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Journal of Inorganic Biochemistry Oct 2007The hydrolysis of a 5' cap analogue, diadenosinyl-5',5'-triphosphate (ApppA), and two dinucleoside monophosphates: adenylyl(3',5')adenosine (ApA) and...
The hydrolysis of a 5' cap analogue, diadenosinyl-5',5'-triphosphate (ApppA), and two dinucleoside monophosphates: adenylyl(3',5')adenosine (ApA) and uridylyl(3',5')uridine (UpU) promoted by an imidazolate-bridged heterobinuclear copper(II)-zinc(II) complex, Cu(II)-diethylenetriamino-micro-imidazolato-Zn(II)- tris(aminoethyl)amine trisperchlorate (denoted as Cu,Zn-complex in the followings) has been investigated. Kinetic measurements were performed in order to explore the effects of pH, the total concentration of the Cu,Zn-complex and temperature on the cleavage rate. The catalytic activity of the Cu,Zn-complex was quantified by pseudo-first-order rate constants obtained in the excess of the cleaving agent. The results show that the Cu,Zn-complex and its deprotonated forms have phosphoesterase activity and with ApppA the metal complex promoted cleavage takes place selectively within the triphosphate bridge.
Topics: Copper; Dinucleoside Phosphates; Hydrolysis; RNA Caps; RNA, Messenger; Zinc
PubMed: 17640737
DOI: 10.1016/j.jinorgbio.2007.05.017 -
Pharmacological Research Mar 2019Uridine adenosine tetraphosphate (UpA), biosynthesized by activation of vascular endothelial growth factor receptor (VEGFR) 2, was initially identified as a potent... (Review)
Review
Uridine adenosine tetraphosphate (UpA), biosynthesized by activation of vascular endothelial growth factor receptor (VEGFR) 2, was initially identified as a potent endothelium-derived vasoconstrictor in perfused rat kidney. Subsequently, the effect of UpA on vascular tone regulation was intensively investigated in arteries isolated from different vascular beds in rodents including rat pulmonary arteries, aortas, mesenteric and renal arteries as well as mouse aortas, in which UpA produces vascular contraction. In contrast, UpA produces vascular relaxation in porcine coronary small arteries and rat aortas. Intravenous infusion of UpA into conscious rats or mice decreases blood pressure, and intravenous bolus injection of UpA into anesthetized mice increases coronary blood flow, indicating an overall vasodilator influence in vivo. Although UpA is the first dinucleotide described that contains both purine and pyrimidine moieties, its cardiovascular effects are exerted mainly through activation of purinergic receptors. These effects not only encompass regulation of vascular tone, but also endothelial angiogenesis, smooth muscle cell proliferation and migration, and vascular calcification. Furthermore, this review discusses a potential role for UpA in cardiovascular pathophysiology, as plasma levels of UpA are elevated in juvenile hypertensive patients and UpA-mediated vascular purinergic signaling changes in cardiovascular disease such as hypertension, diabetes, atherosclerosis and myocardial infarction. Better understanding the vascular effect of the novel dinucleotide UpA and the purinergic signaling mechanisms mediating its effects will enhance its potential as target for treatment of cardiovascular disease.
Topics: Animals; Cardiovascular Physiological Phenomena; Cardiovascular System; Dinucleoside Phosphates; Humans; Receptors, Purinergic; Signal Transduction
PubMed: 30553823
DOI: 10.1016/j.phrs.2018.12.009 -
Cyclic di-AMP, a second messenger of primary importance: tertiary structures and binding mechanisms.Nucleic Acids Research Apr 2020Cyclic diadenylate (c-di-AMP) is a widespread second messenger in bacteria and archaea that is involved in the maintenance of osmotic pressure, response to DNA damage,... (Review)
Review
Cyclic diadenylate (c-di-AMP) is a widespread second messenger in bacteria and archaea that is involved in the maintenance of osmotic pressure, response to DNA damage, and control of central metabolism, biofilm formation, acid stress resistance, and other functions. The primary importance of c-di AMP stems from its essentiality for many bacteria under standard growth conditions and the ability of several eukaryotic proteins to sense its presence in the cell cytoplasm and trigger an immune response by the host cells. We review here the tertiary structures of the domains that regulate c-di-AMP synthesis and signaling, and the mechanisms of c-di-AMP binding, including the principal conformations of c-di-AMP, observed in various crystal structures. We discuss how these c-di-AMP molecules are bound to the protein and riboswitch receptors and what kinds of interactions account for the specific high-affinity binding of the c-di-AMP ligand. We describe seven kinds of non-covalent-π interactions between c-di-AMP and its receptor proteins, including π-π, C-H-π, cation-π, polar-π, hydrophobic-π, anion-π and the lone pair-π interactions. We also compare the mechanisms of c-di-AMP and c-di-GMP binding by the respective receptors that allow these two cyclic dinucleotides to control very different biological functions.
Topics: Animals; Dinucleoside Phosphates; Molecular Conformation; Riboswitch; Second Messenger Systems; Signal Transduction
PubMed: 32095817
DOI: 10.1093/nar/gkaa112 -
Journal of Chemical Theory and... Jun 2022RNA modulation via small molecules is a novel approach in pharmacotherapies, where the determination of the structural properties of RNA motifs is considered a promising...
RNA modulation via small molecules is a novel approach in pharmacotherapies, where the determination of the structural properties of RNA motifs is considered a promising way to develop drugs capable of targeting RNA structures to control diseases. However, due to the complexity and dynamic nature of RNA molecules, the determination of RNA structures using experimental approaches is not always feasible, and computational models employing force fields can provide important insight. The quality of the force field will determine how well the predictions are compared to experimental observables. Stacking in nucleic acids is one such structural property, originating mainly from London dispersion forces, which are quantum mechanical and are included in molecular mechanics force fields through nonbonded interactions. Geometric descriptions are utilized to decide if two residues are stacked and hence to calculate the stacking free energies for RNA dinucleoside monophosphates (DNMPs) through statistical mechanics for comparison with experimental thermodynamics data. Here, we benchmark four different stacking definitions using molecular dynamics (MD) trajectories for 16 RNA DNMPs produced by two different force fields (RNA-IL and ff99OL3) and show that our stacking definition better correlates with the experimental thermodynamics data. While predictions within an accuracy of 0.2 kcal/mol at 300 K were observed in RNA CC, CU, UC, AG, GA, and GG, stacked states of purine-pyrimidine and pyrimidine-purine DNMPs, respectively, were typically underpredicted and overpredicted. Additionally, population distributions of RNA UU DNMPs were poorly predicted by both force fields, implying a requirement for further force field revisions. We further discuss the differences predicted by each RNA force field. Finally, we show that discrete path sampling (DPS) calculations can provide valuable information and complement the MD simulations. We propose the use of experimental thermodynamics data for RNA DNMPs as benchmarks for testing RNA force fields.
Topics: DNA; Dinucleoside Phosphates; Molecular Dynamics Simulation; Nucleic Acid Conformation; Purines; Pyrimidines; RNA; Thermodynamics
PubMed: 35652685
DOI: 10.1021/acs.jctc.2c00178 -
The Journal of Organic Chemistry Aug 2011Dinucleoside 5',5'-polyphosphates (N(p)(n)N) play important roles in biological processes and have been developed into drugs. However, their synthesis still remains a...
Dinucleoside 5',5'-polyphosphates (N(p)(n)N) play important roles in biological processes and have been developed into drugs. However, their synthesis still remains a challenge. Here we report a rapid and general approach to the synthesis of dinucleoside 5',5'-polyphosphates by coupling highly reactive nucleoside 5'-monophosphate-N-methylimidazolium salts donors with nucleoside 5'-mono-, -di-, and -triphosphate acceptors.
Topics: Dinucleoside Phosphates; Magnetic Resonance Spectroscopy; Molecular Structure; Nucleotides; Polyphosphates
PubMed: 21688809
DOI: 10.1021/jo200540e -
Nature Immunology Feb 2022
Topics: Anions; Dinucleoside Phosphates; T-Lymphocytes
PubMed: 35105986
DOI: 10.1038/s41590-021-01118-6 -
Methods in Molecular Biology (Clifton,... 2017To identify cytosolic proteins that bind to cyclic di-AMP, a biotinylated analog of the nucleotide is used for protein pull-down experiments. In this approach,...
To identify cytosolic proteins that bind to cyclic di-AMP, a biotinylated analog of the nucleotide is used for protein pull-down experiments. In this approach, biotinylated c-di-AMP is coupled to Streptactin-covered beads. After protein separation using standard SDS-PAGE, the protein(s) of interest are identified by mass spectrometric analyses.
Topics: Bacterial Proteins; Biotinylation; DNA-Binding Proteins; Dinucleoside Phosphates; Electrophoresis, Polyacrylamide Gel; Mass Spectrometry; Microspheres; Protein Binding; Proteomics
PubMed: 28889307
DOI: 10.1007/978-1-4939-7240-1_27 -
British Journal of Pharmacology Aug 2015Vascular dysfunction plays a pivotal role in the development of systemic complications associated with arterial hypertension and diabetes. The endothelium, or more... (Review)
Review
Vascular dysfunction plays a pivotal role in the development of systemic complications associated with arterial hypertension and diabetes. The endothelium, or more specifically, various factors derived from endothelial cells tightly regulate vascular function, including vascular tone. In physiological conditions, there is a balance between endothelium-derived factors, that is, relaxing factors (endothelium-derived relaxing factors; EDRFs) and contracting factors (endothelium-derived contracting factors; EDCFs), which mediate vascular homeostasis. However, in disease states, such as diabetes and arterial hypertension, there is an imbalance between EDRF and EDCF, with a reduction of EDRF signalling and an increase of EDCF signalling. Among EDCFs, COX-derived vasoconstrictor prostanoids play an important role in the development of vascular dysfunction associated with hypertension and diabetes. Moreover, uridine adenosine tetraphosphate (Up4 A), identified as an EDCF in 2005, also modulates vascular function. However, the role of Up4 A in hypertension- and diabetes-associated vascular dysfunction is unclear. In the present review, we focused on experimental and clinical evidence that implicate these two EDCFs (vasoconstrictor prostanoids and Up4 A) in vascular dysfunction associated with hypertension and diabetes.
Topics: Animals; Diabetes Mellitus; Dinucleoside Phosphates; Endothelins; Gonadal Steroid Hormones; Humans; Hypertension; Myocytes, Smooth Muscle; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Vasoconstriction
PubMed: 26031319
DOI: 10.1111/bph.13205 -
Biochemical and Biophysical Research... May 2003Dinucleoside polyphosphates have been characterised as extracellular mediators controlling numerous physiological functions like vascular tone or cell proliferation....
Dinucleoside polyphosphates have been characterised as extracellular mediators controlling numerous physiological functions like vascular tone or cell proliferation. Here we describe the isolation and identification of dinucleoside polyphosphates Ap(n)A (with n=2-3), Ap(n)G (with n=2-6) as well as Gp(n)G (with n=2-6) from adrenal glands. These dinucleoside polyphosphates are localised in granules of the adrenal glands. The dinucleoside polyphosphates diadenosine diphosphate (Ap(2)A), diadenosine triphosphate (Ap(3)A), adenosine guanosine polyphosphates (Ap(n)G) and diguanosine polyphosphates (Gp(n)G), both with phosphate group (p) numbers (n) ranging from 2 to 6, were identified by fractionating them to homogeneity by preparative size-exclusion- and affinity-chromatography as well as analytical anion-exchange and reversed-phase-chromatography from deproteinised adrenal glands and by analysis of the homogeneous dinucleoside polyphosphates containing fractions with post-source-decay (PSD) matrix-assisted laser desorption/ionisation mass spectrometry (MALDI-MS). The identity of the dinucleoside polyphosphates was confirmed by retention time comparison with authentic dinucleoside polyphosphates. Enzymatic analysis demonstrated an interconnection of the phosphate groups with the adenosines in the 5(')-positions of the riboses in all dinucleoside polyphosphates purified from adrenal glands. In conclusion, the identification of these dinucleoside polyphosphates in adrenal gland granules emphasises that these dinucleoside polyphosphates can be released from the adrenal glands upon stimulation into the circulation.
Topics: Adrenal Glands; Animals; Cattle; Cytoplasmic Granules; Dinucleoside Phosphates; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
PubMed: 12711324
DOI: 10.1016/s0006-291x(03)00596-5 -
Cardiovascular Research Apr 1999Diadenosine polyphosphates are members of a group of dinucleoside polyphosphates that are ubiquitous, naturally occurring molecules. They form a recently identified... (Review)
Review
Diadenosine polyphosphates are members of a group of dinucleoside polyphosphates that are ubiquitous, naturally occurring molecules. They form a recently identified class of compounds derived from ATP and consist of two adenosine molecules bridged by up to six phosphate groups. These compounds are stored in high concentrations in platelet dense granules and are released when platelets become activated. Some of the compounds promote platelet aggregation, while others are inhibitory. Possible roles as neurotransmitters, extracellular signalling molecules or 'alarmones' secreted by cells in response to physiologically stressful stimuli have been postulated. Recent studies suggest a role for these compounds in atrial and synaptic neurotransmission. Studies using isolated mesenteric arteries indicate an important role of phosphate chain length in determining whether diadenosine polyphosphates produce vasodilation or vasoconstriction, but in the coronary circulation, diadenosine polyphosphates generally produce vasodilation via mechanisms thought to involve release of NO or prostacyclin (PGI2). They produce cardiac electrophysiological effects by altering ventricular refractoriness at submicromolar concentrations and reduce heart rate. Mechanisms involving KATP channels have been proposed in addition to the involvement of P1- and P2-purinergic receptors and the specific diadenosine polyphosphate receptor identified on isolated cardiac myocytes. Clinical evidence suggests a role for diadenosine polyphosphates in hypertensive patients and those with the Chédiak-Higashi syndrome. This review outlines the effects of these compounds on the cardiovascular system and considers their potential involvement in mediating the pathophysiological effects associated with platelet activation during myocardial ischaemia.
Topics: Action Potentials; Animals; Cardiovascular System; Dinucleoside Phosphates; Endothelium, Vascular; Humans; Myocardial Ischemia; Platelet Aggregation Inhibitors; Potassium Channels; Receptors, Purinergic; Second Messenger Systems; Vascular Resistance; Vasodilation
PubMed: 10434992
DOI: 10.1016/s0008-6363(99)00004-8