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231.
CHIP-mediated hyperubiquitylation of tau promotes its self-assembly into the insoluble tau filaments
Ji Hyeon Kim Jeeyoung Lee Won Hoon Choi Seoyoung Park Seo Hyeong Park Jung Hoon Lee Sang Min Lim Ji Young Mun Hyun-Soo Cho Dohyun Han Young Ho Suh Min Jae Lee 《Chemical science》2021,12(15):5599
The tau protein is a highly soluble and natively unfolded protein. Under pathological conditions, tau undergoes multiple post-translational modifications (PTMs) and conformational changes to form insoluble filaments, which are the proteinaceous signatures of tauopathies. To dissect the crosstalk among tau PTMs during the aggregation process, we phosphorylated and ubiquitylated recombinant tau in vitro using GSK3β and CHIP, respectively. The resulting phospho–ub-tau contained conventional polyubiquitin chains with lysine 48 linkages, sufficient for proteasomal degradation, whereas unphosphorylated ub-tau species retained only one–three ubiquitin moieties. Mass-spectrometric analysis of in vitro reconstituted phospho–ub-tau revealed seven additional ubiquitylation sites, some of which are known to stabilize tau protofilament stacking in the human brain with tauopathy. When the ubiquitylation reaction was prolonged, phospho–ub-tau transformed into insoluble hyperubiquitylated tau species featuring fibrillar morphology and in vitro seeding activity. We developed a small-molecule inhibitor of CHIP through biophysical screening; this effectively suppressed tau ubiquitylation in vitro and delayed its aggregation in cultured cells including primary cultured neurons. Our biochemical findings point to a “multiple-hit model,” where sequential events of tau phosphorylation and hyperubiquitylation function as a key driver of the fibrillization process, thus indicating that targeting tau ubiquitylation may be an effective strategy to alleviate the course of tauopathies.Multiple-hit model for tau aggregation, where sequential events of tau phosphorylation and hyperubiquitylation function as a key driver of the fibrillization process. 相似文献
232.
Shibuya H Kitamura C Maehara S Nagahata M Winarno H Simanjuntak P Kim HS Wataya Y Ohashi K 《Chemical & pharmaceutical bulletin》2003,51(1):71-74
The microbial transformation of four Cinchona alkaloids (quinine, quinidine, cinchonidine, and cinchonine) by endophytic fungi isolated from Cinchona pubescens was investigated. The endophytic filamentous fungus Xylaria sp. was found to transform the Cinchona alkaloids into their 1-N-oxide derivatives. 相似文献
233.
Kim HG Lee CW Yun S Hong BH Kim YO Kim D Ihm H Lee JW Lee EC Tarakeshwar P Park SM Kim KS 《Organic letters》2002,4(22):3971-3974
[formula: see text] A new molecular system, 2,11-dithio[4,4]metametaquinocyclophane containing a quinone moiety, was designed and synthesized. As the quinone moiety can readily be converted into an aromatic pi-system (hydroquinone) upon reduction, the nanomechanical molecular cyclophane system exhibits a large flapping motion like a molecular flipper from the electrochemical redox process. The conformational changes upon reduction and oxidation are caused by changes of nonbonding interaction forces (devoid of bond formation/breaking) from the edge-to-face to face-to-face aromatic interactions and vice versa, respectively. 相似文献
234.
Osteoprotegerin (OPG), a member of the tumor necrosis factor receptor superfamily, is known to inhibit osteoclastogenesis by acting as a soluble decoy receptor for the receptor activator of NF-kappaB ligand (RANKL). We report the presence of OPG on the membrane of osteoclasts and the possibility of the direct action of OPG on them. Highly pure osteoclast precursors were isolated from mouse long bones and induced to differentiate into mature osteoclasts by M-CSF and soluble RANKL (sRANKL). The presence of OPG on the membrane of these cells was confirmed by western blotting and immunostaining. Furthermore, sRANKL was found to be bound to the OPG on the osteoclast precursors. These results suggest that OPG might have a new role during the differentiation of osteoclasts beyond its role as a soluble decoy receptor. The mechanism of the existence of OPG on osteoclast precursors remains to be found. 相似文献
235.
A series of calixcrown ethers for which the cavity size of the crown ring is varied from crown-6 to crown-7 to crown-8 were examined for the transport abilities toward alkali metal ions. These ligands were incorporated into supported liquid membranes (SLMs) and into polymer inclusion membranes (PIMs) composed of cellulose triacetate (CTA) as a support and 2-nitrophenyl octyl ether (NPOE) and tris(2-butoxyethyl) phosphate (TBEP) as a plasticizer. In both membrane systems, calixcrown-6 showed the best selectivity toward a cesium ion over other alkali metal ions. The polymeric CTA membrane showed more rapid transport rate as well as higher durability than did the SLMs. 相似文献
236.
[reaction: see text] A new iterative strategy for the synthesis of unsymmetrically substituted polyynes has been developed. The starting bromoalkyne is homologated by one acetylene unit through palladium-catalyzed cross-coupling with a TIPS-protected terminal acetylene and a subsequent in situ one-pot AgF-mediated desilylative bromination. The utility of this new synthetic method is demonstrated by its application to the total synthesis of (S)-(E)-15,16-dihydrominquartynoic acid. 相似文献
237.
Hohyun Kim Hyeongjin Roh Seung-Bock Yeom Hee Joo Lee Sang Beom Han 《Chromatographia》2003,58(3-4):235-240
Summary A sensitive and selective liquid chromatographic method coupled with electrospray ionization tandem mass spectrometry (LC–ESI–MS–MS) has been developed for quantification of felodipine in human and dog plasma. Compounds were separated on a 2.0 mm × 150 mm, 5.0 m particle, C8 column with 1 m m ammonium acetate–acetonitrile, 20:80, pH 6.0, as mobile phase at a flow rate of 200 L min–1. Nifedipine was used as internal standard. Plasma samples were extracted with diethyl ether, the centrifuged upper layer was evaporated, the residue was reconstituted with mobile phase, and the reconstituted samples were injected. The analytical column lasted for at least 1000 injections. By use of multiple reaction monitoring (MRM) mode in MS–MS felodipine and nifedipine were detected without severe interference from the human or dog plasma matrix. Felodipine produced a protonated precursor ion ([M + H]+) at m/z 384 and a corresponding product ion at m/z 338. And internal standard (nifedipine) produced a protonated precursor ion ([M + H]+) at m/z 347 and a corresponding product ion at m/z 315. Detection of felodipine in human and dog plasma was accurate and precise, with a limit of quantification of 0.05 ng mL–1. The method has been successfully applied to preliminary pharmacokinetic study of felodipine in human and dog plasma. 相似文献
238.
Hong J Kim YH Gil JH Cho K Jung JH Han SY 《Rapid communications in mass spectrometry : RCM》2002,16(22):2089-2093
The structural determination of sn-1 and sn-2 hexadecanoic lysophosphatidylcholine (LPC) regioisomers was carried out using fast atom bombardment tandem mass spectrometry (FAB-MS/MS). The collision-induced dissociation (CID) of protonated and sodiated molecules produced diverse product ions due mainly to charge remote fragmentations. Based on the information obtained from the CID spectra of protonated and sodiated molecules, sn-1 and sn-2 hexadecanoic LPC isomers could be discriminated. Especially, the abundance ratio of the diagnostic ion pair [m/z 224/226] in the CID spectra of [M + H](+) ions was shown to be greatly different. Moreover, the CID-MS/MS spectra of sodium-adducted molecules for hexadecanoic LPC isomers showed characteristic product ions such as [M + Na - 103](+), [M + Na - 85](+), and [M + Na - 59](+), by which their regio-specificity can be differentiated. 相似文献
239.
Lipophilic acyclic dibenzopolyether diamides, 12 kinds, have been designed to prepare solvent polymeric membrane ion-selective electrodes (ISEs) for Pb(2+). The ionophores include 1,5-bis[2-(N,N-dialkylcarbamoylmethoxy)phenoxy]-3-oxapentanes1-4, 1,5-bis[2-(N,N-dialkylcarbamoylpentadecyloxy)phenoxy]-3-oxapentanes 5-8, and 1,2-bis[2-(2'-N,N-dialkylcarbamoylpentadecyloxy)phenoxy]ethanes 9-12. Linear response concentration range of the ISE based on 9 is 3 x 10(-2) - 1 x 10(-6) M of Pb(2+) (average slope = 28.5 mV decade(-1)). Potentiometric selectivities of the ISEs based on 1-12 for Pb(2+) over other heavy metal cations, alkali metal cations, and alkaline earth metal cations have been assessed. These ISEs exhibit remarkably high selectivities for Pb(2+) relative to heavy metal cations, such as Cu(2+), Fe(2+), and Ni(2+), the selectivity coefficients (K(Pot)(Pb,Cu)) being 5 x 10(-5) - 6 x 10(-5) for 1-4 and ca. 6 x 10(-4) for 9. For the Pb(2+) selectivities over alkali metal cations, such as Na(+) and K(+), 9 which has an ethylene glycol spacer and a N,N-diethyl group is superior to other dibenzopolyether diamide ionophores 1-8 and 10-12. 相似文献
240.
We investigate the equilibrium dynamics of our recently proposed toy model of dense fluid in the infinite damping limit. Contrary to naive expectation, the correlators involving the velocity-like variables do not quickly relax away. Instead, after a very fast transient relaxation, they exhibit rather slow relaxations due to the coupling to the density-like variable. Hence, the so-called "hopping" processes are not suppressed even in the large damping limit. These hopping processes can only be controlled by tuning the parameter delta, which is the ratio of the numbers of the components of the velocity-like and the density-like variables in the model. We analytically prove that there must exist an ergodic-to-nonergodic phase transition for delta such that 0 < delta < 1. The slow dynamics and the dynamic transition in the model are distinct from those in the idealized mode coupling theory. 相似文献