of literature has shown the role of IP6Ks in the central nervous system (CNS). IP6Ks have a key role in synaptic vesicle regulation, Akt/GSK3 signaling, neuronal migration, cell death, autophagy, nuclear translocation, and phosphate homeostasis. IP6Ks’ regulation of these cellular processes has functional implications in vivo in behavior and CNS anatomy. Full article

Pathological calcifications may consist of calcium oxalate (CaOx), hydroxyapatite (HAP), and brushite (BRU). The objective of this study was to evaluate the effect of phytate (inositol hexakisphosphate, InsP6), InsP6 hydrolysates, and individual lower InsPs (InsP5, InsP4, InsP3, and InsP2) on the crystallization of CaOx, HAP and BRU in artificial urine. All of the lower InsPs seem to inhibit the crystallization of calcium salts in biological fluids, although our in vitro results showed that InsP6 and InsP5 were stronger inhibitors of CaOx crystallization, and InsP5 and InsP4 were stronger inhibitors of BRU crystallization. For the specific in vitro experimental conditions we examined, the InsPs had very weak effects on HAP crystallization, although it is likely that a different mechanism is responsible for HAP crystallization in vivo. For example, calciprotein particles seem to have an important role in the formation of cardiovascular calcifications in vivo. The experimental conditions that we examined partially reproduced the in vivo conditions of CaOx and BRU crystallization, but not the in vivo conditions of HAP crystallization. Full article

Multiple inositol polyphosphate phosphatase (MINPP1) is an enigmatic enzyme that is responsible for the metabolism of inositol hexakisphosphate (InsP₆) and inositol 1,3,4,5,6 pentakisphosphate (Ins(1,3,4,5,6)P₅ in mammalian cells, despite being restricted to the confines of the ER. The reason for this compartmentalization is unclear. In our previous studies in the insulin-secreting HIT cell line, we expressed MINPP1 in the cytosol to artificially reduce the concentration of these higher inositol phosphates. Undocumented at the time, we noted cytosolic MINPP1 expression reduced cell growth. We were struck by the similarities in substrate preference between a number of different enzymes that are able to metabolize both inositol phosphates and lipids, notably IPMK and PTEN. MINPP1 was first characterized as a phosphatase that could remove the 3-phosphate from inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P₄)_. This molecule shares strong structural homology with the major product of the growth-promoting Phosphatidyl 3-kinase (PI3K), phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P₃) and PTEN can degrade both this lipid and Ins(1,3,4,5)P₄. Because of this similar substrate preference, we postulated that the cytosolic version of MINPP1 (cyt-MINPP1) may not only attack inositol polyphosphates but also PtdIns(3,4,5)P₃, a key signal in mitogenesis. Our experiments show that expression of cyt-MINPP1 in HIT cells lowers the concentration of PtdIns(3,4,5)P₃. We conclude this reflects a direct effect of MINPP1 upon the lipid because cyt-MINPP1 actively dephosphorylates synthetic, di(C4:0)PtdIns(3,4,5)P₃ in vitro. These data illustrate the importance of MINPP1′s confinement to the ER whereby important aspects of inositol phosphate metabolism and inositol lipid signaling can be separately regulated and give one important clarification for MINPP1′s ER seclusion. Full article

Altered RNA editing has been linked to several neurodevelopmental disorders, including autism spectrum disorder (ASD) and intellectual disability, in addition to depression, schizophrenia, some cancers, viral infections and autoimmune disorders. The human ADAR2 is a potential therapeutic target for managing these various disorders due to its crucial role in adenosine to inosine editing. This study applied consensus scoring to rank potential ADAR2 inhibitors after performing molecular docking with AutoDock Vina and Glide (Maestro), using a library of 35,161 compounds obtained from traditional Chinese medicine. A total of 47 compounds were predicted to be good binders of the human ADAR2 and had insignificant toxicity concerns. Molecular dynamics (MD) simulations, including the molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) procedure, also emphasized the binding of the shortlisted compounds. The potential compounds had plausible binding free energies ranging from −81.304 to −1068.26 kJ/mol from the MM/PBSA calculations. ZINC000085511995, a naphthoquinone had more negative binding free energy (−1068.26 kJ/mol) than inositol hexakisphosphate (IHP) [−873.873 kJ/mol], an agonist and a strong binder of ADAR2. The potential displacement of IHP by ZINC000085511995 in the IHP binding site of ADAR2 could be explored for possible deactivation of ADAR2. Bayesian-based biological activity prediction corroborates the neuropharmacological, antineoplastic and antiviral activity of the potential lead compounds. All the potential lead compounds, except ZINC000014612330 and ZINC000013462928, were predicted to be inhibitors of various deaminases. The potential lead compounds also had probability of activity (Pa) > 0.442 and probability of inactivity (Pi) < 0.116 values for treating acute neurologic disorders, except for ZINC000085996580 and ZINC000013462928. Pursuing these compounds for their anti-ADAR2 activities holds a promising future, especially against neurological disorders, some cancers and viral infections caused by RNA viruses. Molecular interaction, hydrogen bond and per-residue decomposition analyses predicted Arg400, Arg401, Lys519, Trp687, Glu689, and Lys690 as hot-spot residues in the ADAR2 IHP binding site. Most of the top compounds were observed to have naphthoquinone, indole, furanocoumarin or benzofuran moieties. Serotonin and tryptophan, which are beneficial in digestive regulation, improving sleep cycle and mood, are indole derivatives. These chemical series may have the potential to treat neurological disorders, prion diseases, some cancers, specific viral infections, metabolic disorders and eating disorders through the disruption of ADAR2 pathways. A total of nine potential lead compounds were shortlisted as plausible modulators of ADAR2. Full article