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1.
Chris H. Hill Agnete H. Viuff Samantha J. Spratley Stéphane Salamone Stig H. Christensen Randy J. Read Nigel W. Moriarty Henrik H. Jensen Janet E. Deane 《Chemical science》2015,6(5):3075-3086
Krabbe disease is a devastating neurodegenerative disorder characterized by rapid demyelination of nerve fibers. This disease is caused by defects in the lysosomal enzyme β-galactocerebrosidase (GALC), which hydrolyzes the terminal galactose from glycosphingolipids. These lipids are essential components of eukaryotic cell membranes: substrates of GALC include galactocerebroside, the primary lipid component of myelin, and psychosine, a cytotoxic metabolite. Mutations of GALC that cause misfolding of the protein may be responsive to pharmacological chaperone therapy (PCT), whereby small molecules are used to stabilize these mutant proteins, thus correcting trafficking defects and increasing residual catabolic activity in cells. Here we describe a new approach for the synthesis of galacto-configured azasugars and the characterization of their interaction with GALC using biophysical, biochemical and crystallographic methods. We identify that the global stabilization of GALC conferred by azasugar derivatives, measured by fluorescence-based thermal shift assays, is directly related to their binding affinity, measured by enzyme inhibition. X-ray crystal structures of these molecules bound in the GALC active site reveal which residues participate in stabilizing interactions, show how potency is achieved and illustrate the penalties of aza/iminosugar ring distortion. The structure–activity relationships described here identify the key physical properties required of pharmacological chaperones for Krabbe disease and highlight the potential of azasugars as stabilizing agents for future enzyme replacement therapies. This work lays the foundation for new drug-based treatments of Krabbe disease. 相似文献
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The graph-theoretic operation of rooted subtree prune and regraft is increasingly being used as a tool for understanding and modelling reticulation events in evolutionary biology. In this paper, we show that computing the rooted subtree prune and regraft distance between two rooted binary phylogenetic trees on the same label set is NP-hard. This resolves a longstanding open problem. Furthermore, we show that this distance is fixed parameter tractable when parameterised by the distance between the two trees.Received March 16, 2004 相似文献
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Magnus B. Landstad 《Journal of Functional Analysis》2002,191(2):211-223
We study properties of C*-algebraic deformations of homogeneous spaces G/Γ which are equivariant in the sense that they preserve the natural action of G by left translation. The center is shown to be isomorphic to C(G/G0ρ) for a certain subgroup G0ρ of G, and there is a 1-1 correspondence between normalised traces and probability measures on G/G0ρ. This makes it possible to represent the deformed algebra as operators over L2(G/Γ). Applications to K-theory are also mentioned. 相似文献
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T Christensen E B Jensen F Junker H Dalb?ge F Abildgaard J J Led 《Acta chemica Scandinavica (Copenhagen, Denmark : 1989)》1992,46(1):97-99
Biosynthetic human growth hormone specifically 13C-labelled in the carbonyl positions of all 26 leucine residues has been obtained by recombinant DNA techniques using 13C-labelled leucine and an E. coli strain that requires leucine. It is shown that, on the whole, the labelling is specific with no significant mislabelling as would have been the case had the 13C-labelled leucine been metabolized. 相似文献
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A central problem that arises in evolutionary biology is that of displaying partitions of subsets of a finite set X on a tree whose vertices are partially labelled with the elements of X. Such a tree is called an X-tree and, for a collection of partitions of subsets of X, characterisations for the existence and uniqueness of an X-tree that displays have been previously given in terms of chordal graphs. In this paper, we obtain two closely related characterisations also in terms of chordal graphs. The first describes when identifies an X-tree, and the second describes when a compatible subset of is of maximum size. 相似文献
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Banach frames and atomic decompositions are sequences that have basis-like properties but which need not be bases. In particular, they allow elements of a Banach space to be written as linear combinations of the frame or atomic decomposition elements in a stable manner. In this paper we prove several functional — analytic properties of these decompositions, and show how these properties apply to Gabor and wavelet systems. We first prove that frames and atomic decompositions are stable under small perturbations. This is inspired by corresponding classical perturbation results for bases, including the Paley — Wiener basis stability criteria and the perturbation theorem el kato. We introduce new and weaker conditions which ensure the desired stability. We then prove quality properties of atomic decompositions and consider some consequences for Hilbert frames. Finally, we demonstrate how our results apply in the practical case of Gabor systems in weighted L2 spaces. Such systems can form atomic decompositions for L2w(IR), but cannot form Hilbert frames but L2w(IR) unless the weight is trivial. 相似文献
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Conclusions Prototropic rearrangement in the phenyl radical cannot proceed under ordinary conditions in view of the high energy barrier.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 2, pp. 460–462, February, 1979. 相似文献