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Journal of Cardiovascular Translational... Feb 2024Water-soluble myo-inositol phosphates have long been characterized as second messengers. The signaling properties of these compounds are determined by the number and... (Review)
Review
Water-soluble myo-inositol phosphates have long been characterized as second messengers. The signaling properties of these compounds are determined by the number and arrangement of phosphate groups on the myo-inositol backbone. Recently, higher inositol phosphates with pyrophosphate groups were recognized as signaling molecules. 5-Diphosphoinositol 1,2,3,4,6-pentakisphosphate (5PP-InsP) is the most abundant isoform, constituting more than 90% of intracellular inositol pyrophosphates. 5PP-InsP can be further phosphorylated to 1,5-bisdiphosphoinositol 2,3,4,6-tetrakisphosphate (InsP). These two molecules, 5PP-InsP and InsP, are present in various subcellular compartments, where they participate in regulating diverse cellular processes such as cell death, energy homeostasis, and cytoskeletal dynamics. The synthesis and metabolism of inositol pyrophosphates are subjected to tight regulation, allowing for their highly specific functions. Blocking the 5PP-InsP/InsP signaling pathway by inhibiting the biosynthesis of 5PP-InsP demonstrates therapeutic benefits in preclinical studies, and thus holds promise as a therapeutic approach for certain diseases treatment, such as metabolic disorders.
Topics: Animals; Diphosphates; Inositol Phosphates; Signal Transduction; Mammals
PubMed: 37615888
DOI: 10.1007/s12265-023-10427-0 -
Current Genetics Oct 2020Saccharomyces cerevisiae adapts to oxidative, osmotic stress and nutrient deprivation through transcriptional changes, decreased proliferation, and entry into other... (Review)
Review
Saccharomyces cerevisiae adapts to oxidative, osmotic stress and nutrient deprivation through transcriptional changes, decreased proliferation, and entry into other developmental pathways such as pseudohyphal formation and sporulation. Inositol pyrophosphates are necessary for these cellular responses. Inositol pyrophosphates are molecules composed of the phosphorylated myo-inositol ring that carries one or more diphosphates. Mutations in the enzymes that metabolize these molecules lead to altered patterns of stress resistance, altered morphology, and defective sporulation. Mechanisms to alter the synthesis of inositol pyrophosphates have been recently described, including inhibition of enzyme activity by oxidation and by phosphorylation. Cells with increased levels of 5-diphosphoinositol pentakisphosphate have increased nuclear localization of Msn2 and Gln3. The altered localization of these factors is consistent with the partially induced environmental stress response and increased expression of genes under the control of Msn2/4 and Gln3. Other transcription factors may also exhibit increased nuclear localization based on increased expression of their target genes. These transcription factors are each regulated by TORC1, suggesting that TORC1 may be inhibited by inositol pyrophosphates. Inositol pyrophosphates affect stress responses in other fungi (Aspergillus nidulans, Ustilago maydis, Schizosaccharomyces pombe, and Cryptococcus neoformans), in human and mouse, and in plants, suggesting common mechanisms and possible novel drug development targets.
Topics: Cell Nucleus; DNA-Binding Proteins; Diphosphates; Gene Expression Regulation, Fungal; Heat-Shock Response; Histone Deacetylase 1; Inositol Phosphates; Mechanistic Target of Rapamycin Complex 1; Osmotic Pressure; Oxidative Stress; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Signal Transduction; Stress, Physiological; Transcription Factors
PubMed: 32322930
DOI: 10.1007/s00294-020-01078-8 -
The Journal of Rheumatology Aug 2020
Topics: Arthritis; Calcium Pyrophosphate; Crystal Arthropathies; Humans; Recurrence; Risk Factors
PubMed: 32739900
DOI: 10.3899/jrheum.191316 -
Cell Death & Disease Jul 2023Pathological mineralization of intervertebral disc is debilitating and painful and linked to disc degeneration in a subset of human patients. An adenosine triphosphate...
Pathological mineralization of intervertebral disc is debilitating and painful and linked to disc degeneration in a subset of human patients. An adenosine triphosphate efflux transporter, progressive ankylosis (ANK) is a regulator of extracellular inorganic pyrophosphate levels and plays an important role in tissue mineralization. However, the function of ANK in intervertebral disc has not been fully explored. Herein we analyzed the spinal phenotype of Ank mutant mice (ank/ank) with attenuated ANK function. Micro-computed tomography and histological analysis showed that loss of ANK function results in the aberrant annulus fibrosus mineralization and peripheral disc fusions with cranial to caudal progression in the spine. Vertebrae in ank mice exhibit elevated cortical bone mass and increased tissue non-specific alkaline phosphatase-positive endplate chondrocytes with decreased subchondral endplate porosity. The acellular dystrophic mineral inclusions in the annulus fibrosus were localized adjacent to apoptotic cells and cells that acquired osteoblast-like phenotype. Fourier transform infrared spectral imaging showed that the apatite mineral in the outer annulus fibrosus had similar chemical composition to that of vertebral bone. Transcriptomic analysis of annulus fibrosus and nucleus pulposus tissues showed changes in several biological themes with a prominent dysregulation of BMAL1/CLOCK circadian regulation. The present study provides new insights into the role of ANK in the disc tissue compartments and highlights the importance of local inorganic pyrophosphate metabolism in inhibiting the mineralization of this important connective tissue.
Topics: Animals; Humans; Mice; Calcinosis; Diphosphates; Intervertebral Disc; Intervertebral Disc Degeneration; Loss of Function Mutation; Phenotype; X-Ray Microtomography
PubMed: 37468461
DOI: 10.1038/s41419-023-05893-y -
Inorganic Chemistry Dec 2022The knowledge of accurate geometrical parameters from X-ray diffraction studies in the solid state of metal nucleotide is very important for understanding the...
The knowledge of accurate geometrical parameters from X-ray diffraction studies in the solid state of metal nucleotide is very important for understanding the relationship between structures and properties, including biochemical processes and even enzyme-metal-substrate interactions. The research is also very necessary to precisely and controllably design the functional materials. Here, seven types of coordination polymers of inosine 5'-diphosphate nucleotide (IDP) with transition metals, {[Zn(HIDP)(azpy)(HO)]·4HO} (), {[Cd(IDP)(bpda)]·[Cd(HO)]·11HO} (), {[Cd(IDP)(4,4'-bipy)(HO)]·6HO} (), {[Cd(IDP)(bpe)(HO)]·(Hbpe)·26HO} (), {[Cu(IDP)(azpy)(HO)]·5HO} (), {[Cu(IDP)(bpe)(HO)]·9HO} (), and {[Co(HIDP)(azpy)(HO)]·7HO} () [4,4'-bipy = 4,4'-bipyridine, azpy = 4,4'-azopyridine, bpe = 1,2-bis(4-pyridyl)ethene, and bpda = 1,4-bis(4-pyridyl)-2,3-diaza-1,3-butadiene], were designed, synthesized, and firmly characterized using single-crystal X-ray diffraction. The coordination patterns of the diphosphate group of IDP in these complexes were studied by crystallographic analysis, namely, open, close, and open-close hybrid types. We have investigated the diverse coordination patterns of the diphosphate group and its spatial relationship relative to the pentose ring on the basis of two conformational parameters, the pseudorotation phase angle and the degree of puckering. Crystallographic studies clearly reveal the correlation between the backbone torsion angle (ω' and φ) of the sugar-diphosphate and the conformational preference of the pentose ring, i.e., the signs of the backbone torsion angles ω' and φ are both plus (+) or minus (-), the conformation of the pentose ring is envelope form (E), while when one of the two signs is plus (+) and the other is minus (-), the pentose ring is in the twist form (T). This is the first time elucidation of the coordination pattern of diphosphate relative to the conformation of the pentose ring in nucleotide metal complexes, which are different from the other inorganic or organic diphosphate compounds. The chirality of these coordination polymers was examined by combining solid-state circular dichroism spectroscopy measurements with the explanation of their crystal structures. The results presented in this paper are very important for understanding their nucleotide coordination chemistry, their supramolecular chemistry, and even their biochemistry.
Topics: Diphosphates; Coordination Complexes; Inosine Diphosphate; Cadmium; Nucleotides; Polymers
PubMed: 36413753
DOI: 10.1021/acs.inorgchem.2c03285 -
Journal of the American Heart... Jun 2022Background Several imaging parameters and biomarkers provide diagnostic and prognostic information for wild-type transthyretin amyloid cardiomyopathy. However, the...
Background Several imaging parameters and biomarkers provide diagnostic and prognostic information for wild-type transthyretin amyloid cardiomyopathy. However, the relevance of these parameters and their association with cardiac amyloid load requires further substantiation. We aimed to elucidate the association of imaging parameters obtained using Tc-labeled pyrophosphate scintigraphy, cardiovascular magnetic resonance imaging, global longitudinal strain (GLS), and cardiac biomarkers with cardiac amyloid load in patients with wild-type transthyretin amyloid cardiomyopathy. Methods and Results Eighty-eight patients with wild-type transthyretin amyloid cardiomyopathy who underwent Tc-labeled pyrophosphate scintigraphy and cardiovascular magnetic resonance were retrospectively evaluated. Quantitative cardiac amyloid load was obtained from 61 patients after myocardial biopsy. Correlations were assessed using Pearson's correlation coefficient applied to medical record data. The mean heart to contralateral ratio, native T1, extracellular volume, and GLS were 1.91±0.36, 1419.4±56.4 ms, 56.5±13.6%, and -9.4±2.5%, respectively. Median high-sensitivity cardiac troponin T (hs-cTnT) and BNP (B-type natriuretic peptide) levels were 0.0478 (0.0334-0.0691) ng/mL and 213.8 (125.8-392.7) pg/mL, respectively. The mean cardiac amyloid load was 22.9±15.0%. The heart to contralateral ratio correlated significantly with native T1 (=0.397), extracellular volume (=0.477), GLS (=0.363), cardiac amyloid load (=0.379), and Ln (hs-cTnT) (=0.247). Further, cardiac amyloid load correlated significantly with native T1 (=0.509), extracellular volume (=0.310), GLS (=0.446), and Ln (hs-cTnT) (=0.354). Compared with BNP, hs-cTnT levels better correlated with several imaging parameters and cardiac amyloid load. Conclusions Increased cardiac amyloid load correlated with increased Tc-labeled pyrophosphate positivity, native T1, extracellular volume, and hs-cTnT levels, and an impaired GLS, suggesting that imaging parameters and cardiac biomarkers may reflect histological and functional changes attributable to amyloid deposition in the myocardium.
Topics: Amyloid; Amyloid Neuropathies, Familial; Biomarkers; Cardiomyopathies; Diphosphates; Humans; Prealbumin; Retrospective Studies
PubMed: 35699194
DOI: 10.1161/JAHA.121.024717 -
Biochemistry. Biokhimiia Mar 2020Neurodegenerative diseases are accompanied by changes in the activity of thiamine mono- and diphosphate phosphatases, but molecular identification of these mammalian...
Neurodegenerative diseases are accompanied by changes in the activity of thiamine mono- and diphosphate phosphatases, but molecular identification of these mammalian enzymes is incomplete. In this work, the protein fraction of bovine brain synaptosomes displaying phosphatase activity toward thiamine derivatives was subjected to affinity chromatography on thiamine-Sepharose. Protein fractions eluted with thiamine (pH 7.4 or 5.6), NaCl, and urea were assayed for the phosphatase activity against thiamine monophosphate (ThMP), thiamine diphosphate (ThDP), and structurally similar purine nucleotides. Proteins in each fraction were identified by mass spectrometry using the SwissProt database for all organisms because of insufficient annotation of the bovine genome. Peptides of two annotated bacterial phosphatases, alkaline phosphatase L from the DING protein family and exopolyphosphatase, were identified in the acidic thiamine eluate. The abundance of peptides of alkaline phosphatase L and exopolyphosphatase in the eluted fractions correlated with ThMPase and ThDPase activities, respectively. The elution profiles of the ThMPase and ThDPase activities differed from the elution profiles of nucleotide phosphatases, thus indicating the specificity of these enzymes toward thiamine derivatives. The search for mammalian DING phosphatases in the eluates from thiamine-Sepharose revealed X-DING-CD4, mostly eluted by the acidic thiamine solution (pH 5.6). The identified exopolyphosphatase demonstrated structural similarity with apyrases possessing the ThDPase activity. The obtained results demonstrate that mammalian DING proteins and apyrases exhibit ThMPase and ThDPase activity, respectively.
Topics: Animals; Brain; Catalytic Domain; Cattle; Chromatography, Affinity; Diphosphates; Genome; Humans; Hydrogen-Ion Concentration; Phosphoric Monoester Hydrolases; Substrate Specificity; Synaptosomes; Thiamine; Thiamine Monophosphate; Thiamine Pyrophosphate; Urea
PubMed: 32564742
DOI: 10.1134/S000629792003013X -
Journal of the American Chemical Society Feb 2024Complex bacterial glycoconjugates drive interactions between pathogens, symbionts, and their human hosts. Glycoconjugate biosynthesis is initiated at the membrane...
Complex bacterial glycoconjugates drive interactions between pathogens, symbionts, and their human hosts. Glycoconjugate biosynthesis is initiated at the membrane interface by phosphoglycosyl transferases (PGTs), which catalyze the transfer of a phosphosugar from a soluble uridine diphosphosugar (UDP-sugar) substrate to a membrane-bound polyprenol-phosphate (Pren-P). The two distinct superfamilies of PGT enzymes (polytopic and monotopic) show striking differences in their structure and mechanism. We designed and synthesized a series of uridine bisphosphonates (UBPs), wherein the diphosphate of the UDP and UDP-sugar is replaced by a substituted methylene bisphosphonate (CXY-BPs; X/Y = F/F, Cl/Cl, ()-H/F, ()-H/F, H/H, CH/CH). UBPs and UBPs incorporating an -acetylglucosamine (GlcNAc) substituent at the β-phosphonate were evaluated as inhibitors of a polytopic PGT (WecA from ) and a monotopic PGT (PglC from ). Although CHF-BP most closely mimics diphosphate with respect to its acid/base properties, the less basic CF-BP conjugate more strongly inhibited PglC, whereas the more basic CH-BP analogue was the strongest inhibitor of WecA. These surprising differences indicate different modes of ligand binding for the different PGT superfamilies, implicating a modified P-O interaction with the structural Mg. For the monoPGT enzyme, the two diastereomeric CHF-BP conjugates, which feature a chiral center at the P-CHF-P carbon, also exhibited strikingly different binding affinities and the inclusion of GlcNAc with the native α-anomer configuration significantly improved binding affinity. UBP-sugars are thus revealed as informative new mechanistic probes of PGTs that may aid development of novel antibiotic agents for the exclusively prokaryotic monoPGT superfamily.
Topics: Humans; Transferases; Uridine; Diphosphates; Glycoconjugates; Diphosphonates; Sugars; Uridine Diphosphate
PubMed: 38271668
DOI: 10.1021/jacs.3c11402 -
The Journal of Thoracic and... Nov 2022Cardioplegic ischemia-reperfusion and diabetes mellitus are correlated with coronary endothelial dysfunction and inactivation of small conductance calcium-activated...
OBJECTIVE
Cardioplegic ischemia-reperfusion and diabetes mellitus are correlated with coronary endothelial dysfunction and inactivation of small conductance calcium-activated potassium channels. Increased reactive oxidative species, such as mitochondrial reactive oxidative species, may contribute to oxidative injury. Thus, we hypothesized that inhibition of mitochondrial reactive oxidative species may protect coronary small conductance calcium-activated potassium channels and endothelial function against cardioplegic ischemia-reperfusion-induced injury.
METHODS
Small coronary arteries and endothelial cells from the hearts of mice with and without diabetes mellitus were isolated and examined by using a cardioplegic hypoxia and reoxygenation model to determine whether the mitochondria-targeted antioxidant Mito-Tempo could protect against coronary endothelial and small conductance calcium-activated potassium channel dysfunction. The microvessels or mouse heart endothelial cells were treated with or without Mito-Tempo (0-10 μM) 5 minutes before and during cardioplegic hypoxia and reoxygenation. Microvascular function was assessed in vitro by vessel myography. K currents of mouse heart endothelial cells were measured by whole-cell patch clamp. The levels of intracellular cytosolic free calcium (Ca) concentration, mitochondrial reactive oxidative species, and small conductance calcium-activated potassium protein expression of mouse heart endothelial cells were measured by Rhod-2 fluorescence staining, MitoSox, and Western blotting, respectively.
RESULTS
Cardioplegic hypoxia and reoxygenation significantly attenuated endothelial small conductance calcium-activated potassium channel activity, caused calcium overload, and increased mitochondrial reactive oxidative species of mouse heart endothelial cells in both the nondiabetic and diabetes mellitus groups. In addition, treating mouse heart endothelial cells with Mito-Tempo (10 μM) reduced cardioplegic hypoxia and reoxygenation-induced Ca and mitochondrial reactive oxidative species overload in both the nondiabetic and diabetes mellitus groups, respectively (P < .05). Treatment with Mito-Tempo (10 μM) significantly enhanced coronary relaxation responses to adenosine 5'-diphosphate and NS309 (P < .05), and endothelial small conductance calcium-activated potassium channel currents in both the nondiabetic and diabetes mellitus groups (P < .05).
CONCLUSIONS
Administration of Mito-Tempo improves endothelial function and small conductance calcium-activated potassium channel activity, which may contribute to its enhancement of endothelium-dependent vasorelaxation after cardioplegic hypoxia and reoxygenation.
Topics: Adenosine; Animals; Antioxidants; Calcium; Diabetes Mellitus; Diphosphates; Endothelial Cells; Endothelium, Vascular; Hypoxia; Mice; Mitochondria; Oxidation-Reduction; Potassium; Reactive Oxygen Species; Small-Conductance Calcium-Activated Potassium Channels
PubMed: 34274141
DOI: 10.1016/j.jtcvs.2021.06.029 -
British Dental Journal Nov 2020During the last 50 years, an increasing number of toothpastes have been marketed that include pyrophosphates as anti-tartar (calculus) agents. Pyrophosphates are...
During the last 50 years, an increasing number of toothpastes have been marketed that include pyrophosphates as anti-tartar (calculus) agents. Pyrophosphates are chelating agents with low toxicity and a broad range of applications, such as food additives and in industrial applications. Like other chelating agents, the prime function is to combine with metal elements and, in toothpastes, to inhibit calcium phosphate deposits in the form of dental calculus. It is well established that pyrophosphates inhibit crystal growth of hydroxyapatite in bones and teeth, and theoretically may negatively affect the demineralisation-remineralisation equilibrium at the tooth surface. Surprisingly, little clinical research has been carried out to assess if the caries protection provided by fluoride toothpaste is compromised by the inclusion of pyrophosphates and the existing evidence is inconsistent. In the absence of more clinical research, it is suggested that children should not use pyrophosphate-containing toothpastes under 12 years of age.
Topics: Cariostatic Agents; Child; Dental Caries; Diphosphates; Fluorides; Humans; Retrospective Studies; Toothpastes
PubMed: 33247264
DOI: 10.1038/s41415-020-2346-4