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Chembiochem: a European Journal of Chemical Biology

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https://www.readbyqxmd.com/read/28432776/exploring-non-obvious-hydrophobic-binding-pockets-on-protein-surfaces-increasing-affinities-in-peptide-protein-interactions
#1
Lars Baltzer, Aleksandra Balliu
A 42-residue polypeptide conjugated to a small organic molecule capable of targeting the phosphorylated side chain of Ser-15 was shown to bind glycogen phosphorylase a (GPa) with a KD of 280 nM. The replacement of hydrophobic amino acids by Ala reduced affinities, whereas the incorporation of L-2-aminooctanoic acid (Aoc) increased affinities. Replacing Nle-5, Ile-9 and Leu-12 by Aoc reduced the KD from 280 nM to 27 nM. Downsizing the 42-mer to an 11-mer gave rise to an order of magnitude lower affinity for GPa but the 11-mer where Nle-5, Ile-9 and Leu-12 were replaced by Aoc showed a KD of 550 nM, comparable to that of the parent 42-mer...
April 22, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28430394/structure-based-design-of-a-new-scaffold-for-cell-penetrating-peptidic-inhibitors-of-the-histone-demethylase-phf8
#2
Jerzy Dorosz, Lars Olsen, Signe Teuber Seger, Cornelia Steinhauer, Giorgos Bouras, Charlotte Helgstrand, Anders Wiuf, Michael Gajhede
The histone demethylase PHF8 catalyzes demethylation of mono- and di-methylated lysine 9 on histone H3 (H3K9me1/2) and is a transcriptional activator involved in development and cancer. Affinity and specificity of PHF8 towards H3K9me2 substrate is affected by interaction with both the catalytic domain and a PHD reader domain. The latter specifically recognizes tri-methylated lysine 4 on histone H3. A fragment of the histone H3 tail with tri-methylated lysine 4 was used as template for structure based design of a cyclic, cell-penetrating peptide that exhibits micromolar binding affinity to PHF8 in biochemical assays...
April 21, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28426168/walking-a-fine-line-with-sucrose-phosphorylase-efficient-single-step-biocatalytic-production-of-l-ascorbic-acid-2-glucoside-from-sucrose
#3
Rama Krishna Gudiminchi, Bernd Nidetzky
The 2-O-α-D-glucoside of L-ascorbic acid (AA-2G) is a highly stabilized form of vitamin C, with important applications in cosmetics, foods and pharmaceuticals. Sucrose would be an ideal substrate for AA-2G synthesis, but it cannot be used lacking a suitable transglycosidase. We show that in a narrow pH window with sharp optimum at pH 5.2, select sucrose phosphorylases catalyzed 2-O-α-glucosylation of L-ascorbic acid from sucrose with high efficiency and perfect site-selectivity. Optimized synthesis with the enzyme from Bifidobacterium longum at 40°C gave a concentrated product solution (155 g/L; 460 mM) from which pure AA-2G was recovered in ∼50% overall yield, so providing the basis for an advanced production process...
April 20, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28426149/click-chemistry-mediated-rapid-microbubble-catching-for-acute-thrombus-ultrasound-molecular-imaging
#4
Tuantuan Wang, Chuxiao Yuan, Bingyang Dai, Yang Liu, Mingxi Li, Zhenqiang Feng, Qing Jiang, Zhihong Xu, Ningwei Zhao, Ning Gu, Fang Yang
Bioorthogonal coupling chemistry has been studied as one significant advantage for molecular imaging as it offers rapid, efficient, and strong binding, which may also benefit in stability, production, and chemical conjugation. The inverse-electron-demand Diels-Alder reaction between s-tetrazine and trans-cyclooctene (TCO) is an example of a highly selective and rapid bioorthogonal coupling reaction to be used successfully to prepare targeted molecular imaging probes. Herein, based on a two-step pretargeting bioorthogonal chemistry, we report a fast and reliable highly sensitive approach to achieve activated-platelet-specific CD62p targeted thrombus ultrasound molecular imaging...
April 20, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28426139/engineering-a-promiscuous-tautomerase-into-a-more-efficient-aldolase-for-self-condensations-of-linear-aliphatic-aldehydes
#5
Mehran Rahimi, Jan Ytzen van der Meer, Edzard Geertsema, Gerrit Jan Poelarends
4-Oxalocrotonate tautomerase (4-OT) from P. putida mt-2 takes part in a catabolic pathway for aromatic hydrocarbons, where it catalyzes the conversion of 2-hydroxyhexa-2,4-dienedioate into 2-oxohexa-3-enedioate. This tautomerase can also promiscuously catalyze carbon-carbon bond-forming reactions, including various types of aldol reactions, utilizing its N-terminal proline as a key catalytic residue. Here, we have used a systematic mutagenesis strategy to identify two 'hotspot' positions in 4-OT (Met-45 and Phe-50) at which single mutations give a marked improvement in aldolase activity for the self-condensation of propanal...
April 20, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28425671/activity-based-probes-for-hect-e3-ubiquitin-ligases
#6
Robert Byrne, Thomas Mund, Julien Licchesi
Activity-Based Probes (ABPs) have been used to dissect the biochemical/structural properties and cellular functions of deubiquitinases. However, their utility in studying cysteine-based E3 ubiquitin ligases has so far been limited. In this study, we evaluate the use of Ubiquitin-ABPs (Ub-VME and Ub-PA) and a novel set of E2~Ub-ABPs, on a panel of HECT E3 ubiquitin ligases. Our in vitro data show that ubiquitin-ABPs can label HECT domains and we also provide the first evidence that, in addition to the RBR E3 ubiquitin ligase Parkin, E2~Ub-ABPs can also label the catalytic HECT domain of NEDD4, UBE3C and HECTD1...
April 20, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28425643/chemical-activation-in-blood-serum-and-human-cell-culture-improved-ruthenium-complex-for-catalytic-uncaging-of-alloc-protected-amines
#7
Timo Völker, Eric Meggers
Chemical as opposed to light-induced activation of caged molecules is a rapidly advancing approach to trigger biological processes. We recently introduced a ruthenium-catalyzed release of alloc-protected amines in human cells (Angew. Chem. Int. Ed. 2006, 45, 5645 and 2014, 53, 10536). A restriction of this and all other methods reported to date is a limited lifetime of the catalyst which hampers meaningful applications. In this study we address this problem with the development of a new generation of ruthenium complexes for the uncaging of alloc-protected amines with superior catalytic activity...
April 20, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28425166/uranyl-photocleavage-of-phosphopeptides-yields-truncated-c-terminally-amidated-peptide-products
#8
Rasmus Linde Bang Elnegaard, Niels Erik Møllegaard, Qiang Zhang, Frank Kjeldsen, Thomas J D Jørgensen
The uranyl ion (UO22+) binds phosphopeptides with high affinity and when irradiated with UV-light, it cleaves the peptide backbone. In this study, high mass accuracy tandem mass spectrometry and enzymatic assays were used to characterize the photocleavage products resulting from the uranyl photocleavage reaction of a tetraphosphorylated β-casein model peptide. We show that the primary photocleavage products of the uranyl catalysed reaction are C-terminally amidated. This observation could be of great interest to pharmaceutical industry, as efficient peptide amidating reactions are one of the top challenges of green pharmaceutical chemistry...
April 20, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28423240/biochemical-cellular-physiological-and-pathological-consequences-of-human-loss-of-n-glycolylneuraminic-acid
#9
Jonathan Okerblom, Ajit Varki
About 2-3 million years ago, Alu-mediated deletion of a critical exon in the CMAH gene became fixed in the hominin lineage ancestral to humans, possibly through a stepwise process of selection by pathogen targeting of the CMAH product (the sialic acid Neu5Gc), followed by reproductive isolation via female anti-Neu5Gc antibodies. Loss of CMAH has occurred independently in some other lineages, but is functionally intact in Old World primates, including our closest relatives, the chimpanzees. While the biophysical and biochemical ramifications of losing tens of millions of Neu5Gc hydroxyl groups at most cell surfaces remains poorly understood, there are multi-scale effects functionally relevant to both sides of the host-pathogen interface...
April 19, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28422419/carbohydrate-analog-microarrays-for-identification-of-lectin-selective-ligands
#10
Injae Shin, Ji Young Hyun, Cheol Wan Park, Yanna Liu, Daeun Kwon, Seong-Hyun Park, Sungjin Park, Jaeyoung Pai
Fifty five mono- and disaccharide analogs were prepared and used for construction of microarrays to uncover lectin-selective ligands. The microarray study shows that two disaccharide analogs, 28' and 44', selectively bind to S. tuberosum lectin (STL) and wheat germ agglutinin (WGA), respectively. The results of cell studies also indicate that 28' and 44' selectively block binding of STL and WGA to mammalian cells unlike a natural ligand LacNAc that suppresses binding of both STL and WGA to cells.
April 19, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28422400/sequence-specific-covalent-capture-coupled-with-high-contrast-nanopore-detection-of-a-disease-derived-nucleic-acid-sequence
#11
Maryam Imani Nejad, Ruicheng Shi, Xinyue Zhang, Li-Qun Gu, Kent S Gates
Hybridization-based methods for the detection of nucleic acid sequences are important in research and medicine. Short probes provide sequence specificity, but may not provide a durable signal. Sequence-specific covalent cross-link formation can anchor probes to target DNA and also may provide an additional layer of target selectivity. Here we develop a new cross-linking reaction for the covalent capture of specific nucleic acid sequences. This process involves reaction of an abasic site in a probe strand with an adenine residue in the target strand and was used for the detection of a disease-relevant T→A mutation at position 1799 of the human BRAF kinase gene sequence...
April 19, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28421720/enantioselective-organocatalytic-synthesis-of-a-secoyohimbane-inspired-compound-collection-with-neuritogenic-activity
#12
Herbert Waldmann, Tim Förster, Sara Lopéz-Tosco, Slava Ziegler, Andrey P Antonchick
Natural products provide evolutionary validated core structures inspiring the synthesis of new compound collections endowed with neurite growth-promoting activity. Rhynchophylline is the major component of Uncaria species which has been used to treat neurological diseases in Chinese traditional medicine. According to the structure of this spirocyclic secoyohimbane alkaloid, we developed a highly enantioselective and efficient organocatalyzed synthesis method to provide the tetracyclic secoyohimbane scaffold incorporating a quaternary and three tertiary stereogenic centers in a one-pot multistep reaction sequence...
April 19, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28421660/biocatalytic-asymmetric-phosphorylation-catalyzed-by-recombinant-glycerate-2-kinase
#13
Norman Hardt, Birhanu M Kinfu, Jennifer Chow, Wolfgang R Streit, Bernhard Schoenenberger, Markus Obkircher, Roland Wohlgemuth
The efficient synthesis of pure D-glycerate-2-phosphate is of much interest due to its importance as enzyme substrate and metabolite. A straightforward one-step biocatalytic phosphorylation of glyceric acid has been investigated. Glycerate 2-kinase from Thermotoga maritima has been expressed in Escherichia coli allowing easy purification. The selective glycerate 2-kinase-catalyzed phosphorylation has been followed by 31P-NMR and showed excellent enantioselectivity towards the phosphorylation of the D-enantiomer of glyceric acid...
April 18, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28419658/ancestral-haloalkane-dehalogenases-show-robustness-and-unique-substrate-specificity
#14
Petra Babkova, Eva Sebestova, Jan Brezovsky, Radka Chaloupkova, Jiri Damborsky
Ancestral sequence reconstruction (ASR) represents a powerful approach for empirical testing structure-function relationships of diverse proteins. We employed ASR to predict sequences of five ancestral haloalkane dehalogenases (HLDs) from the HLD-II subfamily. Genes encoding the inferred ancestral sequences were synthesized and expressed in Escherichia coli and the resurrected ancestral enzymes AncHLD1-5 were experimentally characterized. Strikingly, the ancestral HLDs exhibited significantly enhanced thermodynamic stability compared to extant enzymes (ΔTm up to 24 °C)...
April 17, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28407336/stabilization-of-telomeric-i-motif-structures-by-2-s-2-deoxy-2-c-methyl-cytidine-residues
#15
Anna Aviñó, Maria Dellafiore, Raimundo Gargallo, Carlos González, Adolfo M Iribarren, Javier Montserrat, Ramon Eritja
G-quadruplex and i-motif are tetraplex structures present in telomeres and promoter regions of oncogenes. The possibility of producing nanodevices with pH-sensitive functions has triggered the interest for modified oligonucleotides with improved structural properties. We synthesized C-rich oligonucleotides carrying conformationally restricted (2'S)-2'-deoxy-2'-C-methyl-cytidine units. The effect of this modified nucleoside on the stability of intramolecular i-motifs related to vertebrate telomere was investigated by means of spectroscopic methods (UV, CD and NMR)...
April 13, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28395125/probing-the-cmp-sialic-acid-donor-specificity-of-two-human-%C3%AE-d-galactoside-sialyltransferases-st3gal-i-and-st6gal-i-selectively-acting-on-o-and-n-glycosylproteins
#16
Maxence Noel, Pierre-André Gilormini, Virginie Cogez, Nao Yamakawa, Dorothée Vicogne, Cédric Lion, Christophe Biot, Yann Guerardel, Anne Harduin-Lepers
Sialylation of glycoproteins and glycolipids catalyzed by sialyltransferases are enzymatic reactions taking place in the Golgi of mammalian cells whereby sialic acid residues are added at the non-reducing ends of oligosaccharides. Because sialylated glycans play critical roles in a number of human physio-pathological processes, the past two decades have witnessed the development of modified sialic acid derivatives for a better understanding of sialic acid biology and development of new therapeutic targets. However, nothing is known about how individual mammalian sialyltransferases tolerate and behave towards these unnatural CMP-sialic acid donors...
April 10, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28393477/residues-at-a-single-site-differentiate-animal-cryptochromes-from-cyclobutane-pyrimidine-dimer-photolyases-by-affecting-the-proteins-preferences-for-reduced-fad
#17
Lei Xu, Bin Wen, Yuan Wang, Changqing Tian, Mingcai Wu, Guoping Zhu
Cryptochromes (CRYs) and photolyases belong to the cryptochrome/photolyase family (CPF). Reduced FAD is essential for photolyases to photorepair UV induced cyclobutane pyrimidine dimers (CPDs) or 6-4 photoproducts in DNA. In Drosophila CRY (dCRY, a type I animal CRY), FAD is converted to the anionic radical but not to the reduced state during illumination, which may induce a conformational change in the protein to relay the light signal downstream. To explore the foundation of these differences, multiple sequence alignment of 650 CPF protein sequences was performed...
April 10, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28393452/minimization-of-the-thiolactomycin-biosynthetic-pathway-reveals-that-the-cytochrome-p450-enzyme-tlmf-is-required-for-five-membered-thiolactone-ring-formation
#18
Xiaoyu Tang, Jie Li, Bradley S Moore
Thiolactomycin (TLM) belongs to a class of rare and unique thiotetronate antibiotics inhibiting bacterial fatty acid synthesis. Although this group of natural product antibiotics was first discovered over 30 years, the study of TLM biosynthesis remains in its infancy. We recently discovered the biosynthetic gene cluster (BGC) for TLM from the marine bacterium Salinispora pacifica CNS-863. Here, we report the investigation of TLM biosynthetic logic through mutagenesis and comparative metabolic analyses. Our results reveal that only four genes (tlmF, tlmG, tlmH, and tlmI) are required for the construction of the characteristic γ-thiolactone skeleton of this class of antibiotics...
April 10, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28388005/a-novel-methodology-for-the-incorporation-of-chiral-linkers-in-stapled-peptides
#19
Juan C Serrano, James Sipthorp, Wenshu Xu, Laura S Itzhaki, Steven V Ley
Stapled peptides have arisen as a new class of chemical probe and potential therapeutic agents to modulate protein-protein interactions. Here, we report the first two-component i,i+7 stapling methodology using two orthogonal, on-resin stapling reactions to incorporate linkers bearing a chiral center on a p53-derived stapled peptide. Post-stapling modifications to the staple chain were performed on-resin, enabling rapid access to various peptide derivatives from a single staple. The stapled peptides have increased helicity, protease stability and in vitro binding affinities to MDM2 compared to the unstapled peptide...
April 7, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28383803/expanding-the-scope-of-metabolic-glycan-labeling-in-arabidopsis-thaliana
#20
Yuntao Zhu, Xing Chen
Metabolic glycan labeling (MGL) has gained wide utility and has become a useful tool for probing glycosylation in living systems. For the past three decades, the development and application of MGL have been mostly focused on animal glycosylation. Recently, exploiting MGL for studying plant glycosylation has started to gain interest. Here, we describe a systematic evaluation of MGL for fluorescence imaging of root glycans in Arabidopsis thaliana. A collection of nineteen monosaccharide analogs containing a bioorthogonal group (i...
April 6, 2017: Chembiochem: a European Journal of Chemical Biology
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