Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q8NEX9 (reductase)
 26,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Flavonoids have been identified as the antidiabetic components in a number of traditional ethnic remedies. However, the mechanisms whereby these compounds exert their hypoglycemic and hypolipidemic action in type-2 diabetes have rarely been investigated. Therefore, this study investigated the effect of the flavonoids hesperidin and naringin on glucose and lipid regulation in C57BL/KsJ-db/db mice. Hesperidin and naringin both significantly increased the glucokinase mRNA level, while naringin also lowered the mRNA expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase in the liver. In addition, the hepatic glucose transporter 2 protein expression was significantly reduced, while the expression of adipocyte glucose transporter 4 and hepatic and adipocyte peroxisome proliferator-activated receptor gamma were elevated in the hesperidin and naringin groups when compared with the control group. Furthermore, hesperidin and naringin effectively lowered the plasma free fatty acid and plasma and hepatic triglyceride levels, and simultaneously reduced the hepatic fatty acid oxidation and carnitine palmitoyl transferase activity. These changes were seemingly attributable to a suppression of the hepatic fatty acid synthase, glucose-6-phosphate dehydrogenase, and phosphatidate phosphohydrolase activities and an increase in the fecal triglycerides. The two flavonoids also led to a decrease in the plasma and hepatic cholesterol levels that may have been partly due to the decreased hepatic 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase and acyl CoA: cholesterol acyltransferase (ACAT) activities and increased fecal cholesterol. Consequently, the current results suggest that hesperidin and naringin are beneficial for improving hyperlipidemia and hyperglycemia in type-2 diabetic animals by partly regulating the fatty acid and cholesterol metabolism and affecting the gene expression of glucose-regulating enzymes.
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PMID:Effect of citrus flavonoids on lipid metabolism and glucose-regulating enzyme mRNA levels in type-2 diabetic mice. 1642 99

It was found that chlorogenic acid inhibited in vitro animal fatty acid synthase (FAS I) and the ss-ketoacyl-ACP reductase (FabG) from Escherichia coli in a concentration-dependent manner with respective IC50 of 94.8 and 88.1 microM. The results of Lineweaver-Burk plots indicated that chlorogenic acid inhibited competitively the binding of NADPH to FAS I, while left those of acetyl-CoA and malonyl-CoA unaffected. Further kinetic studies showed that chlorogenic acid blocked the activity of FAS I mainly by inhibiting the ss-ketoacyl reductase domain, which catalyzed the same reaction as that done by FabG in the fatty acid synthesis. The ss-ketoacyl reduction reactions accomplished by both FAS I and FabG required nucleotide cofactor, NADPH. Furthermore, the Lineweaver-Burk and Yonetani-Theorell analyses implicated that chlorogenic acid filled competitively in the binding-pocket of NADPH in the ss-ketoacyl reductase domain of FAS I. The similar results were also obtained from the inhibition of FabG by chlorogenic acid. As observed in these results, the inhibitions of FAS I and FabG by chlorogenic acid were highly related to the interference of the inhibitor with NADPH, which was possibly due to the similarity between chlorogenic acid and some portion of NADPH, maybe the section consisting of the two ribose groups.
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PMID:Inhibitory activity of chlorogenic acid on enzymes involved in the fatty acid synthesis in animals and bacteria. 1654 Apr 31

HC-toxin is a cyclic tetrapeptide of structure cyclo(D-Pro-L-Ala-D-Ala-L-Aeo), where Aeo stands for 2-amino-9,10-epoxi-8-oxodecanoic acid. It is a determinant of specificity and virulence in the interaction between the producing fungus, Cochliobolus carbonum, and its host, maize. HC-toxin qualifies as one of the few microbial secondary metabolites whose ecological function in nature is understood. Reaction to C. carbonum and to HC-toxin is controlled in maize by the Hm1 and Hm2 loci. These loci encode HC-toxin reductase, which detoxifies HC-toxin by reducing the 8-carbonyl group of Aeo. HC-toxin is an inhibitor of histone deacetylases (HDACs) in many organisms, including plants, insects, and mammals, but why inhibition of HDACs during infection by C. carbonum leads to disease is not understood. The genes for HC-toxin biosynthesis (collectively known as the TOX2 locus) are loosely clustered over >500 kb in C. carbonum. All of the known TOX2 genes are present in multiple, functional copies and are absent from natural toxin non-producing isolates. The central enzyme in HC-toxin biosynthesis is a 570-kDa non-ribosomal synthetase encoded by a 15.7-kb open reading frame. Other genes known to be required for HC-toxin encode alpha and beta subunits of fatty acid synthase, which are presumed to contribute to the synthesis of Aeo; a pathway-specific transcription factor; an efflux carrier; a predicted branched-chain amino acid aminotransferase; and an alanine racemase.
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PMID:HC-toxin. 1683 76

The type II fatty acid synthase pathway of Plasmodium falciparum is a validated unique target for developing novel antimalarials because of its intrinsic differences from the type I pathway operating in humans. beta-Ketoacyl-acyl carrier protein reductase is the only enzyme of this pathway that has no isoforms and thus selective inhibitors can be developed for this player of the pathway. We report here intensive studies on the direct interactions of Plasmodiumbeta-ketoacyl-acyl carrier protein reductase with its cofactor, NADPH, acyl carrier protein, acetoacetyl-coenzyme A and other ligands in solution, by monitoring the intrinsic fluorescence (lambdamax 334 nM) of the protein as a result of its lone tryptophan, as well as the fluorescence of NADPH (lambdamax 450 nM) upon binding to the enzyme. Binding of the reduced cofactor makes the enzyme catalytically efficient, as it increases the binding affinity of the substrate, acetoacetyl-coenzyme A, by 16-fold. The binding affinity of acyl carrier protein to the enzyme also increases by approximately threefold upon NADPH binding. Plasmodiumbeta-ketoacyl-acyl carrier protein reductase exhibits negative, homotropic co-operative binding for NADPH, which is enhanced in the presence of acyl carrier protein. Acyl carrier protein increases the accessibility of NADPH to beta-ketoacyl-acyl carrier protein reductase, as evident from the increase in the accessibility of the tryptophan of beta-ketoacyl-acyl carrier protein reductase to acrylamide, from 81 to 98%. In the presence of NADP+, the reaction proceeds in the reverse direction (Ka=23.17 microM-1). These findings provide impetus for exploring the influence of ligands on the structure-activity relationship of Plasmodiumbeta-ketoacyl-acyl carrier protein reductase.
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PMID:Analyses of co-operative transitions in Plasmodium falciparum beta-ketoacyl acyl carrier protein reductase upon co-factor and acyl carrier protein binding. 1693 37

Liver fatty acid-binding protein (L-Fabp) regulates murine hepatic fatty acid trafficking in response to fasting. In this study, we show that L-Fabp(-/-) mice fed a high-fat Western diet for up to 18 weeks are less obese and accumulate less hepatic triglyceride than C57BL/6J controls. Paradoxically, both control and L-Fabp(-/-) mice manifested comparable glucose intolerance and insulin resistance when fed a Western diet. Protection against obesity in Western diet-fed L-Fabp(-/-) mice was not due to discernable changes in food intake, fat malabsorption, or heat production, although intestinal lipid secretion kinetics were significantly slower in both chow-fed and Western diet-fed L-Fabp(-/-) mice. By contrast, there was a significant increase in the respiratory exchange ratio in L-Fabp(-/-) mice, suggesting a shift in energy substrate use from fat to carbohydrate, findings supported by an approximately threefold increase in serum lactate. Microarray analysis revealed increased expression of genes involved in lipid synthesis (fatty acid synthase, squalene epoxidase, hydroxy-methylglutaryl coenzyme A reductase), while genes involved in glycolysis (glucokinase and glycerol kinase) were decreased in L-Fabp(-/-) mice. Fatty acid synthase expression was also increased in the skeletal muscle of L-Fabp(-/-) mice. In conclusion, L-Fabp may function as a metabolic sensor in regulating lipid homeostasis. We suggest that L-Fabp(-/-) mice are protected against Western diet-induced obesity and hepatic steatosis through a series of adaptations in both hepatic and extrahepatic energy substrate use. (HEPATOLOGY 2006;44:1191-1205.).
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PMID:Protection against Western diet-induced obesity and hepatic steatosis in liver fatty acid-binding protein knockout mice. 1705 18

Hepatic lipogenesis is the principal route to convert excess carbohydrates into fatty acids and is mainly regulated by two opposing hormones, insulin and glucagon. Although insulin stimulates hepatic lipogenesis, glucagon inhibits it. However, the mechanism by which glucagon suppresses lipogenesis remains poorly understood. In this study, we have observed that p38 mitogen-activated protein kinase plays an inhibitory role in hepatic lipogenesis. Levels of plasma triglyceride and triglyceride accumulation in the liver were both elevated when p38 activation was blocked. Expression levels of central lipogenic genes, including sterol regulatory element-binding protein-1 (SREBP-1), fatty acid synthase, hydroxy-3-methylglutaryl coenzyme A reductase, farnesyl pyrophosphate synthase, and cytochrome P-450-51, were decreased in liver by fasting and in primary hepatocytes by glucagon but increased by the inhibition of p38. In addition, we have shown that p38 can inhibit insulin-induced expression of key lipogenic genes in isolated hepatocytes. Our results in hepatoma cells demonstrate that p38 plays an inhibitory role in the activation of the SREBP-1c promoter. Finally, we have shown that transcription of the PGC-1beta gene, a key coactivator of SREBP-1c, was reduced in liver by fasting and in isolated hepatocytes by glucagon. This reduction was significantly reversed by the blockade of p38. Insulin-induced expression of the PGC-1beta gene was enhanced by the inhibition of p38 but suppressed by the activation of p38. Together, we have identified an inhibitory role for p38 in the transcription of central lipogenic genes, SREBPs, and PGC-1beta and hepatic lipogenesis.
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PMID:p38 mitogen-activated protein kinase plays an inhibitory role in hepatic lipogenesis. 1717 44

We examined the physiological importance of bovine dietary proteins in rats fed diets prepared from bovine Achilles' tendons and arteries. Rats were fed for 4 weeks, with a 20% casein diet (CON), in comparison with two diets containing 15% casein and 5% of either bovine Achilles' tendon (AC) or artery (AR) protein preparations. The serum total cholesterol concentration and non-HDL-cholesterol level in the AR-fed group were significantly lower (P< 0.05) than those in the CON-fed group at the end of the 4-week feeding period. The hepatic mRNA were measured, and the hydroxyl methyl glutaryl-CoA reductase mRNA level was significantly lower (P< 0.05) in the AR-fed group compared with the CON-fed group. Total hepatic cholesterol concentration in AC-fed rats was significantly (P < 0.05) higher than in the CON-fed group. The serum TAG concentration and fatty acid synthase mRNA level in AC- and AR-fed groups were significantly lower (P<0.05) compared with the CON-fed group throughout the feeding period. Faecal neutral sterol excretion was significantly (P<0.05) higher in the AC- and AR-fed groups compared with the CON-fed group. The results of the present study demonstrate that some bovine dietary proteins have similar functions as dietary fibres, lowering serum lipid concentration by enhancing faecal neutral sterol excretion or suppressing lipid synthesis in the liver. Moreover, favourable amino acid compositions in the AR and AC preparations may also have a lowering effect on plasma lipid concentration in bovine protein diet-fed groups.
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PMID:Some bovine proteins behave as dietary fibres and reduce serum lipids in rats. 1738 83

Brassica napus cv Westar plants were transformed with 3-oxoacyl-ACP reductase (KR) in antisense orientation, driven by either the cauliflower mosaic virus 35S promoter or a seed-specific acyl carrier protein promoter to determine the effects on plant productivity and on the activity of other fatty acid synthase (FAS) components. In plants with altered KR activity, total seed yield was reduced in all cases. In less severely affected plant lines, seeds had a normal appearance and composition but the yield of seeds was reduced by approximately 50%. In more severely affected lines, reductions in both seed fatty acid content and the number of seeds produced per plant were evident, resulting in a 90% reduction in fatty acid synthesized per plant. These phenotypes were independent of the promoter used. In severely affected lines, a large proportion of seeds showed precocious germination, and these had a reduced oleate content and increased levels of polyunsaturated 18-carbon fatty acids, compared with normal seeds of the same line. This reduction in 18:1 fatty acids was mimicked on imbibition of seeds with a normal appearance, indicating a preferential use of oleate moieties in precocious germination events. The reduction in activity of KR was mirrored for a second fatty acid synthase component, enoyl-ACP reductase, indicating a mechanism to maintain the ratio of fatty acid synthase components throughout embryogenesis.
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PMID:Antisense expression of 3-oxoacyl-ACP reductase affects whole plant productivity and causes collateral changes in activity of fatty acid synthase components. 1740 Nov 35

Domains within the multienzyme polyketide synthases are linked by noncatalytic sequences of variable length and unknown function. Recently, the crystal structure was reported of a portion of the linker between the acyltransferase (AT) and ketoreductase (KR) domains from module 1 of the erythromycin synthase (6-deoxyerythronolide B synthase), as a pseudodimer with the adjacent ketoreductase (KR). On the basis of this structure, the homologous linker region between the dehydratase (DH) and enoyl reductase (ER) domains in fully reducing modules has been proposed to occupy a position on the periphery of the polyketide synthases complex, as in porcine fatty acid synthase. We report here the expression and characterization of the same region of the 6-deoxyerythronolide B synthase module 1 AT-KR linker, without the adjacent KR domain (termed DeltaN AT1-KR1), as well as the corresponding section of the DH-ER linker. The linkers fold autonomously and are well structured. However, analytical gel filtration and ultracentrifugation analysis independently show that DeltaN AT1-KR1 is homodimeric in solution; site-directed mutagenesis further demonstrates that linker self-association is compatible with the formation of a linker-KR pseudodimer. Our data also strongly indicate that the DH-ER linker associates with the upstream DH domain. Both of these findings are incompatible with the proposed model for polyketide synthase architecture, suggesting that it is premature to allocate the linker regions to a position in the multienzymes based on the solved structure of animal fatty acid synthase.
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PMID:Autonomous folding of interdomain regions of a modular polyketide synthase. 1741 33

Apicomplexan parasites of the genus Eimeria are the major causative agent of avian coccidiosis, leading to high economic losses in the poultry industry. Recent results show that Eimeria tenella harbours an apicoplast organelle, and that a key biosynthetic enzyme, enoyl reductase, is located in this organelle. In related parasites, enoyl reductase is one component of a type II fatty acid synthase (FAS) and has proven to be an attractive target for antimicrobial compounds. We cloned and expressed the mature form of E. tenella enoyl reductase (EtENR) for biochemical and structural studies. Recombinant EtENR exhibits NADH-dependent enoyl reductase activity and is inhibited by triclosan with an IC50 value of 60 nm. The crystal structure of EtENR reveals overall similarity with other ENR enzymes; however, the active site of EtENR is unoccupied, a state rarely observed in other ENR structures. Furthermore, the position of the central beta-sheet appears to block NADH binding and would require significant movement to allow NADH binding, a feature not previously seen in the ENR family. We analysed the E. tenella genomic database for orthologues of well-characterized bacterial and apicomplexan FAS enzymes and identified 6 additional genes, suggesting that E. tenella contains a type II FAS capable of synthesizing saturated, but not unsaturated, fatty acids. Interestingly, we also identified sequences that appear to encode multifunctional type I FAS enzymes, a feature also observed in Toxoplasma gondii, highlighting the similarity between these apicomplexan parasites.
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PMID:Type I and type II fatty acid biosynthesis in Eimeria tenella: enoyl reductase activity and structure. 1769 96


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