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921.
Front Cover: A Possible Path to Prebiotic Peptides Involving Silica and Hydroxy Acid‐Mediated Amide Bond Formation (ChemBioChem 18/2018) 下载免费PDF全文
922.
Thioether Analogues of Disulfide‐Bridged Cyclic Peptides Targeting Death Receptor 5: Conformational Analysis,Dimerisation and Consequences for Receptor Activation 下载免费PDF全文
Dr. Karolina Pulka‐Ziach Dr. Valeria Pavet Neila Chekkat Dr. Karine Estieu‐Gionnet Roman Rohac Dr. Marie‐Charlotte Lechner Dr. Cristian R. Smulski Dr. Gabrielle Zeder‐Lutz Dr. Danièle Altschuh Dr. Hinrich Gronemeyer Prof. Dr. Sylvie Fournel Dr. Benoit Odaert Dr. Gilles Guichard 《Chembiochem : a European journal of chemical biology》2015,16(2):293-301
Cyclic peptides containing redox‐stable thioether bridges might provide a useful alternative to disulfide‐bridged bioactive peptides. We report the effect of replacing the disulfide bridge with a lanthionine linkage in a 16‐mer cyclic peptide that binds to death receptor 5 (DR5, TRAIL‐R2). Upon covalent oligomerisation, the disulfide‐bridged peptide has previously shown similar behaviour to that of TNF‐related apoptosis inducing ligand (TRAIL), by selectively triggering the DR5 cell death pathway. The structural and biological properties of the DR5‐binding peptide and its desulfurised analogue were compared. Surface plasmon resonance (SPR) data suggest that these peptides bind DR5 with comparable affinities. The same holds true for dimeric versions of these peptides: the thioether is able to induce DR5‐mediated apoptosis of BJAB lymphoma and tumorigenic BJELR cells, albeit to a slightly lower extent compared to its disulfide homologue. NMR analysis revealed subtle variation in the conformations of the two peptides and suggests that the thioether peptide is slightly less folded than its disulfide homologue. These observations could account for the different capability of the two dimers to cluster DR5 receptors on the cell surface and to trigger apoptosis. Nevertheless, our results suggest that the thioether peptide is a potential candidate for evaluation in animal models. 相似文献
923.
Chemical Synthesis of A Pore‐Forming Antimicrobial Protein,Caenopore‐5, by Using Native Chemical Ligation at a Glu‐Cys Site 下载免费PDF全文
Karima Medini Dr. Paul W. R. Harris Kiel Hards Dr. Andrew J. Dingley Gregory M. Cook Prof. Margaret A. Brimble 《Chembiochem : a European journal of chemical biology》2015,16(2):328-336
The 2014 report from the World Health Organization (WHO) on antimicrobial resistance revealed an alarming rise in antibiotic resistance all around the world. Unlike classical antibiotics, with the exception of a few species, no acquired resistance towards antimicrobial peptides (AMPs) has been reported. Therefore, AMPs represent leads for the development of novel antibiotics. Caenopore‐5 is constitutively expressed in the intestine of the nematode Caenorhabditis elegans and is a pore‐forming AMP. The protein (82 amino acids) was successfully synthesised by using Boc solid‐phase peptide synthesis and native chemical ligation. No γ‐linked by‐product was observed despite the use of a C‐terminal Glu‐thioester. The folding of the synthetic protein was confirmed by 1H NMR spectroscopy and circular dichroism and compared with data recorded for recombinant caenopore‐5. The permeabilisation activities of the protein and of shortened analogues were evaluated. 相似文献
924.
Dr. Bettina Sommer Dr. Holger von Moeller Martina Haack Dr. Farah Qoura Clemens Langner Dr. Gleb Bourenkov Dr. Daniel Garbe Dr. Bernhard Loll Prof. Dr. Thomas Brück 《Chembiochem : a European journal of chemical biology》2015,16(1):110-118
Isobutanol is deemed to be a next‐generation biofuel and a renewable platform chemical. 1 Non‐natural biosynthetic pathways for isobutanol production have been implemented in cell‐based and in vitro systems with Bacillus subtilis acetolactate synthase (AlsS) as key biocatalyst. 2 – 6 AlsS catalyzes the condensation of two pyruvate molecules to acetolactate with thiamine diphosphate and Mg2+ as cofactors. AlsS also catalyzes the conversion of 2‐ketoisovalerate into isobutyraldehyde, the immediate precursor of isobutanol. Our phylogenetic analysis suggests that the ALS enzyme family forms a distinct subgroup of ThDP‐dependent enzymes. To unravel catalytically relevant structure‐function relationships, we solved the AlsS crystal structure at 2.3 Å in the presence of ThDP, Mg2+ and in a transition state with a 2‐lactyl moiety bound to ThDP. We supplemented our structural data by point mutations in the active site to identify catalytically important residues. 相似文献
925.
Rachel Anne P. Valenzuela Scott R. Suter Alexi A. Ball‐Jones Dr. José M. Ibarra‐Soza Yuxuan Zheng Prof. Dr. Peter A. Beal 《Chembiochem : a European journal of chemical biology》2015,16(2):262-267
Immune stimulation triggered by siRNAs is one of the major challenges in the development of safe RNAi‐based therapeutics. Within an immunostimulatory siRNA sequence, this hurdle is commonly addressed by using ribose modifications (e.g., 2′‐OMe or 2′‐F), which results in decreased cytokine production. However, as immune stimulation by siRNAs is a sequence‐dependent phenomenon, recognition of the nucleobases by the trigger receptor(s) is also likely. Here, we use the recently published crystal structures of Toll‐like receptor 8 (TLR8) bound to small‐molecule agonists to generate computational models for ribonucleotide binding by this immune receptor. Our modeling suggested that modification of either the Watson–Crick or Hoogsteen face of adenosine would disrupt nucleotide/TLR8 interactions. We employed chemical synthesis to alter either the Watson–Crick or Hoogsteen face of adenosine and evaluated the effect of these modifications in an siRNA guide strand by measuring the immunostimulatory and RNA interference properties. For the siRNA guide strand tested, we found that modifying the Watson–Crick face is generally more effective at blocking TNFα production in human peripheral blood mononuclear cells (PBMCs) than modification at the Hoogsteen edge. We also observed that modifications near the 5′‐end were more effective at blocking cytokine production than those placed at the 3′‐end. This work advances our understanding of how chemical modifications can be used to optimize siRNA performance. 相似文献
926.
Hydrogen‐Bonding‐Driven Enantioselective Resolution against the Kazlauskas Rule To Afford γ‐Amino Alcohols by Candida rugosa Lipase 下载免费PDF全文
Bora Min Jeemin Park Yong‐Kyun Sim Dr. Suhyun Jung Seong‐Ho Kim Dr. Jae Kwang Song Dr. Bum Tae Kim Prof. Sang Youn Park Prof. Jaesook Yun Prof. Seongsoon Park Dr. Hyuk Lee 《Chembiochem : a European journal of chemical biology》2015,16(1):77-82
Most lipases resolve secondary alcohols in accordance with the “Kazlauskas rule” to give the R enantiomers. In a similar manner to other lipases, Candida rugosa lipase (CRL) exhibits R enantioselectivity towards heptan‐2‐ol, although the enantiomeric ratio (E) is low (E=1.6). However, unexpected enantioselectivity (i.e., S enantioselectivity, E=58) of CRL towards 4‐(tert‐butoxycarbonylamino)butan‐2‐ol, which has a similar chain length to heptan‐2‐ol, has been observed. To develop a deeper understanding of the molecular basis for this unusual enantioselectivity, we have conducted a series of molecular modeling and substrate engineering experiments. The results of these computational and experimental analyses indicated that a hydrogen bond between the Ser450 residue and the nitrogen atom of the carbamate group is critical to stabilize the transition state of the S enantiomer. 相似文献
927.
Applying γ‐Substituted Prolines in the Foldon Peptide: Polarity Contradicts Preorganization 下载免费PDF全文
Dennis Dietz Dr. Vladimir Kubyshkin Prof. Dr. Nediljko Budisa 《Chembiochem : a European journal of chemical biology》2015,16(3):403-406
Rational choice of chemical modifications to proline residues allows the preorganization principle to be exploited for more stable assembly of the foldon domain as a tag for trimerization. With systematic knowledge of how chemical and steric variations of the ring substituents affect the relative stabilities of exo and endo puckers, the preorganization principle should then be usable in biotechnologically synthesized foldon mutants and applicable for protein tagging elsewhere. 相似文献
928.
Dr. Thomas Hauch Fenger Prof. Dr. Harry Brumer 《Chembiochem : a European journal of chemical biology》2015,16(4):575-583
A series of N‐bromoacetylglycosylamines and bromoketone C‐glycosides were synthesised from complex xyloglucan oligosaccharide (XyGO) scaffolds as specific active‐site affinity labels for endo‐xyloglucanases. Compounds based on XXXG (Xyl3Glc4) and XLLG (Xyl3Glc4Gal2) oligosaccharides exhibited strikingly higher affinities and higher rates of irreversible inhibition than known cellobiosyl and new lactosyl disaccharide congeners when tested with endo‐xyloglucanases from two distinct glycoside hydrolase (GH) families. Intact‐protein mass spectrometry indicated that inactivation with XyGO derivatives generally resulted in a 1:1 labelling stoichiometry. Together, these results indicate that XyGO‐based affinity reagents have significant potential as inhibitors and proteomic reagents for the identification and analysis of diverse xyloglucan‐active enzymes in nature, to facilitate industrial enzyme applications. 相似文献
929.
Advanced Mutasynthesis Studies on the Natural α‐Pyrone Antibiotic Myxopyronin from Myxococcus fulvus 下载免费PDF全文
J. Henning Sahner Hilda Sucipto Dr. Silke C. Wenzel Dr. Matthias Groh Prof. Dr. Rolf W. Hartmann Prof. Dr. Rolf Müller 《Chembiochem : a European journal of chemical biology》2015,16(6):946-953
Myxopyronin is a natural α‐pyrone antibiotic from the soil bacterium Myxococcus fulvus Mx f50. Myxopyronin inhibits bacterial RNA polymerase (RNAP) by binding to a part of the enzyme not targeted by the clinically used rifamycins. This mode of action makes myxopyronins promising molecules for the development of novel broad‐spectrum antibacterials. We describe the derivatization of myxopyronins by an advanced mutasynthesis approach as a first step towards this goal. Site‐directed mutagenesis of the biosynthetic machinery was used to block myxopyronin biosynthesis at different stages. The resulting mutants were fed with diverse precursors that mimic the biosynthetic intermediates to restore production. Mutasynthon incorporation and production of novel myxopyronin derivatives were analyzed by HPLC‐MS/MS. This work sets the stage for accessing numerous myxopyronin derivatives, thus significantly expanding the chemical space of f α‐pyrone antibiotics. 相似文献
930.
Dr. Teshome Aboye Yuting Kuang Prof. Dr. Nouri Neamati Prof. Dr. Julio A. Camarero 《Chembiochem : a European journal of chemical biology》2015,16(5):827-833
We report here the first rapid parallel production of bioactive folded cyclotides by using Fmoc‐based solid‐phase peptide synthesis in combination with a “tea‐bag” approach. Using this approach, we efficiently synthesized 15 analogues of the CXCR4 antagonist cyclotide MCo‐CVX‐5c. Cyclotides were synthesized in a single‐pot, cyclization/folding reaction in the presence of reduced glutathione. Natively folded cyclotides were quickly purified from the cyclization/folding crude mixture by activated thiol Sepharose‐based chromatography. The different folded cyclotide analogues were then tested for their ability to inhibit the CXCR4 receptor in a cell‐based assay. The results indicated that this approach can be used for the efficient chemical synthesis of libraries of cyclotides with improved biological properties that can be easily interfaced with solution or cell‐based assays for rapid screening. 相似文献