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461.
Aldose reductase and aldehyde reductase belong to the aldo-keto reductase superfamily of enzymes whose members are responsible
for a wide variety of biological functions. Aldose reductase has been identified as the first enzyme involved in the polyol
pathway of glucose metabolism which converts glucose into sorbitol. Glucose over-utilization through the polyol pathway has
been linked to tissue-based pathologies associated with diabetes complications, which make the development of a potent aldose
reductase inhibitor an obvious and attractive strategy to prevent or delay the onset and progression of the complications.
Structural studies of aldose reductase and the homologous aldehyde reductase in complex with inhibitor were carried out to
explain the difference in the potency of enzyme inhibition. The aim of this review is to provide a comprehensive summary of
previous studies to aid the development of aldose reductase inhibitors that may have less toxicity problems than the currently
available ones.
Received 4 December 2006; received after revision 12 February 2007; accepted 20 April 2007 相似文献
462.
Modulation of protein biophysical properties by chemical glycosylation: biochemical insights and biomedical implications 总被引:2,自引:0,他引:2
Solá RJ Rodríguez-Martínez JA Griebenow K 《Cellular and molecular life sciences : CMLS》2007,64(16):2133-2152
Glycosylation constitutes one of the most important posttranslational modifications employed by biological systems to modulate
protein biophysical properties. Due to the direct biochemical and biomedical implications of achieving control over protein
stability and function by chemical means, there has been great interest in recent years towards the development of chemical
strategies for protein glycosylation. Since current knowledge about glycoprotein biophysics has been mainly derived from the
study of naturally glycosylated proteins, chemical glycosylation provides novel insights into its mechanistic understanding
by affording control over glycosylation parameters. This review presents a survey of the effects that natural and chemical
glycosylation have on the fundamental biophysical properties of proteins (structure, dynamics, stability, and function). This
is complemented by a mechanistic discussion of how glycans achieve such effects and discussion of the implications of employing
chemical glycosylation as a tool to exert control over protein biophysical properties within biochemical and biomedical applications.
Received 15 December 2006; received after revision 28 March 2007; accepted 25 April 2007 相似文献
463.
Komen JC Distelmaier F Koopman WJ Wanders RJ Smeitink J Willems PH 《Cellular and molecular life sciences : CMLS》2007,64(24):3271-3281
Refsum disease is a rare, inherited neurodegenerative disorder characterized by accumulation of the dietary branched-chain
fatty acid phytanic acid in plasma and tissues caused by a defect in the alphaoxidation pathway. The accumulation of phytanic
acid is believed to be the main pathophysiological cause of the disease. However, the exact mechanism(s) by which phytanic
acid exerts its toxicity have not been resolved. In this study, the effect of phytanic acid on mitochondrial respiration was
investigated. The results show that in digitonin-permeabilized fibroblasts, phytanic acid decreases ATP synthesis, whereas
substrate oxidation per se is not affected. Importantly, studies in intact fibroblasts revealed that phytanic acid decreases both the mitochondrial
membrane potential and NAD(P)H autofluorescence. Taken together, the results described here show that unesterified phytanic
acid exerts its toxic effect mainly through its protonophoric action, at least in human skin fibroblasts.
Received 4 August 2007; received after revision 26 September 2007; accepted 10 October 2007
J. C. Komen, F. Distelmaier: These authors contributed equally to this work. 相似文献
464.
Dhar-Chowdhury P Malester B Rajacic P Coetzee WA 《Cellular and molecular life sciences : CMLS》2007,64(23):3069-3083
Glycolysis is an evolutionary conserved metabolic pathway that provides small amounts of energy in the form of ATP when compared
to other pathways such as oxidative phosphorylation or fatty acid oxidation. The ATP levels inside metabolically active cells
are not constant and the local ATP level will depend on the site of production as well as the respective rates of ATP production,
diffusion and consumption. Membrane ion transporters (pumps, exchangers and channels) are located at sites distal to the major
sources of ATP formation (the mitochondria). We review evidence that the glycolytic complex is associated with membranes;
both at the plasmalemma and with membranes of the endo/sarcoplasmic reticular network. We examine the evidence for the concept
that many of the ion transporters are regulated preferentially by the glycolytic process. These include the Na+/K+-ATPase, the H+-ATPase, various types of Ca2+-ATPases, the Na+/H+ exchanger, the ATP-sensitive K+ channel, cation channels, Na+ channels, Ca2+ channels and other channels involved in intracellular Ca2+ homeostasis. Regulation of these pumps, exchangers and ion channels by the glycolytic process has important consequences
in a variety of physiological and pathophysiological processes, and a better understanding of this mode of regulation may
have important consequences for developing future strategies in combating disease and developing novel therapeutic approaches.
Received 20 July 2007; received after revision 30 July 2007; accepted 17 August 2007 相似文献
465.
Edouard T Montagner A Dance M Conte F Yart A Parfait B Tauber M Salles JP Raynal P 《Cellular and molecular life sciences : CMLS》2007,64(13):1585-1590
Activating and inactivating mutations of SHP-2 are responsible, respectively, for the Noonan (NS) and the LEOPARD (LS) syndromes.
Clinically, these developmental disorders overlap greatly, resulting in the apparent paradox of similar diseases caused by
mutations that oppositely influence SHP-2 phosphatase activity. While the mechanisms remain unclear, recent functional analysis
of SHP-2, along with the identification of other genes involved in NS and in other related syndromes (neurofibromatosis-1,
Costello and cardio-facio-cutaneous syndromes), strongly suggest that Ras/MAPK represents the major signaling pathway deregulated
by SHP-2 mutants. We discuss the idea that, with the exception of LS mutations that have been shown to exert a dominant negative
effect, all disease-causing mutations involved in Ras/MAPK-mediated signaling, including SHP-2, might lead to enhanced MAPK
activation. This suggests that a narrow range of MAPK signaling is required for appropriate development. We also discuss the
possibility that LS mutations may not simply exhibit dominant negative activity.
Received 30 November 2006; received after revision 8 February 2007; accepted 13 March 2007 相似文献
466.
467.
468.
RNA polymerase is poised for activation across the genome 总被引:2,自引:0,他引:2
Muse GW Gilchrist DA Nechaev S Shah R Parker JS Grissom SF Zeitlinger J Adelman K 《Nature genetics》2007,39(12):1507-1511
469.
Houlden H Johnson J Gardner-Thorpe C Lashley T Hernandez D Worth P Singleton AB Hilton DA Holton J Revesz T Davis MB Giunti P Giunti P Wood NW 《Nature genetics》2007,39(12):1434-1436
The microtubule-associated protein tau (encoded by MAPT) and several tau kinases have been implicated in neurodegeneration, but only MAPT has a proven role in disease. We identified mutations in the gene encoding tau tubulin kinase 2 (TTBK2) as the cause of spinocerebellar ataxia type 11. Affected brain tissue showed substantial cerebellar degeneration and tau deposition. These data suggest that TTBK2 is important in the tau cascade and in spinocerebellar degeneration. 相似文献
470.
Romeo S Pennacchio LA Fu Y Boerwinkle E Tybjaerg-Hansen A Hobbs HH Cohen JC 《Nature genetics》2007,39(4):513-516
Resequencing genes provides the opportunity to assess the full spectrum of variants that influence complex traits. Here we report the first application of resequencing to a large population (n = 3,551) to examine the role of the adipokine ANGPTL4 in lipid metabolism. Nonsynonymous variants in ANGPTL4 were more prevalent in individuals with triglyceride levels in the lowest quartile than in individuals with levels in the highest quartile (P = 0.016). One variant (E40K), present in approximately 3% of European Americans, was associated with significantly lower plasma levels of triglyceride and higher levels of high-density lipoprotein cholesterol in European Americans from the Atherosclerosis Risk in Communities Study and in Danes from the Copenhagen City Heart Study. The ratio of nonsynonymous to synonymous variants was higher in European Americans than in African Americans (4:1 versus 1.3:1), suggesting population-specific relaxation of purifying selection. Thus, resequencing of ANGPTL4 in a multiethnic population allowed analysis of the phenotypic effects of both rare and common variants while taking advantage of genetic variation arising from ethnic differences in population history. 相似文献