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1.
Marisa Cabeza Alejandro Posada Araceli Sánchez-Márquez Yvonne Heuze Isabel Moreno Juan Soriano 《Journal of enzyme inhibition and medicinal chemistry》2016,31(1):53-62
The enzyme type 5 17β-hydroxysteroid dehydrogenase 5 (17β-HSD5) catalyzes the transformation of androstenedione (4-dione) to testosterone (T) in the prostate. This metabolic pathway remains active in cancer patients receiving androgen deprivation therapy. Since physicians seek to develop advantageous and better new treatments to increase the average survival of these patients, we synthesized several different dehydroepiandrosterone derivatives. These compounds have a pyrazole or imidazole function at C-17 and an ester moiety at C-3 and were studied as inhibitors of 17β-HSD5. The kinetic parameters of this enzyme were determined for use in inhibition assays. Their pharmacological effect was also determined on gonadectomized hamsters treated with Δ4-androstenedione (4-dione) or testosterone (T) and/or the novel compounds. The results indicated that the incorporation of a heterocycle at C-17 induced strong 17β-HSD5 inhibition. These derivatives decreased flank organ diameter and prostate weight in castrated hamsters treated with T or 4-dione. Inhibition of 17β-HSD5 by these compounds could have therapeutic potential for the treatment of prostate cancer and benign prostatic hyperplasia. 相似文献
2.
Polyamines such as spermine can have interaction with protein. The aim of the present study was to investigate how spermine could influence the structure, thermal stability, and the activity of α-chymotrypsin. Kinetics, thermodynamics, molecular dynamics (MD), and docking simulations studies were conducted to investigate the effect of spermine on the activity and structure of α-Chymotrypsin (α-Chy) in 50 mM Tris–HCl buffer, with the pH 8, using different spectroscopic techniques as well as molecular docking and MD simulations. The stability and activity of α-Chy were increased in the presence of spermine. The results of the kinetic study showed that the activity of spermine was increased. Enzyme activation was accompanied by changes on the α-Chy conformation. Fluorescence intensity changes showed dynamic quenching during spermine binding. The fluorescence quenching of the α-Chy suggested the more polar location of Trp residues. Near-UV and Far-UV circular dichroism studies also demonstrated the transfer of Trp, Phe, and Tyr residues to a more flexible environment. The increase in the absorption of α-Chy in the presence of spermine was as a result of the formation of spermine–α-Chy complex. Molecular docking results revealed the presence of one binding site with a negative value for the Gibbs free energy of the binding of spermine to α-Chy. Docking study also revealed that van der Waals interactions and hydrogen bonds played a major role in stabilizing the complex. 相似文献
3.
Luis J del Valle Cristina Escribano Juan J Pérez Pere Garriga 《Biochimica et Biophysica Acta - Proteins and Proteomics》2002,1601(1):100-109
α-Crystallin, one of the major proteins in the vertebrate eye lens, acts as a molecular chaperone, like the small heat-shock proteins, by protecting other proteins from denaturing under stress or high temperature conditions. α-Crystallin aggregation is involved in lens opacification, and high [Ca2+] has been associated with cataract formation, suggesting a role for this cation in the pathological process. We have investigated the effect of Ca2+ on the thermal stability of α-crystallin by UV and Fourier-transform infrared (FTIR) spectroscopies. In both cases, a Ca2+-induced decrease in the midpoint of the thermal transition is detected. The presence of high [Ca2+] results also in a marked decrease of its chaperone activity in an insulin-aggregation assay. Furthermore, high Ca2+ concentration decreases Cys reactivity towards a sulfhydryl reagent. The results obtained from the spectroscopic analysis, and confirmed by circular dichroism (CD) measurements, indicate that Ca2+ decreases both secondary and tertiary–quaternary structure stability of α-crystallin. This process is accompanied by partial unfolding of the protein and a clear decrease in its chaperone activity. It is concluded that Ca2+ alters the structural stability of α-crystallin, resulting in impaired chaperone function and a lower protective ability towards other lens proteins. Thus, α-crystallin aggregation facilitated by Ca2+ would play a role in the progressive loss of transparency of the eye lens in the cataractogenic process. 相似文献
4.
Tuti Wukirsari Hisashi Nishiwaki Kosuke Nishi Takuya Sugahara Koichi Akiyama Taro Kishida 《Bioscience, biotechnology, and biochemistry》2016,80(4):669-675
We compared the cytotoxic activities of dietary epoxylignans and their stereoisomers and found (?)-verrucosin, which is (7S,7′R,8R,8′R)-7,7′-epoxylignan, to be the most cytotoxic epoxylignan against HeLa cells (IC50 = 6.6 μM). On the other hand, the activity was about a factor of 10 less against HL-60. In this research on the relationship between the structure and cytotoxic activity of (?)-verrucosin 13, the 7-(4-methoxyphenyl)-7′-(3,4-dimethoxyphenyl) derivative 60, for which the activity (IC50 = 2.4 μM) is three times greater than (?)-verrucosin 13, was discovered. The induction of apoptosis by caspase 3/7 was observed upon treatment with the (?)-verrucosin derivative. 相似文献
5.
Bunta Watanabe Yukiko Tabuchi Kei Wada Jun Hiratake 《Bioorganic & medicinal chemistry letters》2017,27(21):4920-4924
2-Amino-4-{[3-(carboxymethyl)phenoxy](methoxy)phosphoryl}butanoic acid (GGsTop) is a potent, highly selective, nontoxic, and irreversible inhibitor of γ-glutamyl transpeptidase (GGT). GGsTop has been widely used in academic and medicinal research, and also as an active ingredient (Nahlsgen) in commercial anti-aging cosmetics. GGsTop consists of four stereoisomers due to the presence of two stereogenic centers, i.e., the α-carbon atom of the glutamate mimic (l/d) and the phosphorus atom (RP/SP). In this study, each stereoisomer of GGsTop was synthesized stereoselectively and their inhibitory activity against human GGT was evaluated. The l- and d-configurations of each stereoisomer were determined by a combination of a chiral pool synthesis and chiral HPLC analysis. The synthesis of the four stereoisomers of GGsTop used chiral synthetic precursors that were separated by chiral HPLC on a preparative scale. With respect to the configuration of the α-carbon atom of the glutamate mimic, the l-isomer (kon = 174 M?1 s?1) was ca. 8-fold more potent than the d-isomer (kon = 21.5 M?1 s?1). In contrast, the configuration of the phosphorus atom is critical for GGT inhibitory activity. Based on a molecular modeling approach, the absolute configuration of the phosphorus atom of the active GGsTop isomers was postulated to be SP. The SP-isomers inhibited human GGT (kon = 21.5–174 M?1 s?1), while the RP-isomers were inactive even at concentrations of 0.1 mM. 相似文献
6.
A growing body of Alzheimer's disease (AD) research is concerned with understanding the interaction between amyloid-β (Aβ) peptides and metal ions (e.g., Cu, Zn, and Fe) and determining the biological relevance of the metal-Aβ complexes to essential metal homeostasis and neuronal cell loss. Previously, many studies have dealt with the interaction between Aβ and "single" but not "multiple" metal ions in terms of binding affinity and coordination chemistry. In the present work, we found that Zn(II) ions modified the configuration of Aβ-Cu(II) by forming Zn(II)-Aβ-Cu(II) ternary complexes. As a result, the catalytic activity of Aβ-Cu(II) against a biological ascorbic acid species was repressed by Zn(II) binding. The formation of the ternary complex can therefore explain the protective role of Zn(II) in AD. 相似文献
7.
Historically, the link between elevated cholesterol and increased risk of cardiovascular disease has been based on fasting measurements. This is appropriate for total, low-density lipoprotein and high-density lipoprotein cholesterol. However, triglyceride concentrations vary considerably throughout the day in response to the regular consumption of food and drink. Recent findings indicate that postprandial triglyceride concentrations independently predict future cardiovascular risk. Potential modulators of postprandial lipidemia include meal composition and physical activity. Early cross sectional studies indicated that physically active individuals had a lower postprandial lipidemic response compared to inactive individuals. However, the effect of physical activity on postprandial lipidemia is an acute phenomenon, which dissipates within 60 h of a single bout of exercise. Total exercise induced energy expenditure, rather than duration or intensity of the physical activity is commonly reported to be a potent modulator of postprandial lipidemia. However, the pooled results of studies in this area suggest that energy expenditure exerts most of its influence on fasting triglyceride concentrations rather than on the incremental change in triglyceride concentrations seen following meal consumption. It seems more likely that energy expenditure is one component of a multifactorial list of mediators that may include local muscle contractile activity, and other yet to be elucidated mechanisms. 相似文献
8.
Choon Kim Dusan Hesek Mijoon Lee Shahriar Mobashery 《Bioorganic & medicinal chemistry letters》2018,28(4):642-645
Farnesol, a sesquiterpene alcohol, potentiates the activity of β-lactam antibiotics against antibiotic-resistant bacteria. We document that farnesol and two synthetic derivatives (compounds 2 and 6) have poor antibacterial activities of their own, but they potentiate the activities of ampicillin and oxacillin against Staphylococcus aureus strains (including methicillin-resistant S. aureus). These compounds attenuate the rate of growth of bacteria, which has to be taken into account in assessment of the potentiation effect. 相似文献
9.
Hu W Splith K Neundorf I Merz K Schatzschneider U 《Journal of biological inorganic chemistry》2012,17(2):175-185
Organometallic complexes conjugated to cell-penetrating peptides (CPPs) are promising systems for diagnostic imaging and therapeutic
applications in human medicine. Recently, we reported on the synthesis of cymantrene(CpMn(CO)3)–CPP conjugates with biological activity on different cancer cell lines. However, the precise mechanism of cytotoxicity remained
elusive in these studies. To investigate the role of the metal center and the linker between the CpM(CO)3 moiety and the peptide, a number of derivatives with manganese replaced by rhenium and the keto linker originally used substituted
by a methylene group were prepared and fully characterized by 1H NMR spectroscopy, infrared spectroscopy, electrospray ionization mass spectrometry, and elemental analysis as well as X-ray
structure determination. The organometal–peptide conjugates as well as carboxyfluorescein-labeled derivatives thereof were
prepared by solid-phase peptide synthesis, purified by high-performance liquid chromatography, and analyzed by mass spectrometry.
Fluorescence microscopy studies of MCF-7 human breast cancer cells revealed an efficient cellular uptake and pronounced nuclear
localization of the bioconjugates with the methylene linker compared with systems with the keto group. In addition, the latter
also showed a higher cytotoxicity. In contrast, the variation of the metal center from manganese to rhenium had a negligible
effect. The structure–activity relationships determined in the present work will aid in the further tuning of the biological
activity of organometal–peptide conjugates. 相似文献
10.
《Journal of Asia》2014,17(1):7-11
The Sunn pest, Eurygaster integriceps Puton (Hemiptera: Scutelleridae), is a significant limiting factor in the production of wheat and barley in many areas of the world. In the current study, the effect of semi-purified proteinaceous extracts of seeds on digestive enzymes, and the growth and development of the Sunn pest were studied. The results showed that the purified α-amylase inhibitor from Triticum aestivum (type І) and rice semi-purified seed extract did not significantly affect the Sunn pest α-amylase activity. However, bean and cowpea seed extracts significantly affected α-amylase activity in vitro. For example, the bean seed extract at concentrations of 0.125 and 2.0 mg · mL− 1 inhibited α-amylase activity of the pest by 15% and 45%, respectively, while the cowpea seed extract, at the same concentrations, inhibited α-amylase activity of the pest by 9% and 40%, respectively. Further, incorporation of the seed extracts into the insect diet showed that the rice seed extract did not affect insect development time, while bean and cowpea seed extracts at high concentrations (e.g., 3.0%) significantly affected nymphal development time and survivability (P > 0.05). These results show that semi-purified seed extracts affect α-amylase activity, developmental time, and survivability but not the adult weight of the Sunn pest. 相似文献
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12.
The 19-transmembrane multisubunit γ-secretase complex generates the amyloid β-peptide (Aβ) of Alzheimer's disease (AD) by intramembrane proteolysis of the β-amyloid precursor protein (APP). Despite substantial advances in elucidating how this protein complex functions, the effect of the local membrane lipid microenvironment on γ-secretase cleavage of substrates is still poorly understood. Using detergent-free proteoliposomes to reconstitute purified human γ-secretase, we examined the effects of fatty acyl (FA) chain length, saturation and double-bond isomerization, and membrane lipid polar headgroups on γ-secretase function. We analyzed γ-secretase activity and processivity [i.e., sequential cleavages in the APP transmembrane domain that convert longer Aβ species (e.g., Aβ(46)) into shorter ones (e.g., Aβ(40))] by quantifying the APP intracellular domain (AICD) and various Aβ peptides, including via a bicine/urea gel system that detects multiple Aβ lengths. These assays revealed several trends. (1) Switching from a cis to a trans isomer of a monounsaturated FA chain in phosphatidylcholine (PC) increased γ-activity, did not affect Aβ(42):Aβ(40) ratios, but decreased the ratio of long (≥42) versus short (≤41) Aβ peptides. (2) Increasing the FA carbon chain length (14, 16, 18, and 20) increased γ-activity, reduced longer Aβ species, and reduced the Aβ(42):Aβ(40) ratio. (3) Shifting the position of the double bond in 18:1(Δ9-cis) PC to the Δ6 position substantially reduced activity. (4) Gangliosides increased γ-activity but decreased processivity, thus elevating the Aβ(42):Aβ(40) ratio. (5) Phosphatidylserine decreased γ-activity but increased processivity. (6) Phosphatidylinositol strongly inhibited γ-activity. Overall, our results show that subtle changes in membrane lipid composition can greatly influence γ-secretase activity and processivity, suggesting that relatively small changes in lipid membrane composition may affect the risk of AD at least as much as presenilin or APP mutations do. 相似文献
13.
Summary A previously suggested model for the correlation between residual activity of a lysosomal enzyme and the turnover rate of its substrate(s) has been extended to a discussion of substrate accumulation rates in individual cells and whole organs. With these considerations, much of the observed variability in age of onset and clinical phenotype, as well as the phenomenon of pseudodeficiency, can be understood as the consequences of small differences in the residual activity of the affected enzyme. In order to experimentally verify the basic assumptions on which this model rests, studies were performed in cell culture. The radiolabeled substrates ganglioside GM2 and sulfatide were added to cultures of skin fibroblasts with different activities of -hexosaminidase A or arylsulfatase A, respectively, and their uptake and turnover measured. In both series of experiments, the correlation between residual enzyme activity and the turnover rate of the substrate was essentially as predicted: degradation increased steeply with residual activity, to reach the control level at a residual activity of approximately 10–15% of normal. All cells with an activity above this critical threshold had a normal turnover. Comparison of the results of these feeding studies with the clinical status of the donor of each cell line basically confirmed our notions but also revealed the limitations of the cell culture approach. 相似文献
14.
15.
<正>Transforming growth factorβ(TGF-β) regulates various physiological processes such as cell proliferation, differentiation, morphogenesis, andt tissue homeostasis and regeneration. The deregulation of these processes leads to many types of human diseases such as cancer (Massagué,2008). TGF-βsignaling is initiated upon active TGF-βdimer 相似文献
16.
Auldridge ME Guo Y Austin MB Ramsey J Fridman E Pichersky E Noel JP 《The Plant cell》2012,24(4):1596-1607
Specialized methylketone-containing metabolites accumulate in certain plants, in particular wild tomatoes in which they serve as toxic compounds against chewing insects. In Solanum habrochaites f. glabratum, methylketone biosynthesis occurs in the plastids of glandular trichomes and begins with intermediates of de novo fatty acid synthesis. These fatty-acyl intermediates are converted via sequential reactions catalyzed by Methylketone Synthase2 (MKS2) and MKS1 to produce the n-1 methylketone. We report crystal structures of S. habrochaites MKS1, an atypical member of the α/β-hydrolase superfamily. Sequence comparisons revealed the MKS1 catalytic triad, Ala-His-Asn, as divergent to the traditional α/β-hydrolase triad, Ser-His-Asp. Determination of the MKS1 structure points to a novel enzymatic mechanism dependent upon residues Thr-18 and His-243, confirmed by biochemical assays. Structural analysis further reveals a tunnel leading from the active site consisting mostly of hydrophobic residues, an environment well suited for fatty-acyl chain binding. We confirmed the importance of this substrate binding mode by substituting several amino acids leading to an alteration in the acyl-chain length preference of MKS1. Furthermore, we employ structure-guided mutagenesis and functional assays to demonstrate that MKS1, unlike enzymes from this hydrolase superfamily, is not an efficient hydrolase but instead catalyzes the decarboxylation of 3-keto acids. 相似文献
17.
Adsorption of β-glucosidase from almonds, an enzyme with big molecular size (130?kDa, 6.7?nm molecular diameter), on mesoporous SBA-15 silica in fixed bed column was studied. Previously, zeta potential analysis confirmed that the electrostatic interactions between β-glucosidase and SBA-15 were the driving force of the immobilization process. The maximum difference in the zeta potential was 25?mV at pH 3.5. Adsorption isotherm was classified as an L3 (Langmuir type 3) curve according to the Giles classification and fitted to a double Langmuir equation. The adsorbed amount in a fixed bed column was around 3.5 times higher than the amount reached in the adsorption in batch. In addition, the β-glucosidase was strongly immobilized on SBA-15 with only 7?% of leaching in the washing step with buffer solution. Immobilized β-glucosidase was catalytically active in a continuous process, reaching 100?% substrate conversion and maintaining this activity level for more than 10?h without deactivation of the enzyme. Adsorption-desorption isotherms at 77?K before and after the adsorption were carried out, concluding that the adsorption of β-glucosidase was produced blocking the pore mouth, so that a part of the enzyme penetrates inside and another part stays outside the pore. 相似文献
18.
Marković ZS Dimitrić Marković JM Milenković D Filipović N 《Journal of molecular modeling》2011,17(10):2575-2584
Density functional theory calculations were performed to evaluate the antioxidant activity of baicalein. The conformational
behaviors of both the isolated and the aqueous-solvated species (simulated with the conductor-like polarizable continuum solvation
model) were analyzed at the M052X/6-311 + G(d,p) level. The most stable tautomers of various forms of baicalein displayed
three IHBs between O4 and OH5, O5 and OH6, and O6 and OH7. The most stable tautomer of the baicalein radical was obtained
by dehydrogenating the hydroxyl at C6, while the most stable anion tautomer was obtained by deprotonating the C7 hydroxyl
in gaseous and aqueous phases. The expected antioxidant activity of baicalein was explained by its ionization potentials (IPs)
and homolytic O–H bond dissociation enthalpies (BDEs), which were obtained via the UM052X optimization level of the corresponding
radical species. Heterolytic O–H bond cleavages (proton dissociation enthalpies, PDEs) were also computed. The calculated
IP, BDE, and PDE values suggested that one-step H-atom transfer, rather than sequential proton loss–electron transfer or electron
transfer–proton transfer, would be the most favorable mechanism for explaining the antioxidant activity of baicalein in the
gas phase and in nonpolar solvents. In aqueous solution, the SPLET mechanism was more important. 相似文献
19.
Postnatal development of β-galactosidase activity in the small intestine of the rat. Effect of adrenalectomy and diet 总被引:5,自引:5,他引:0
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1. β-Galactosidase activity was studied in homogenates of the proximal and distal thirds of the small intestine from adult and infant rats. o-Nitrophenyl β-d-galactoside served as the substrate. 2. Activity in suckling rats is highest in the distal part of the small intestine. 3. The pH optimum was 3·5 in the distal third of the small intestine in rats aged 5 and 15 days, whereas in the proximal third the maximum was not clearly defined. 4. Activity was higher in both thirds in newborn than in adult rats, expressed per wet wt. or per wt. of protein. In the proximal third activity continually decreases with age, whereas in the distal part there is a rise up to day 15 and then a sudden decrease. Total β-galactosidase activity changes very little in the proximal third during postnatal development; the greatest changes occur in the distal third. 5. Adrenalectomy performed on day 15 postnatally slows down the decrease in β-galactosidase activity, particularly in the distal part. 6. Feeding a lactose diet to infant rats from day 14 postnatally in the presence of the mother rat also slows down the decrease in β-galactosidase activity and this is not found with a diet containing glucose and galactose instead of lactose. 相似文献