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131.
132.
Molecular targeting of inhibitor of apoptosis proteins based on small molecule mimics of natural binding partners 总被引:3,自引:0,他引:3
Kipp RA Case MA Wist AD Cresson CM Carrell M Griner E Wiita A Albiniak PA Chai J Shi Y Semmelhack MF McLendon GL 《Biochemistry》2002,41(23):7344-7349
An assay based on a solvent-sensitive fluorogenic dye molecule, badan, is used to test the binding affinity of a library of tetrapeptide molecules for the BIR3 (baculovirus IAP repeat) domain of XIAP (X-linked inhibitor of apoptosis protein). The fluorophore is attached to a tetrapeptide, Ala-Val-Pro-Cys-NH(2), through a thiol linkage and, upon binding to XIAP, undergoes a solvatochromic shift in fluorescence emission. When a molecule (e.g., a natural protein known to bind to XIAP or a tetrapeptide mimic) displaces the dye, the emission shifts back to the spectrum observed in water. As emission intensity is related to the binding of the tetrapeptide, the intensity can be used to determine the equilibrium constant, K, for the displacement of the dye by the tetrapeptide. The results permit residue-specific analysis of the interaction. Furthermore, we show that hydrophobic effects in the fourth position are general and can effectively increase overall affinity. 相似文献
133.
In the frame of the activities carried out to exploit Sicilian local cultivars of brassicas, we focused our attention on some of the potential health compounds of various local cruciferous crops. These compounds are of interest to improve the quality of the produce with the aim to develop new cultivars capable of providing functional foods able to prevent disease. In this context, we surveyed for the presence of specific glucosinolates in local cultivars of broccoli, cauliflower, kale, and in some wild species widespread in Sicily, using as control various commercial cultivars. Glucosinolate composition varied extensively among species and crops of the same species, such as cauliflower, broccoli and kale. Cultivar variation for glucosinolate profile was also observed for some crops. For example, Sicilian cultivars of cauliflower possessing colored curds displayed a high content of glucosinolates, glucoraphanin in particular, compared to white curd commercial cultivars. Also some wild species had a high content of other glucosinolates. 相似文献
134.
DCMU inhibits in vivo nitrate reduction in illuminated barley (C(3)) leaves but not in maize (C(4)): a new mechanism for the role of light? 总被引:1,自引:0,他引:1
The leaves of C(4) plants possess a superior metabolic efficiency not only in terms of photosynthetic carbon assimilation, but also in terms of inorganic nitrogen assimilation, when compared to C(3)plants. In vivo nitrate assimilation efficiency of leaves is dependent on light, but the obligatory presence of light has been debated and its role remains confounded. This problem has not been addressed from the standpoint of the C(3) vs. C(4) nature of the species investigated, which may actually hold the key to resolve the controversy. Here, we present the first report providing evidence for differential photo-regulation of leaf nitrate reduction in barley ( Hordeum vulgare L.) vs. maize ( Zea mays L.) plants, which may help explain the superior nitrogen-use efficiency (and hence superior productivity) of maize plants. The novel finding that carbohydrate-depleted maize leaves were able to reduce nitrate when photosynthesis was inhibited by 3-(3',4'-dichlorophenyl)-1,1'-dimethylurea (DCMU) in the presence of light, raises a very important question about the possibilities of a new photo-regulatory mechanism for supporting nitrate reduction in maize leaves operating independently of photosynthetic carbon dioxide fixation. On the other hand, leaves of barley could not carry out any in vivo nitrate assimilation, whatsoever, under these conditions. We find another fundamental difference between the two species in terms of differential regulation of nitrate reductase (NR; EC 1.6.6.1). In barley leaves, NR activity and activation state remained unaffected due to DCMU, but in sharp contrast, both were appreciably upregulated in maize. Collectively, the results indicate that enzyme capacity is not limiting for nitrate reduction in leaves, as the NR activity was higher in barley than in maize. The maize leaves may have had a selective advantage due to C(4) morphology/metabolism in terms of maintaining a better reductant/carbon skeleton supply for nitrate reduction. 相似文献
135.
Pathak R Pant CS Shaw AK Bhaduri AP Gaikwad AN Sinha S Srivastava A Srivastava KK Chaturvedi V Srivastava R Srivastava BS 《Bioorganic & medicinal chemistry》2002,10(10):3187-3196
A series of acyclic deoxy carbohydrate derivatives from easily available carbohydrate enals 1, 2, 3 or 5 were prepared involving the Baylis-Hillman reaction. These newly formed carbohydrate based Baylis-Hillman adducts and their amino derivatives were evaluated for their antimycobacterial activity against Mycobacterium tuberculosis H(37)R(v). Among the compounds evaluated for their antimycobacterial activity, compound (10) showed the desired activity in the range of 3.125 microg/mL. 相似文献
136.
Pryor DE O'Brate A Bilcer G Díaz JF Wang Y Wang Y Kabaki M Jung MK Andreu JM Ghosh AK Giannakakou P Hamel E 《Biochemistry》2002,41(29):9109-9115
Laulimalide is a cytotoxic natural product that stabilizes microtubules. The compound enhances tubulin assembly, and laulimalide is quantitatively comparable to paclitaxel in its effects on the reaction. Laulimalide is also active in P-glycoprotein overexpressing cells, while isolaulimalide, a congener without the drug's epoxide moiety, was reported to have negligible cytotoxic and biochemical activity [Mooberry et al. (1999) Cancer Res. 59, 653-660]. We report here that laulimalide binds at a site on tubulin polymer that is distinct from the taxoid site. We found that laulimalide, while as active as paclitaxel, epothilone A, and eleutherobin in promoting the assembly of cold-stable microtubules, was unable to inhibit the binding of radiolabeled paclitaxel or of 7-O-[N-(2,7-difluoro-4'-fluoresceincarbonyl)-L-alanyl]paclitaxel, a fluorescent paclitaxel derivative, to tubulin. Confirming this observation, we demonstrated that microtubules formed in the presence of both laulimalide and paclitaxel contained near-molar quantities, relative to tubulin, of both drugs. Laulimalide was active against cell lines resistant to paclitaxel or epothilones A and B on the basis of mutations in the M40 human beta-tubulin gene. We also report that a laulimalide analogue lacking the epoxide moiety, while less active than laulimalide in biochemical and cellular systems, is probably more active than isolaulimalide. Further exploration of the role of the epoxide in the interaction of laulimalide with tubulin is therefore justified. 相似文献
137.
Crystal structure of memapsin 2 (beta-secretase) in complex with an inhibitor OM00-3 总被引:3,自引:0,他引:3
The structure of the catalytic domain of human memapsin 2 bound to an inhibitor OM00-3 (Glu-Leu-Asp-LeuAla-Val-Glu-Phe, K(i) = 0.3 nM, the asterisk denotes the hydroxyethylene transition-state isostere) has been determined at 2.1 A resolution. Uniquely defined in the structure are the locations of S(3)' and S(4)' subsites, which were not identified in the previous structure of memapsin 2 in complex with the inhibitor OM99-2 (Glu-Val-Asn-LeuAla-Ala-Glu-Phe, K(i) = 1 nM). Different binding modes for the P(2) and P(4) side chains are also observed. These new structural elements are useful for the design of new inhibitors. The structural and kinetic data indicate that the replacement of the P(2)' alanine in OM99-2 with a valine in OM00-3 stabilizes the binding of P(3)' and P(4)'. 相似文献
138.
We report that the monolayer phase diagram for binary mixtures of dimyristoylphosphatidylethanolamine (DMPE) and dihydrocholesterol (DChol) is largely unchanged when each phospholipid molecule is replaced by two myristic acid (MA) molecules or various mixtures of the lysophospholipid and myristic acid. The corresponding phase diagrams all show the formation of "condensed complexes" of DChol and lipid. The condensed complex stoichiometry is thus largely determined by the C14 fatty acid acyl chains, in this case about 4-4.6 per DChol molecule. 相似文献
139.
Delivery of nucleic acid into mammalian cells by anthrax toxin 总被引:1,自引:0,他引:1
Gaur R Gupta PK Goyal A Wels W Singh Y 《Biochemical and biophysical research communications》2002,297(5):1121-1127
Gene delivery vehicles based on receptor-mediated endocytosis offer an attractive long-term solution as they might overcome the limitations of toxicity and cargo capacity inherent to many viral gene delivery systems. The protective antigen component of anthrax toxin bind to specific receptors and deliver lethal factor or edema factor into the cytosol of mammalian cells. The N-terminal 254 amino acids of LF (LF(1-254)) binds to PA and, when fused to heterologous proteins, delivers such proteins into the cytosol. However, so far no attempt has been made to use the anthrax toxin system for the intracellular delivery of DNA. In the present study, LF(1-254) of anthrax toxin was fused to the DNA-binding domain of GAL4 protein. The fusion protein (LF(254)-GAL4DBD) showed both PA binding as well as DNA-binding activity in solution. The complex of fusion protein with plasmid DNA containing a reporter gene (luciferase or green fluorescent protein) along with PA delivered plasmid DNA into the cytosol of COS-1 cells. These results suggest that anthrax toxin components can be used as a non-viral system for the efficient delivery of DNA into the cytosol of mammalian cells. 相似文献
140.