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Current Medicinal Chemistry 2015The bio-reversible protection of nucleoside diphosphates is summarized. The design, hydrolytic characteristics, and the antiviral activity of these prodrugs of NDPs are... (Review)
Review
The bio-reversible protection of nucleoside diphosphates is summarized. The design, hydrolytic characteristics, and the antiviral activity of these prodrugs of NDPs are described. In contrast to earlier attempts, the DiPPro-approach [β-(bis(acyloxybenzyl) nucleoside diphosphates)] leads to the successful delivery of the desired nucleoside diphosphates. The stability towards hydrolysis is dependent on the specific acyl moieties in the bis(acyloxybenzyl) unit as well as on the particular nucleoside analogue. Hydrolysis studies in aqueous PBS buffer (pH 7.3), 20 % human plasma in PBS, RPMI-1640 culture medium, and CEM cell extracts were carried out. Contrary to a high chemical and plasma stability, the compounds showed a very low half-life in CEM cell extracts, and efficiently released the nucleoside analogues diphosphates, e.g. of AZT, d4T and BVDU. Two additional types of cycloSal- NDP prodrugs were studied but neither proved to be useful as nucleoside diphosphate prodrugs. In summary, the results led to the development of a new series of non-symmetric nucleoside diphosphate prodrugs that selectively delivered the nucleoside diphosphate in cell extracts.
Topics: Animals; Anti-HIV Agents; Cell Proliferation; Diphosphates; Esterases; HIV-1; HIV-2; Humans; Nucleosides; Prodrugs
PubMed: 26303175
DOI: 10.2174/0929867322666150825163119 -
Journal of Nuclear Cardiology :... Dec 2023Technetium-labeled bone-avid radiotracers can be used to diagnose transthyretin cardiac amyloidosis (ATTR-CA). Extracardiac uptake of technetium pyrophosphate (Tc-99m...
INTRODUCTION
Technetium-labeled bone-avid radiotracers can be used to diagnose transthyretin cardiac amyloidosis (ATTR-CA). Extracardiac uptake of technetium pyrophosphate (Tc-99m PYP) in this context has not been extensively explored and its significance is not well characterized. We assessed extracardiac Tc-99m PYP uptake in individuals undergoing nuclear scintigraphy and the extent of clinically actionable findings.
METHODS
The Screening for Cardiac Amyloidosis with Nuclear Imaging in Minority Populations (SCAN-MP) study utilizes Tc-99m PYP imaging to identify ATTR-CA in self-identified Black and Caribbean Hispanic participants ≥ 60 years old with heart failure. We characterized the distribution of extracardiac uptake, including stratification of findings by timing of scan (1 hour vs 3 hours after Tc-99m PYP administration) and noted any additional testing in these subjects.
RESULTS
Of 379 participants, 195 (51%) were male, 306 (81%) Black race, and 120 (32%) Hispanic ethnicity; mean age was 73 years. Extracardiac Tc-99m PYP uptake was found in 42 subjects (11.1%): 21 with renal uptake only, 14 with bone uptake only, 4 with both renal and bone uptake, 2 with breast uptake, and 1 with thyroid uptake. Extracardiac uptake was more common in subjects with Tc-99m PYP scans at 1 hour (23.8%) than at 3 hours (6.2%). Overall, four individuals (1.1%) had clinically actionable findings.
CONCLUSION
Extracardiac Tc-99m PYP uptake manifested in about 1 in 9 SCAN-MP subjects but was clinically actionable in only 1.1% of cases.
Topics: Male; Humans; Aged; Middle Aged; Female; Diphosphates; Technetium; Technetium Tc 99m Pyrophosphate; Prevalence; Cardiomyopathies; Tomography, X-Ray Computed; Amyloidosis; Radiopharmaceuticals; Prealbumin
PubMed: 37311914
DOI: 10.1007/s12350-023-03310-7 -
Food Chemistry Mar 2021In this study, sodium tripolyphosphate (STP) and tetrasodium pyrophosphate (TSPP) were utilized to modify duck egg white protein (EWP). The phosphorylated EWP was...
In this study, sodium tripolyphosphate (STP) and tetrasodium pyrophosphate (TSPP) were utilized to modify duck egg white protein (EWP). The phosphorylated EWP was prepared as egg white gel (EWG) by adding sodium hydroxide. The phosphorus content of EWP reached 2.18 mg/g and 2.07 mg/g with the addition of STP and TSPP, respectively, after 2 h phosphorylation. The average particle size, absolute zeta potential value, and surface hydrophobicity of EWP increased significantly during phosphorylation. FTIR results indicate that phosphorylation reduced the random structure and α-helical content while increasing the content of β-sheets and β-turn. The mechanical and rheological properties of EWG decreased obviously after phosphorylation. A three-dimensional porous network microstructure was formed, and the gel with added TSPP had larger pores. Adding STP and TSPP to EWG weakened its salt and solvent sensitivity. The findings provide a direction for the exploration of gel properties after protein modification.
Topics: Alkalies; Animals; Diphosphates; Ducks; Egg Proteins; Gels; Hydrophobic and Hydrophilic Interactions; Particle Size; Phosphorylation; Rheology; Sodium Chloride; Sodium Hydroxide
PubMed: 33010647
DOI: 10.1016/j.foodchem.2020.128185 -
Nature Communications May 2023Many proteins involved in eukaryotic phosphate homeostasis are regulated by SPX domains. In yeast, the vacuolar transporter chaperone (VTC) complex contains two such...
Many proteins involved in eukaryotic phosphate homeostasis are regulated by SPX domains. In yeast, the vacuolar transporter chaperone (VTC) complex contains two such domains, but mechanistic details of its regulation are not well understood. Here, we show at the atomic level how inositol pyrophosphates interact with SPX domains of subunits Vtc2 and Vtc3 to control the activity of the VTC complex. Vtc2 inhibits the catalytically active VTC subunit Vtc4 by homotypic SPX-SPX interactions via the conserved helix α1 and the previously undescribed helix α7. Binding of inositol pyrophosphates to Vtc2 abrogates this interaction, thus activating the VTC complex. Accordingly, VTC activation is also achieved by site-specific point mutations that disrupt the SPX-SPX interface. Structural data suggest that ligand binding induces reorientation of helix α1 and exposes the modifiable helix α7, which might facilitate its post-translational modification in vivo. The variable composition of these regions within the SPX domain family might contribute to the diversified SPX functions in eukaryotic phosphate homeostasis.
Topics: Saccharomyces cerevisiae; Diphosphates; Biological Transport; Homeostasis; Inositol Phosphates
PubMed: 37156835
DOI: 10.1038/s41467-023-38315-w -
Biochemistry Feb 2021DNA polymerases play vital roles in the maintenance and replication of genomic DNA by synthesizing new nucleotide polymers using nucleoside triphosphates as substrates....
DNA polymerases play vital roles in the maintenance and replication of genomic DNA by synthesizing new nucleotide polymers using nucleoside triphosphates as substrates. Deoxynucleoside triphosphates (dNTPs) are the canonical substrates for DNA polymerases; however, some bacterial polymerases have been demonstrated to insert deoxynucleoside diphosphates (dNDPs), which lack a third phosphate group, the γ-phosphate. Whether eukaryotic polymerases can efficiently incorporate dNDPs has not been investigated, and much about the chemical or structural role played by the γ-phosphate of dNTPs remains unknown. Using the model mammalian polymerase (Pol) β, we examine how Pol β incorporates a substrate lacking a γ-phosphate [deoxyguanosine diphosphate (dGDP)] utilizing kinetic and crystallographic approaches. Using single-turnover kinetics, we determined dGDP insertion across a templating dC by Pol β to be drastically impaired when compared to dGTP insertion. We found the most significant impairment in the apparent insertion rate (), which was reduced 32000-fold compared to that of dGTP insertion. X-ray crystal structures revealed similar enzyme-substrate contacts for both dGDP and dGTP. These findings suggest the insertion efficiency of dGDP is greatly decreased due to impairments in polymerase chemistry. This work is the first instance of a mammalian polymerase inserting a diphosphate nucleotide and provides insight into the nature of polymerase mechanisms by highlighting how these enzymes have evolved to use triphosphate nucleotide substrates.
Topics: DNA; DNA Polymerase beta; DNA-Directed DNA Polymerase; Deoxyguanine Nucleotides; Deoxyguanosine; Diphosphates; Humans; Kinetics; Substrate Specificity
PubMed: 33475337
DOI: 10.1021/acs.biochem.0c00847 -
Journal of Nuclear Cardiology :... Dec 2023
Topics: Humans; Diphosphates; Technetium; Technetium Tc 99m Pyrophosphate; Heart; Radionuclide Imaging; Cardiomyopathies
PubMed: 37468745
DOI: 10.1007/s12350-023-03341-0 -
Journal of Nuclear Cardiology :... Oct 2023Technetium-99mm pyrophosphate (Tc-PYP) scintigraphy is a highly accurate non-invasive method for the diagnosis of transthyretin (ATTR) cardiac amyloidosis. Prognosis for...
Technetium-99mm pyrophosphate (Tc-PYP) scintigraphy is a highly accurate non-invasive method for the diagnosis of transthyretin (ATTR) cardiac amyloidosis. Prognosis for this disease is improved following treatment with the transthyretin (TTR) stabilizer tafamidis. Although tafamidis slows disease progression, its effects on myocardial amyloid and Tc-PYP uptake remain unclear. We present a patient with ATTR cardiac amyloidosis who had a strongly positive initial Tc-PYP scan, with a dramatic decrease in Tc-PYP uptake on repeat scan after 3 years of tafamidis treatment. However, myocardial biopsy showed persistent diffuse amyloid deposits. This case highlights the need for further studies regarding the utility of serial Tc-PYP scans in monitoring the progress of ATTR cardiomyopathy.
Topics: Humans; Diphosphates; Technetium; Technetium Tc 99m Pyrophosphate; Prealbumin; Cardiomyopathies; Amyloidosis; Radionuclide Imaging; Radiopharmaceuticals
PubMed: 37340232
DOI: 10.1007/s12350-023-03316-1 -
Chemical Senses Jun 2017Rodents consume solutions of phosphates and pyrophosphates in preference to water. Recently, we found that the preference for trisodium pyrophosphate (Na3HP2O7) was...
Rodents consume solutions of phosphates and pyrophosphates in preference to water. Recently, we found that the preference for trisodium pyrophosphate (Na3HP2O7) was greater in T1R3 knockout (KO) mice than wild-type (WT) controls, suggesting that T1R3 is a pyrophosphate detector. We now show that this heightened Na3HP2O7 preference of T1R3 KO mice extends to disodium phosphate (Na2HPO4), disodium and tetrasodium pyrophosphate (Na2H2PO4 and Na4H2PO4), a tripolyphosphate (Na5P3O10), a non-sodium phosphate [(NH4)2HPO4], and a non-sodium pyrophosphate (K4P2O7) but not to non-P salts with large anions (sodium gluconate, acetate, or propionate). Licking rates for Na3HP2O7 are higher in T1R2 KO mice than WT controls; Na3HP2O7 preference scores are increased even more in T1R2 KO mice and T1R2+T1R3 double KO mice than in T1R3 KO mice; preference scores for Na3HP2O7 are normal in T1R1 KO mice. These results implicate each subunit of the T1R2+T1R3 dimer in the behavioral response to P-containing taste compounds.
Topics: Animals; Diphosphates; Food Preferences; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, G-Protein-Coupled; Taste
PubMed: 28383662
DOI: 10.1093/chemse/bjx019 -
ACS Chemical Biology Dec 2022hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) is essential for purine salvage of hypoxanthine into parasite purine nucleotides. Transition state...
hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) is essential for purine salvage of hypoxanthine into parasite purine nucleotides. Transition state analogue inhibitors of HGXPRT are characterized by kinetic analysis, thermodynamic parameters, and X-ray crystal structures. Compound , 9-deazaguanine linked to an acyclic ribocation phosphonate mimic, shows a kinetic of 0.5 nM. Isothermal titration calorimetry (ITC) experiments of binding to HGXPRT reveal enthalpically driven binding with negative cooperativity for the binding of two inhibitor molecules in the tetrameric enzyme. Crystal structures of bound to HGXPRT define the hydrogen bond and ionic contacts to complement binding thermodynamics. Dynamics of ribosyl transfer from 5-phospho-α-d-ribosyl 1-pyrophosphate (PRPP) to hypoxanthine were examined by O isotope exchange at the bridging phosphoryl oxygen of PRPP pyrophosphate. Rotational constraints or short transition state lifetimes prevent torsional rotation and positional isotope exchange of bridging to nonbridging oxygen in the α-pyrophosphoryl group. Thermodynamic analysis of the transition state analogue and magnesium pyrophosphate binding reveal random and cooperative binding to HGXPRT, unlike the obligatory ordered reaction kinetics reported earlier for substrate kinetics.
Topics: Plasmodium falciparum; Diphosphates; Kinetics; Isotopes; Oxygen; Hypoxanthines
PubMed: 36413975
DOI: 10.1021/acschembio.2c00546 -
Current Opinion in Rheumatology May 2024In 1977, McCarty astutely observed, 'The variety of names suggested for the condition associated with deposits of calcium pyrophosphate dihydrate crystals is exceeded... (Review)
Review
PURPOSE OF REVIEW
In 1977, McCarty astutely observed, 'The variety of names suggested for the condition associated with deposits of calcium pyrophosphate dihydrate crystals is exceeded only by the variations of its clinical presentation'. Fast forward to 2024, a standardized nomenclature for calcium pyrophosphate deposition (CPPD) is still lacking. This review aims to delineate the challenges in characterizing CPPD through nomenclature and imaging.
RECENT FINDINGS
Despite the effort of nomenclature standardization in 2011 by the EULAR, confusion persists in the literature and clinical practice, with pseudo-forms and obscure abbreviations. The Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN) has launched a project to redefine CPPD nomenclature and formulate a user-friendly language for effective communication with patients and other stakeholders. Additionally, recent advancements in imaging, have shed light on various aspects of the disorder.
SUMMARY
Almost 60 years from the first description of a clinical manifestation related to calcium pyrophosphate crystals, a common language describing the disorder is still lacking. A redefined CPPD nomenclature, together with lay-friendly terminology, would significantly contribute to the uniformity of CPPD research, enhance public understanding and awareness and improve doctor-patient communication and therefore disease outcomes. Imaging can provide deep insights into CPPD elements, promoting comprehension of this disorder.
Topics: Humans; Calcium Pyrophosphate; Chondrocalcinosis; Diphosphates; Gout; Calcinosis
PubMed: 38517340
DOI: 10.1097/BOR.0000000000001001