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Haushalter RW Worthington AS Hur GH Burkart MD 《Bioorganic & medicinal chemistry letters》2008,18(10):3039-3042
Chemo-enzymatic methods for covalently crosslinking carrier proteins with partner enzymes within modular synthases hold promise for elucidating and engineering metabolic pathways. Our efforts to crystallize the ACP-KS complexes of fatty acid synthases have been complicated by difficulties in the purification of the crosslinked complex from the other proteins in the reaction. Here we present a solution that employs an orthogonal purification strategy to achieve the quantity and level of purity necessary for further studies of this complex. 相似文献
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Structure and specificity of the vertebrate anti-mutator uracil-DNA glycosylase SMUG1 总被引:1,自引:0,他引:1
Cytosine deamination is a major promutagenic process, generating G:U mismatches that can cause transition mutations if not repaired. Uracil is also introduced into DNA via nonmutagenic incorporation of dUTP during replication. In bacteria, uracil is excised by uracil-DNA glycosylases (UDG) related to E. coli UNG, and UNG homologs are found in mammals and viruses. Ung knockout mice display no increase in mutation frequency due to a second UDG activity, SMUG1, which is specialized for antimutational uracil excision in mammalian cells. Remarkably, SMUG1 also excises the oxidation-damage product 5-hydroxymethyluracil (HmU), but like UNG is inactive against thymine (5-methyluracil), a chemical substructure of HmU. We have solved the crystal structure of SMUG1 complexed with DNA and base-excision products. This structure indicates a more invasive interaction with dsDNA than observed with other UDGs and reveals an elegant water displacement/replacement mechanism that allows SMUG1 to exclude thymine from its active site while accepting HmU. 相似文献
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Abstract The palatability to common carp, Cyprinus carpio L. of three newly developed differently flavoured floating pellets made from a high proportion (40%) of brewer's spent grain (BSG) was tested using a multiple-offer feeding experiment. The addition of ‘bold’ flavours, such as vanilla or strawberry essence, may help mask the unpleasant taste of some piscicides; however, their inclusion must not compromise uptake by carp. There were no significant differences between the consumption rates of the three varieties, and all flavours were readily consumed. Therefore, it is suggested that highly flavoured pellets made with BSG have a strong potential to mask the flavour of an unpalatable toxin, and further research is now needed to test this hypothesis. 相似文献
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Yurong Guo Manjula Darshi Yuliang Ma Guy A. Perkins Zhouxin Shen Kristofer J. Haushalter Rintaro Saito Ai Chen Yun Sok Lee Hemal H. Patel Steven P. Briggs Mark H. Ellisman Jerrold M. Olefsky Susan S. Taylor 《Molecular & cellular proteomics : MCP》2013,12(12):3744-3758
Insulin resistance plays a major role in the development of type 2 diabetes and obesity and affects a number of biological processes such as mitochondrial biogenesis. Though mitochondrial dysfunction has been linked to the development of insulin resistance and pathogenesis of type 2 diabetes, the precise mechanism linking the two is not well understood. We used high fat diet (HFD)-induced obesity dependent diabetes mouse models to gain insight into the potential pathways altered with metabolic disease, and carried out quantitative proteomic analysis of liver mitochondria. As previously reported, proteins involved in fatty acid oxidation, branched chain amino acid degradation, tricarboxylic acid cycle, and oxidative phosphorylation were uniformly up-regulated in the liver of HFD fed mice compared with that of normal diet. Further, our studies revealed that retinol metabolism is distinctly down-regulated and the mitochondrial structural proteins—components of mitochondrial inter-membrane space bridging (MIB) complex (Mitofilin, Sam50, and ChChd3), and Tim proteins—essential for protein import, are significantly up-regulated in HFD fed mice. Structural and functional studies on HFD and normal diet liver mitochondria revealed remodeling of HFD mitochondria to a more condensed form with increased respiratory capacity and higher ATP levels compared with normal diet mitochondria. Thus, it is likely that the structural remodeling is essential to accommodate the increased protein content in presence of HFD: the mechanism could be through the MIB complex promoting contact site and crista junction formation and in turn facilitating the lipid and protein uptake.Obesity has become a global epidemic and in the United States alone more than one third of adults (34%) are obese and over 11% of the population over the age of 20 are diabetic (1, 2). Even though the precise mechanisms causing obesity are still being determined, it is well established that obesity induces insulin resistance leading to the pathogenesis of type 2 diabetes (T2D)1 (3, 4). Insulin resistance has been implicated in multiple organ damage such as liver, skeletal muscle, and adipose tissues (5). This is in view of the fact that cellular glucose homeostasis is tightly regulated by insulin secretion from the pancreatic β-cells and glucose uptake by muscle and output by liver. Thus, failure of insulin secretion by pancreatic β-cells to compensate for insulin resistance results in hyperglycemia (6, 7) and uncontrolled hyperglycemia has the potential to negatively impact a number of organ systems.Mitochondrial dysfunction has been thought to play a critical role in insulin resistance and T2D (8–11), and the role of mitochondria in insulin resistance is highly tissue specific. Despite this the mechanisms of action is controversial: in skeletal muscle, oxidative metabolism of lipids is reduced in T2D patients (11, 12). However, it has been reported that carnitine palmitoyl transferase (CPT) activity is decreased or long-chain acyl-CoA dehydrogenase (LACD) is deficient, and these lead to an accumulation of intracellular lipids and insulin resistance in insulin-targeting cells (13). These excess metabolites eventually cause the decrease in glucose transport and other events downstream of insulin receptor signaling (14). In adipose tissue, it has been shown that adiponectin expression and mitochondrial content in obese db/db mice were reduced (15). One of the favorable effects of adiponectin is the improvement of insulin action (16) and it has been reported that mitochondrial dysfunction in adipose tissue explains decreased adiponectin synthesis in obesity (15). In contrast to muscle, coordinated up-regulation of oxidative phosphorylation (OXPHOS) subunits in obese liver has been previously reported at mRNA (17) and protein (18) levels. Liver mitochondria also showed significant up-regulation of beta-oxidation, branched chain amino acid degradation, pyruvate metabolism, TCA cycle, and apoptotic pathways (18, 19).In the fasting state, blood glucose levels are maintained by liver regulated gluconeogenesis. T2D is characterized by defects in insulin''s ability to inhibit gluconeogenesis. Hepatic insulin resistance and impaired fatty acid oxidation have been the major contributors for the development of hepatic steatosis and the progression of nonalcoholic fatty liver disease (NAFLD) (20). Mitochondrial abnormalities have also been associated with NAFLD, and hence liver insulin sensitivity and the potential relationship with mitochondria appear to be crucial.In this study, we used a proteomic approach to investigate the biological pathways leading to insulin resistance in T2D in the liver and analyzed the protein expression profiles from mitochondria of mice fed on a high fat diet (HFD) for 30 weeks. Increased insulin resistance, elevated plasma insulin and impaired glucose tolerance were observed in mice after 16 weeks of HFD (21). Consistent with previous studies, liver mitochondria showed significant up-regulation of oxidation-phosphorylation (OXPHOS), beta-oxidation, branched chain amino acid degradation, pyruvate metabolism, TCA cycle, and apoptotic pathways (18, 19). Additionally, in our study we show that retinol metabolism was consistently down-regulated, and the proteins involved in the protein import into mitochondria, mitochondrial biogenesis and regulation of crista morphology are up-regulated in HFD versus normal diet (ND) liver mitochondria. We further examined the ultrastructure of the mitochondria from the liver and show that under HFD conditions the mitochondria are often condensed with a remodeling of crista and increased number of cristae. We suggest that the structural change in cristae is likely to be a necessary event to accommodate the increased OXPHOS gene expression and other proteins that are residents of the inner membrane. The remodeling of cristae is also accompanied by increased mitofilin expression and its interacting proteins, which include ChChd3 and OPA1, that are critical for cristae organization. Finally our oxygen consumption experiment showed increased activities of complex I and complex II in liver mitochondria of HFD versus ND mice and our ATP assay confirmed increased ATP production in HFD versus ND mice. 相似文献