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Author (up) Hall, A.C.; Stevens, R.J.N.; Betts, B.A.; Yeung, W.-Y.; Kelley, J.C.; Harrison, N.L. file  url
doi  openurl
  Title Subunit-dependent block by isoflurane of wild-type and mutant alpha(1)S270H GABA(A) receptor currents in Xenopus oocytes Type Journal Article
  Year 2005 Publication Neuroscience Letters Abbreviated Journal Neurosci Lett  
  Volume 382 Issue 3 Pages 332-337  
  Keywords Anesthetics, Inhalation/*pharmacology; Animals; Bicuculline/pharmacology; Dose-Response Relationship, Drug; Excitatory Postsynaptic Potentials/drug effects/physiology; GABA Antagonists/pharmacology; Isoflurane/*pharmacology; Membrane Potentials/*drug effects/physiology; Mutation; Oocytes/drug effects; Patch-Clamp Techniques; Picrotoxin/pharmacology; Protein Subunits/*drug effects/metabolism; Receptors, GABA-A/*drug effects/genetics/metabolism; Recombinant Proteins/drug effects; Substrate Specificity; Xenopus  
  Abstract The volatile anesthetic isoflurane both prolongs and reduces the amplitude of GABA-mediated inhibitory postsynaptic currents (IPSCs) recorded in neurons. To explore the latter effect, we investigated isoflurane-induced inhibition of steady-state desensitized GABA currents in Xenopus oocytes expressing wild-type alpha(1)beta(2), alpha(1)beta(2)gamma(2s), mutant alpha(1)(S270H)beta(2) (serine to histidine at residue 270) or alpha(1)(S270H)beta(2)gamma(2s) receptors. The alpha(1) serine 270 site in TM2 (second transmembrane domain of the subunit) is postulated as a binding site for some volatile agents and is critical for positive modulation of sub-maximal GABA responses by isoflurane. For all receptor combinations, at < or =0.6 mM isoflurane (< or =2 minimum alveolar concentration (MAC)) current inhibitions were not pronounced ( approximately 10%) with block reaching half-maximal levels at supraclinical concentrations ( approximately 2 mM isoflurane, 6 MAC). Comparisons with other GABA(A) receptor blockers indicated that isoflurane blocks in a similar manner to picrotoxin, possibly via the pore of the receptor. The extent of isoflurane-induced inhibition was significantly attenuated by inclusion of the gamma(2s)-subunit but was unaffected by introduction of the S270H mutation in the alpha(1)-subunit. In conclusion, isoflurane binds with low affinity and with subunit-specificity to an inhibitory site on the GABA(A) receptor that is distinct from the site that facilitates positive modulation at the extracellular end of the pore.  
  Call Number Serial 507  
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Author (up) Kohli, R.M.; Walsh, C.T.; Burkart, M.D. file  url
openurl 
  Title Biomimetic synthesis and optimization of cyclic peptide antibiotics Type Journal Article
  Year 2002 Publication Nature Abbreviated Journal Nature  
  Volume 418 Issue 6898 Pages 658-661  
  Keywords Amino Acid Sequence; Anti-Bacterial Agents/*biosynthesis/*chemical synthesis/pharmacology; Bacteria/drug effects; Biological Products/biosynthesis/chemical synthesis/pharmacology; Catalysis; Cyclization; Erythrocytes/drug effects; Humans; Hydrolysis; Microbial Sensitivity Tests; Molecular Mimicry; Molecular Sequence Data; Peptides, Cyclic/*biosynthesis/*chemical synthesis/pharmacology; Substrate Specificity; Thiolester Hydrolases/metabolism; Tyrocidine/analogs & derivatives/biosynthesis/chemical synthesis/pharmacology  
  Abstract Molecules in nature are often brought to a bioactive conformation by ring formation (macrocyclization). A recurrent theme in the enzymatic synthesis of macrocyclic compounds by non-ribosomal and polyketide synthetases is the tethering of activated linear intermediates through thioester linkages to carrier proteins, in a natural analogy to solid-phase synthesis. A terminal thioesterase domain of the synthetase catalyses release from the tether and cyclization. Here we show that an isolated thioesterase can catalyse the cyclization of linear peptides immobilized on a solid-phase support modified with a biomimetic linker, offering the possibility of merging natural-product biosynthesis with combinatorial solid-phase chemistry. Starting from the cyclic decapeptide antibiotic tyrocidine A, this chemoenzymatic approach allows us to diversify the linear peptide both to probe the enzymology of the macrocyclizing enzyme, TycC thioesterase, and to create a library of cyclic peptide antibiotic products. We have used this method to reveal natural-product analogues of potential therapeutic utility; these compounds have an increased preference for bacterial over eukaryotic membranes and an improved spectrum of activity against some common bacterial pathogens.  
  Call Number Serial 1894  
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Author (up) Van de Ven, W.J.; Creemers, J.W.; Roebroek, A.J. file  url
openurl 
  Title Furin: the prototype mammalian subtilisin-like proprotein-processing enzyme. Endoproteolytic cleavage at paired basic residues of proproteins of the eukaryotic secretory pathway Type Journal Article
  Year 1991 Publication Enzyme Abbreviated Journal Enzyme  
  Volume 45 Issue 5-6 Pages 257-270  
  Keywords Animals; Binding Sites; Catalysis; Cloning, Molecular; Drosophila melanogaster; Furin; Humans; Invertebrate Hormones/genetics/metabolism; Mice; Models, Molecular; Multigene Family; Protein Conformation; Protein Precursors/*metabolism; *Protein Processing, Post-Translational; Sequence Homology, Amino Acid; Substrate Specificity; Subtilisins/genetics/*metabolism  
  Abstract Furin, the translational product of the recently discovered fur gene, appears to be the first known mammalian member of the subtilisin family of serine proteases and the first known mammalian proprotein-processing enzyme with cleavage selectivity for paired basic amino acid residues. Structurally and functionally, it resembles the prohormone-processing enzyme, kexin (EC 3.4.21.61), which is encoded by the KEX2 gene of yeast Saccharomyces cerevisiae. Most likely, furin is primarily involved in the processing of precursors of proteins that are secreted via the constitutive secretory pathway. Here, we review the discovery of the fur gene and describe the isolation of cDNA clones corresponding to human and mouse fur and to two fur-like genes of Drosophila melanogaster, Dfur1 and Dfur2. We also compare the structural organization of the various deduced furin proteins to that of yeast kexin, and of other members of the subtilisin family of serine proteases. Furthermore, the biosynthesis of biologically active human and mouse furin is evaluated. Finally, the cleavage specificity for paired basic amino acid residues of human and mouse furin is demonstrated by the correct processing of the precursor for von Willebrand factor.  
  Call Number Serial 524  
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Author (up) Wilcock, B.C.; Uno, B.E.; Bromann, G.L.; Clark, M.J.; Anderson, T.M.; Burke, M.D. file  url
openurl 
  Title Electronic tuning of site-selectivity Type Journal Article
  Year 2012 Publication Nature Chemistry Abbreviated Journal Nat Chem  
  Volume 4 Issue 12 Pages 996-1003  
  Keywords *Acylation; Benzoates/chemistry; Binding Sites; *Electronics; Ergosterol/chemistry; Molecular Structure; Phenazopyridine/chemistry; Substrate Specificity  
  Abstract Site-selective functionalizations of complex small molecules can generate targeted derivatives with exceptional step efficiency, but general strategies for maximizing selectivity in this context are rare. Here, we report that site-selectivity can be tuned by simply modifying the electronic nature of the reagents. A Hammett analysis is consistent with linking this phenomenon to the Hammond postulate: electronic tuning to a more product-like transition state amplifies site-discriminating interactions between a reagent and its substrate. This strategy transformed a minimally site-selective acylation reaction into a highly selective and thus preparatively useful one. Electronic tuning of both an acylpyridinium donor and its carboxylate counterion further promoted site-divergent functionalizations. With these advances, we achieve a range of modifications to just one of the many hydroxyl groups appended to the ion channel-forming natural product amphotericin B. Thus, electronic tuning of reagents represents an effective strategy for discovering and optimizing site-selective functionalization reactions.  
  Call Number Serial 1606  
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