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https://www.readbyqxmd.com/read/28748719/synthesis-of-potential-hiv-integrase-inhibitors-inspired-by-natural-polyphenol-structures
#1
Giuliana Righi, Romina Pelagalli, Valerio Isoni, Ilaria Tirotta, Martina Marini, Matteo Palagri, Roberto Dallocchio, Alessandro Dessì, Beatrice Macchi, Caterina Frezza, Gianpiero Forte, Antonella Dalla Cort, Gustavo Portalone, Paolo Bovicelli
Drawing inspiration from the structural features of some natural polyphenols, the synthesis of two different model compounds as potential inhibitors of HIV integrase (IN) has been described. The former was characterised by a diketo acid (DKA) bioisostere, such as a β-hydroxycarbonyl moiety, between two fragments containing aromatic groups, while in the latter an epoxide linked two polyoxygenated aromatic residues. The moieties present in the structures are thought to function by chelating divalent metal ions on the enzyme catalytic site...
July 27, 2017: Natural Product Research
https://www.readbyqxmd.com/read/28748551/identification-of-a-dimeric-kdg-aldolase-from-agrobacterium-tumefaciens
#2
Tatiana P Soares da Costa, Madhvi Patel, Sebastien Desbois, Ruchi Gupta, Pierre Faou, Matthew A Perugini
Agrobacterium tumefaciens is a Gram-negative bacterium and causative agent of Crown Gall disease that infects a variety of economically-important plants. The annotated A. tumefaciens genome contains 10 putative dapA genes, which code for dihydrodipicolinate synthase (DHDPS). However, we have recently demonstrated that only one of these genes (dapA7) encodes a functional DHDPS. The function of the other nine putative dapA genes is yet to be determined. Here, we demonstrate using bioinformatics that the product of the dapA5 gene (DapA5) possesses all the catalytic residues canonical to 2-keto-3-deoxygluconate (KDG) aldolase, which is a class I aldolase involved in glucose metabolism...
July 27, 2017: Proteins
https://www.readbyqxmd.com/read/28747242/identification-and-characterization-of-ace1-type-acetylcholinesterase-in-insecticide-resistant-and-susceptible-propylaea-japonica-thunberg
#3
M M Wang, L Y Xing, Z W Ni, G Wu
Characterization and gene cloning of acetylecholinesterase (AChE) in the insecticide-resistant (R) and -susceptible (S) insects have been reported in the past. However, the studies focused mostly on herbivorous pests, rather than predacious species, such as ladybird beetles. Using R and S Propylaea japonica (thunberg), a full-length cDNA sequence (2928 bp) of the ace1-type AChE gene was determined for the first time. The ace1 encoding a protein of 645 amino acids contained typical conserved motifs, such as FGESAG domains, catalytic triad, acyl pocket, oxyanino hole, choline binding site, peripheral anionic site, omega loop and conserved aromatic residues...
July 27, 2017: Bulletin of Entomological Research
https://www.readbyqxmd.com/read/28746905/a-pm7-dynamic-residue-ligand-interactions-energy-landscape-of-the-bace1-inhibitory-pathway-by-hydroxyethylamine-compounds-part-i-the-flap-closure-process
#4
Carlos Gueto-Tettay, Alejandro Martinez-Consuegra, Joshua Zuchniarz, Luis Roberto Gueto-Tettay, Juan Carlos Drosos-Ramírez
BACE1 is an enzyme of scientific interest because it participates in the progression of Alzheimer's disease. Hydroxyethylamines (HEAs) are a family of compounds which exhibit inhibitory activity toward BACE1 at a nanomolar level, favorable pharmacokinetic properties and oral bioavailability. The first step in the inhibition of BACE1 by HEAs consists of their entrance into the protease active site and the resultant conformational change in the protein, from Apo to closed form. These two conformations differ in the position of an antiparallel loop (called the flap) which covers the entrance to the catalytic site...
July 14, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28744694/structural-and-functional-diversity-of-caspase-homologues-in-non-metazoan-organisms
#5
REVIEW
Marina Klemenčič, Christiane Funk
Caspases, the proteases involved in initiation and execution of metazoan programmed cell death, are only present in animals, while their structural homologues can be found in all domains of life, spanning from simple prokaryotes (orthocaspases) to yeast and plants (metacaspases). All members of this wide protease family contain the p20 domain, which harbours the catalytic dyad formed by the two amino acid residues, histidine and cysteine. Despite the high structural similarity of the p20 domain, metacaspases and orthocaspases were found to exhibit different substrate specificities than caspases...
July 25, 2017: Protoplasma
https://www.readbyqxmd.com/read/28743811/structural-and-in-vivo-studies-on-trehalose-6-phosphate-synthase-from-pathogenic-fungi-provide-insights-into-its-catalytic-mechanism-biological-necessity-and-potential-for-novel-antifungal-drug-design
#6
Yi Miao, Jennifer L Tenor, Dena L Toffaletti, Stacey A Maskarinec, Jiuyu Liu, Richard E Lee, John R Perfect, Richard G Brennan
The disaccharide trehalose is critical to the survival of pathogenic fungi in their human host. Trehalose-6-phosphate synthase (Tps1) catalyzes the first step of trehalose biosynthesis in fungi. Here, we report the first structures of eukaryotic Tps1s in complex with substrates or substrate analogues. The overall structures of Tps1 from Candida albicans and Aspergillus fumigatus are essentially identical and reveal N- and C-terminal Rossmann fold domains that form the glucose-6-phosphate and UDP-glucose substrate binding sites, respectively...
July 25, 2017: MBio
https://www.readbyqxmd.com/read/28743532/a-synthetic-peptide-hijacks-the-catalytic-subunit-of-class-i-pi3k-to-suppress-the-growth-of-cancer-cells
#7
Weiwei Guo, Xue You, Xiao Wang, Lin Wang, Yan Chen
Activation of class I Phosphoinositide 3-kinases (PI3Ks) by mutation or overexpression closely correlates with the development of various human cancers. Class I PI3Ks are heterodimers composed of p110 catalytic subunits and regulatory subunits represented by p85. PAQR3 has been found to inhibit p110α activity by blocking its interaction with p85. In this study, we identified the N-terminal 6-55 amino acid residues of PAQR3 being sufficient for its interaction with p110α. A synthetic peptide, P6-55, that contains the N-terminus of PAQR3 could disrupt the interactions of p110α with both PAQR3 and p85...
July 22, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28742821/evolution-of-the-camp-dependent-protein-kinase-pka-catalytic-subunit-isoforms
#8
Kristoffer Søberg, Line Victoria Moen, Bjørn Steen Skålhegg, Jon Kristen Laerdahl
The 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase, or protein kinase A (PKA), pathway is one of the most versatile and best studied signaling pathways in eukaryotic cells. The two paralogous PKA catalytic subunits Cα and Cβ, encoded by the genes PRKACA and PRKACB, respectively, are among the best understood model kinases in signal transduction research. In this work, we explore and elucidate the evolution of the alternative 5' exons and the splicing pattern giving rise to the numerous PKA catalytic subunit isoforms...
2017: PloS One
https://www.readbyqxmd.com/read/28741300/the-hotdog-fold-thioesterase-pa1618-catalytic-mechanism-revealed-by-x-ray-structure-determination-of-the-substrate-oxygen-ester-analog-complex
#9
John A Latham, Tianyang Ji, Kaila Matthews, Patrick Mariano, Karen N Allen, Debra Dunaway-Mariano
Thioesterase activity (hydrolysis of thioester bonds) accounts for the majority of the activities in the hotdog-fold superfamily. The structure and mechanism of catalysis for many hotdog enzymes have been elucidated by X-ray crystallography and kinetics to probe the specific substrate usage and cellular functions. However, structures of hotdog thioesterases in complex with substrate analogs reported to date utilize ligands that comprise either truncations of the substrate or include additional atoms to prevent the hydrolysis...
July 24, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28739781/structural-insights-into-the-tla-3-extended-spectrum-%C3%AE-lactamase-and-its-inhibition-by-avibactam-and-op0595
#10
Wanchun Jin, Jun-Ichi Wachino, Yoshihiro Yamaguchi, Kouji Kimura, Anupriya Kumar, Mototsugu Yamada, Akihiro Morinaka, Yoshiaki Sakamaki, Minoru Yonezawa, Hiromasa Kurosaki, Yoshichika Arakawa
Development of effective inhibitors that block extended-spectrum β-lactamases (ESBLs) and restore the action of β-lactams represents an effective strategy against ESBL-producing Enterobacteriaceae We evaluated the inhibitory effect of the diazabicyclooctanes avibactam and OP0595 against TLA-3, an ESBL we identified previously. Avibactam and OP0595 inhibited TLA-3 with apparent Ki app of 1.71 ± 0.10 and 1.49 ± 0.05 μM, respectively, and could restore susceptibility to cephalosporins in TLA-3-producing Escherichia coli The acylation rate constant [k2/K, (3...
July 24, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28734977/modulation-of-the-interaction-between-human-p450-3a4-and-b-megaterium-reductase-via-engineered-loops
#11
Silvia Castrignanò, Serena D'Avino, Giovanna Di Nardo, Gianluca Catucci, Sheila J Sadeghi, Gianfranco Gilardi
Chimerogenesis involving cytochromes P450 is a successful approach to generate catalytically self-sufficient enzymes. However, the connection between the different functional modules should allow a certain degree of flexibility in order to obtain functional and catalytically efficient proteins. We previously applied the molecular Lego approach to develop a chimeric P450 3A4 enzyme linked to the reductase domain of P450 BM3 (BMR). Three constructs were designed with the connecting loop containing no glycine, 3 glycine or 5 glycine residues and showed a different catalytic activity and coupling efficiency...
July 19, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28734645/computational-study-of-the-competitive-binding-of-valproic-acid-glucuronide-and-carbapenem-antibiotics-to-acylpeptide-hydrolase
#12
Takeshi Ishikawa, Hiroki Otaki, Satoshi Mizuta, Masami Kuriyama, Osamu Onomura, Norihide Higuchi, Mihoko N Nakashima, Mikiro Nakashima, Kaname Ohyama
The efficacy of the antiepileptic drug VPA is decreased by co-administered carbapenems (CBPMs). The mechanism of CBPM selective inhibition of acylpeptide hydrolase (APEH) hydrolysis of VPA-glucuronide (VPA-G) to VPA is unclear due to the lack of APEH structural information. Here we performed homology modeling of the three-dimensional structure of APEH and subsequent docking simulations with a modeled structure to understand this mechanism. Docking simulations indicated that four groups of binding structures were involved in the binding of VPA-G, panipenem, and meropenem to APEH, but only one or two binding structures were involved in the binding of meropenem with an open β-lactam ring structure and other antibiotics involving ampicillin...
April 30, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28734024/effect-of-solvent-and-protein-dynamics-in-ligand-recognition-and-inhibition-of-aminoglycoside-adenyltransferase-2%C3%A2-ia
#13
Valjean R Bacot-Davis, Angelia V Bassenden, Tara Sprules, Albert M Berghuis
The aminoglycoside modifying enzyme (AME) ANT(2″)-Ia is a significant target for next generation antibiotic development. Structural studies of a related aminoglycoside-modifying enzyme, ANT(3″)(9), revealed this enzyme contains dynamic, disordered, and well-defined segments that modulate thermodynamically before and after antibiotic binding. Characterizing these structural dynamics is critical for in situ screening, design, and development of contemporary antibiotics that can be implemented in a clinical setting to treat potentially lethal, antibiotic resistant, human infections...
July 21, 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/28733938/molecular-cloning-heterologous-expression-and-functional-characterization-of-a-cellulolytic-enzyme-cel-prii-from-buffalo-rumen-metagenome
#14
Ravi K Shah, Amrutlal K Patel, Deepti M Davla, Ishan K Parikh, Ramalingam B Subramanian, Kamlesh C Patel, Subhash J Jakhesara, Chaitanya G Joshi
A cellulase encoding gene, Cel PRII, was identified from Mehsani buffalo rumen metagenome, and cloned and expressed in Escherichia coli BL21(DE3)pLysS. The 1170 bp full length gene encodes a 389 residue polypeptide (Cel PRII) containing a catalytic domain belonging to glycosyl hydrolase (GH) 5 family. The fusion protein consisting of the Cel PRII, thioredoxin tag and 6x Histidine tag with predicted molecular weight of 63 kDa when recovered from inclusion bodies under denaturing conditions, exhibited cellulolytic activity against carboxymethyl cellulose (CMC)...
August 2017: 3 Biotech
https://www.readbyqxmd.com/read/28733281/structural-and-mechanistic-insights-into-the-improvement-of-halotolerant-ability-of-a-marine-microbial-esterase-by-increasing-intra-and-inter-domain-hydrophobic-interactions
#15
Ping-Yi Li, Yi Zhang, Bin-Bin Xie, Yan-Qi Zhang, Jie Hao, Yue Wang, Peng Wang, Chun-Yang Li, Qi-Long Qin, Xi-Ying Zhang, Hai-Nan Su, Mei Shi, Yu-Zhong Zhang, Xiu-Lan Chen
Halotolerant enzymes are beneficial for industrial processes requiring high salts and low water activity. Most halophilic proteins are evolved to have reduced hydrophobic interactions on the surface and in the hydrophobic cores for their haloadaptation. However, in this study, we improved the halotolerance of a thermolablie esterase, E40, by increasing intra-protein hydrophobic interactions. E40 was quite unstable in buffers containing more than 0.3 M NaCl and its kcat and substrate affinity were both significantly reduced in 0...
July 21, 2017: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/28732729/crystal-structures-of-an-atypical-aldehyde-dehydrogenase-having-bidirectional-oxidizing-and-reducing-activities
#16
Kyoungho Jung, Seung-Hye Hong, Ho-Phuong-Thuy Ngo, Thien-Hoang Ho, Yeh-Jin Ahn, Deok-Kun Oh, Lin-Woo Kang
Aldehyde dehydrogenases (ALDHs) are NAD(P)(+)-dependent oxidoreductases that catalyze the oxidation of a variety of aldehydes to their acid forms. In this study, we determined the crystal structures of ALDH from Bacillus cereus (BcALDH), alone, and in complex with NAD(+) and NADP(+). This enzyme can oxidize all-trans-retinal to all-trans-retinoic acid using either NAD(+) or NADP(+) with equal efficiency, and atypically, as a minor activity, can reduce all-trans-retinal to all-trans-retinol using NADPH. BcALDH accommodated the additional 2'-phosphate of NADP(+) by expanding the cofactor-binding pocket and upshifting the AMP moiety in NADP(+)...
July 18, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28732290/synergistic-effect-of-uv-pretreated-fe-zsm-5-catalysts-for-heterogeneous-catalytic-complete-oxidation-of-voc-a-technology-development-for-sustainable-use
#17
Abdul Aziz, Kwang Soo Kim
In this work, the performance of benzene, toluene, ethylbenzene, and xylene (BTEX) removal and degradation from gas, air streams on UV pretreated Fe-ZSM-5 in a batch reactor at room temperature were studied. The Fe-ZSM-5 zeolite catalyst was prepared by hydrothermal reaction method. The influence of UV pre-irradiation time on the removal of BTEX were assessed by varying the time, ranging from 15min to 60smin. Then, sustainability of the activation of the catalyst resulted by UV pretreatment was studied by the four-cycle experiment with one time UV irradiation and after each cycle irradiation followed by BTEX removal after every cycle respectively...
July 10, 2017: Journal of Hazardous Materials
https://www.readbyqxmd.com/read/28729759/transcriptome-wide-identification-and-characterization-of-starch-branching-enzyme-in-finger-millet
#18
Rajhans Tyagi, Apoorv Tiwari, Vijay Kumar Garg, Sanjay Gupta
Starch-branching enzymes (SBEs) are one of the four major enzyme classes involved in starch biosynthesis in plants and play an important role in determining the structure and physical properties of starch granules. Multiple SBEs are involved in starch biosynthesis in plants. Finger millet is calcium rich important serial crop belongs to grass family and the transcriptome data of developing spikes is available on NCBI. In this study it was try to find out the gene sequence of starch branching enzyme and annotate the sequence and submit the sequence for further use...
2017: Bioinformation
https://www.readbyqxmd.com/read/28728943/production-and-biophysical-characterization-of-a-mini-membrane-protein-ost4v23d-a-functionally-important-mutant-of-yeast-oligosaccharyltransferase-subunit-ost4p
#19
Bharat Chaudhary, Suman Mazumder, Smita Mohanty
N-linked glycosylation of proteins is an essential and highly conserved co- and post-translational protein modification reaction that occurs in all eukaryotes. Oligosaccharyltransferase (OST), a multi-subunit membrane-associated enzyme complex, carries out this reaction. In the central reaction, a carbohydrate group is transferred to the side chain of a consensus asparagine residue in the newly synthesized protein. Genetic defects in humans cause a series of disorders known as congenital disorders of glycosylation (CDG) that include mental retardation, developmental delay, hypoglycemia etc...
July 17, 2017: Protein Expression and Purification
https://www.readbyqxmd.com/read/28728106/multipotent-ache-and-bace-1-inhibitors-for-the-treatment-of-alzheimer-s-disease-design-synthesis-and-bio-analysis-of-7-amino-1-4-dihydro-2h-isoquilin-3-one-derivates
#20
Xiong-Jie Zhao, Da-Min Gong, Yu-Ren Jiang, Dong Guo, Yao Zhu, You-Chao Deng
In this paper, the preparation of a new class of multi-target-directed ligands (MTDLs) based on a 7-amino-1,4-dihydro-2H-isoquilin-3-one, whose lead (compound I) showed promising properties in acetylcholinesterase (AChE) inhibitory activity [1], is described. The results of in vitro activities and molecular docking demonstrated that the target molecule (compounds 10a-n) with three parts of aromatic moieties and appropriate structural length can interact with aromatic residues in catalytic active site (CAS), peripheral anionic site (PAS) and the channel of AChE...
July 5, 2017: European Journal of Medicinal Chemistry
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