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251.
The major sialic acid containing glycolipid has been isolated from rat intestinal mucosa. Characterization of this ganglioside by thin layer and gas chromatographic analysis indicates that it is an hematoside (GM3) with the major portion of the sialic acid in the N-glycolyl form. The distribution of this ganglioside was determined in villus and crypt cells isolated from rat intestine. The hematoside content of crypt cells was found to be significantly decreased when compared to villus cells. CMP-sialic acid:lactosylceramide sialyltransferase, responsible for the sialylation of lactosylceramide, was measured in differentiated villus and undifferentiated crypt cells and found to be greatly reduced in the crypt cell fraction. The present study demonstrates that marked differences in ganglioside content and biosynthesis occur in contiguous populations of cells in varying states of differentiation when isolated from normal rat intestine. 相似文献
252.
Garrett M Warren Anam Ejaz Allison Fay Michael S Glickman Stewart Shuman 《Nucleic acids research》2023,51(1):218
Mycobacterium smegmatis Lhr exemplifies a novel clade of helicases composed of an N-terminal ATPase/helicase domain (Lhr-Core) and a large C-terminal domain (Lhr-CTD) that nucleates a unique homo-tetrameric quaternary structure. Expression of Lhr, and its operonic neighbor Nei2, is induced in mycobacteria exposed to mitomycin C (MMC). Here we report that lhr deletion sensitizes M. smegmatis to killing by DNA crosslinkers MMC and cisplatin but not to killing by monoadduct-forming alkylating agent methyl methanesulfonate or UV irradiation. Testing complementation of MMC and cisplatin sensitivity by expression of Lhr mutants in Δlhr cells established that: (i) Lhr-CTD is essential for DNA repair activity, such that Lhr-Core does not suffice; (ii) ATPase-defective mutant D170A/E171A fails to complement; (iii) ATPase-active, helicase-defective mutant W597A fails to complement and (iv) alanine mutations at the CTD–CTD interface that interdict homo-tetramer formation result in failure to complement. Our results instate Lhr''s ATP-driven motor as an agent of inter-strand crosslink repair in vivo, contingent on Lhr''s tetrameric quaternary structure. We characterize M. smegmatis Nei2 as a monomeric enzyme with AP β-lyase activity on single-stranded DNA. Counter to previous reports, we find Nei2 is inactive as a lyase at a THF abasic site and has feeble uracil glycosylase activity. 相似文献
253.
254.
We have analyzed the adenine phosphoribosyltransferase (APRT) enzyme from Chinese hamster ovary cells through the study of mutants that are able to grow in the presence of the toxic adenine analogue 8-azaadenine. The distribution of the amino acid alterations was analyzed in terms of the binding regions for the purine and phosphoribosylpyrophosphate substrates and a comparison was made with mutants known in human APRT and human, mouse and hamster hypoxanthine-guanine phosphoribosyltransferase. A number of mutants were found to cluster in several regions of the amino acid sequence. Residual enzyme activity with adenine was determined and this was correlated with substrate binding regions. A model of the secondary structure features is proposed. 相似文献
255.
Wang A Liu M Liu X Dong LQ Glickman RD Slaga TJ Zhou Z Liu F 《The Journal of biological chemistry》2011,286(1):60-66
The natural polyphenol resveratrol (RSV) displays a wide spectrum of health beneficial activities, yet the precise mechanisms remain to be fully elucidated. Here we show that RSV promotes the multimerization and cellular levels of adiponectin in 3T3-L1 adipocytes. The stimulatory effect of RSV was not affected by knocking out Sirt1, but was diminished by suppressing the expression levels of DsbA-L, a recently identified adiponectin-interactive protein that promotes adiponectin multimerization. Suppression of the Akt signaling pathway resulted in an increase in the expression levels of DsbA-L and adiponectin. On the other hand, knocking out FOXO1 or suppressing the activity or expression levels of the AMP-activated protein kinase (AMPK) down-regulated DsbA-L and adiponectin. The stimulatory effect of RSV on adiponectin and DsbA-L expression was completely diminished in FOXO1-suppressed and AMPK-inactivated 3T3-L1 adipocytes. Taken together, our results demonstrate that RSV promotes adiponectin multimerization in 3T3-L1 adipocytes via a Sirt1-independent mechanism. In addition, we show that the stimulatory effect of RSV is regulated by both the Akt/FOXO1 and the AMPK signaling pathways. Last, we show that DsbA-L plays a critical role in the promoting effect of RSV on adiponectin multimerization and cellular levels. 相似文献
256.
Misfolded PrP impairs the UPS by interaction with the 20S proteasome and inhibition of substrate entry 总被引:1,自引:0,他引:1
Deriziotis P André R Smith DM Goold R Kinghorn KJ Kristiansen M Nathan JA Rosenzweig R Krutauz D Glickman MH Collinge J Goldberg AL Tabrizi SJ 《The EMBO journal》2011,30(15):3065-3077
Prion diseases are associated with the conversion of cellular prion protein (PrP(C)) to toxic β-sheet isoforms (PrP(Sc)), which are reported to inhibit the ubiquitin-proteasome system (UPS). Accordingly, UPS substrates accumulate in prion-infected mouse brains, suggesting impairment of the 26S proteasome. A direct interaction between its 20S core particle and PrP isoforms was demonstrated by immunoprecipitation. β-PrP aggregates associated with the 20S particle, but did not impede binding of the PA26 complex, suggesting that the aggregates do not bind to its ends. Aggregated β-PrP reduced the 20S proteasome's basal peptidase activity, and the enhanced activity induced by C-terminal peptides from the 19S ATPases or by the 19S regulator itself, including when stimulated by polyubiquitin conjugates. However, the 20S proteasome was not inhibited when the gate in the α-ring was open due to a truncation mutation or by association with PA26/PA28. These PrP aggregates inhibit by stabilising the closed conformation of the substrate entry channel. A similar inhibition of substrate entry into the proteasome may occur in other neurodegenerative diseases where misfolded β-sheet-rich proteins accumulate. 相似文献
257.
Little is known about the association between health and the quality of the residential environment. What is known is often based on subjective assessments of the environment rather than on measurements by independent observers. The aim of this study, therefore, was to determine the association between self-reported general health and an objectively assessed measure of the residential environment. We studied over 30,000 residents aged 18 or over living in 777 neighbourhoods in south Wales. Built environment quality was measured by independent observers using a validated tool, the Residential Environment Assessment Tool (REAT), at unit postcode level. UK Census data on each resident, which included responses to a question which assessed self-reported general health, was linked to the REAT score. The Census data also contained detailed information on socio-economic and demographic characteristics of all respondents and was also linked to the Welsh Index of Multiple Deprivation. After adjusting for both the individual characteristics and area deprivation, respondents in the areas of poorest neighbourhood quality were more likely to report poor health compared to those living in areas of highest quality (OR 1.36, 95% confidence interval 1.22–1.49). The particular neighbourhood characteristics associated with poor health were physical incivilities and measures of how well the residents maintained their properties. Measures of green space were not associated with self-reported health. This is the first full population study to examine such associations and the results demonstrate the importance for health of the quality of the neighbourhood area in which people live and particularly the way in which residents behave towards their own and their neighbours’ property. A better understanding of causal pathways that allows the development of interventions to improve neighbourhood quality would offer significant potential health gains. 相似文献
258.
Bellar D Kamimori GH Glickman EL 《Journal of strength and conditioning research / National Strength & Conditioning Association》2011,25(5):1225-1228
This double-blind, placebo-controlled, within-subject experiment examined the effects of low-dose caffeine on pain reported during an exhaustive grip task. The grip task consisted of holding a metal block attached to standard Olympic weight plates with the arm at the side until the participants could no longer maintain their grip. Apparently healthy recreationally trained college-aged adults (men, n = 5; women, n = 5) were given either a piece of Stay Alert? gum that delivered 85% of the effective dose of 100 mg of caffeine in 5 minutes or an identical placebo gum that contained no caffeine. Subsequently, pain perception and ratings of perceived exertion were recorded during an exhaustive grip task every 15 seconds and the overall time to exhaustion. No significant difference was found in time to exhaustion between treatments. A significant main effect of treatment for reported pain (p < 0.001, Φ = 0.377) was observed. Thus, in a population of recreationally trained college-aged adults, low-dose caffeine may attenuate the individual's perception of pain during a grip to exhaustion task. 相似文献
259.
The multiubiquitin-chain-binding protein Mcb1 is a component of the 26S proteasome in Saccharomyces cerevisiae and plays a nonessential, substrate-specific role in protein turnover. 总被引:3,自引:0,他引:3 下载免费PDF全文
S van Nocker S Sadis D M Rubin M Glickman H Fu O Coux I Wefes D Finley R D Vierstra 《Molecular and cellular biology》1996,16(11):6020-6028
The 26S proteasome is an essential proteolytic complex that is responsible for degrading proteins conjugated with ubiquitin. It has been proposed that the recognition of substrates by the 26S proteasome is mediated by a multiubiquitin-chain-binding protein that has previously been characterized in both plants and animals. In this study, we identified a Saccharomyces cerevisiae homolog of this protein, designated Mcb1. Mcb1 copurified with the 26S proteasome in both conventional and nickel chelate chromatography. In addition, a significant fraction of Mcb1 in cell extracts was present in a low-molecular-mass form free of the 26S complex. Recombinant Mcb1 protein bound multiubiquitin chains in vitro and, like its plant and animal counterparts, exhibited a binding preference for longer chains. Surprisingly, (delta)mcb1 deletion mutants were viable, grew at near-wild-type rates, degraded the bulk of short-lived proteins normally, and were not sensitive to UV radiation or heat stress. These data indicate that Mcb1 is not an essential component of the ubiquitin-proteasome pathway in S.cerevisiae. However, the (delta)mcb1 mutant exhibited a modest sensitivity to amino acid analogs and had increased steady-state levels of ubiquitin-protein conjugates. Whereas the N-end rule substrate, Arg-beta-galactosidase, was degraded at the wild-type rate in the (delta)mcb1 strain, the ubiquitin fusion degradation pathway substrate, ubiquitin-Pro-beta-galactosidase, was markedly stabilized. Collectively, these data suggest that Mcb1 is not the sole factor involved in ubiquitin recognition by the 26S proteasome and that Mcb1 may interact with only a subset of ubiquitinated substrates. 相似文献
260.
Mycobacterium tuberculosis nuoG is a virulence gene that inhibits apoptosis of infected host cells 总被引:1,自引:0,他引:1
Velmurugan K Chen B Miller JL Azogue S Gurses S Hsu T Glickman M Jacobs WR Porcelli SA Briken V 《PLoS pathogens》2007,3(7):e110
The survival and persistence of Mycobacterium tuberculosis depends on its capacity to manipulate multiple host defense pathways, including the ability to actively inhibit the death by apoptosis of infected host cells. The genetic basis for this anti-apoptotic activity and its implication for mycobacterial virulence have not been demonstrated or elucidated. Using a novel gain-of-function genetic screen, we demonstrated that inhibition of infection-induced apoptosis of macrophages is controlled by multiple genetic loci in M. tuberculosis. Characterization of one of these loci in detail revealed that the anti-apoptosis activity was attributable to the type I NADH-dehydrogenase of M. tuberculosis, and was mainly due to the subunit of this multicomponent complex encoded by the nuoG gene. Expression of M. tuberculosis nuoG in nonpathogenic mycobacteria endowed them with the ability to inhibit apoptosis of infected human or mouse macrophages, and increased their virulence in a SCID mouse model. Conversely, deletion of nuoG in M. tuberculosis ablated its ability to inhibit macrophage apoptosis and significantly reduced its virulence in mice. These results identify a key component of the genetic basis for an important virulence trait of M. tuberculosis and support a direct causal relationship between virulence of pathogenic mycobacteria and their ability to inhibit macrophage apoptosis. 相似文献