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https://www.readbyqxmd.com/read/29757653/metabolism-of-an-oxime-linked-antibody-drug-conjugate-ags62p1-and-characterization-of-its-identified-metabolite
#1
Josh T Snyder, Maria-Christina Malinao, Julien Dugal-Tessier, John E Atkinson, Banmeet S Anand, Akihiro Okada, Brian A Mendelsohn
AGS62P1 is an antibody drug conjugate (ADC) composed of a human IgG1κ monoclonal antibody against FLT3 (FMS-like tyrosine kinase 3) with a p-acetyl phenylalanine (pAF) residue inserted at position 124 of each heavy chain linked to the proprietary microtubule disrupting agent AGL-0182-30 via an alkoxyamine linker that forms an oxime upon conjugation to the antibody. AGS62P1 is currently in Phase I human clinical trials for acute myelogenous leukemia (AML). The identified primary metabolite of an oxime-linked ADC is presented for the first time...
May 14, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29705142/discovery-of-6-pyrimidin-5-ylmethyl-quinoline-8-carboxamide-negative-allosteric-modulators-of-metabotropic-glutamate-receptor-subtype-5
#2
Andrew S Felts, Alice L Rodriguez, Ryan D Morrison, Anna L Blobaum, Frank W Byers, J Scott Daniels, Colleen M Niswender, P Jeffrey Conn, Craig W Lindsley, Kyle A Emmitte
Based on previous work that established fused heterocycles as viable alternatives for the picolinamide core of our lead series of mGlu5 negative allosteric modulators (NAMs), we designed a novel series of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide mGlu5 NAMs. These new quinoline derivatives also contained carbon linkers as replacements for the diaryl ether oxygen atom common to our previously published chemotypes. Compounds were evaluated in a cell-based functional mGlu5 assay, and an exemplar analog 27 was >60-fold selective versus the other seven mGlu receptors...
April 22, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29192758/the-thioesterase-domain-in-glycopeptide-antibiotic-biosynthesis-is-selective-for-cross-linked-aglycones
#3
Madeleine Peschke, Clara Brieke, Michael Heimes, Max J Cryle
The biosynthesis of the glycopeptide antibiotics (GPAs)-which include teicoplanin and vancomycin-is a complex enzymatic process relying on the interplay of nonribosomal peptide synthesis and a cytochrome P450-mediated cyclization cascade. This unique cyclization cascade generates the highly cross-linked state of these nonribosomal peptides, which is crucial for their antimicrobial activity. Given that these essential oxidative transformations occur while the peptide remains bound to the terminal module of the nonribosomal peptide synthetase (NRPS) machinery, it is important to assess the selectivity of the terminal thioesterase (TE) domain and how this domain contributes to the maintenance of an efficient biosynthetic pathway while at the same time ensuring GPA maturation is completed...
January 19, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29185746/novel-aryl-substituted-pyrazoles-as-small-molecule-inhibitors-of-cytochrome-p450-cyp121a1-synthesis-and-antimycobacterial-evaluation
#4
Ismail M Taban, Hosam E A E Elshihawy, Beyza Torun, Benedetta Zucchini, Clare J Williamson, Dania Altuwairigi, Adeline S T Ngu, Kirsty J McLean, Colin W Levy, Sakshi Sood, Leonardo B Marino, Andrew W Munro, Luiz Pedro S de Carvalho, Claire Simons
Three series of biarylpyrazole imidazole and triazoles are described, which vary in the linker between the biaryl pyrazole and imidazole/triazole group. The imidazole and triazole series with the short -CH2 - linker displayed promising antimycobacterial activity, with the imidazole-CH2 - series (7) showing low MIC values (6.25-25 μg/mL), which was also influenced by lipophilicity. Extending the linker to -C(O)NH(CH2 )2 - resulted in a loss of antimycobacterial activity. The binding affinity of the compounds with CYP121A1 was determined by UV-visible optical titrations with KD values of 2...
December 28, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29163152/the-hinge-segment-of-human-nadph-cytochrome-p450-reductase-in-conformational-switching-the-critical-role-of-ionic-strength
#5
Diana Campelo, Thomas Lautier, Philippe Urban, Francisco Esteves, Sophie Bozonnet, Gilles Truan, Michel Kranendonk
NADPH-cytochrome P450 reductase (CPR) is a redox partner of microsomal cytochromes P450 and is a prototype of the diflavin reductase family. CPR contains 3 distinct functional domains: a FMN-binding domain (acceptor reduction), a linker (hinge), and a connecting/FAD domain (NADPH oxidation). It has been demonstrated that the mechanism of CPR exhibits an important step in which it switches from a compact, closed conformation (locked state) to an ensemble of open conformations (unlocked state), the latter enabling electron transfer to redox partners...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28944003/partial-fusion-of-a-cytochrome-p450-system-by-carboxy-terminal-attachment-of-putidaredoxin-reductase-to-p450cam-cyp101a1
#6
Eachan O Johnson, Luet-Lok Wong
Cytochrome P450 (CYP) enzymes catalyze the insertion of oxygen into carbon-hydrogen bonds and have great potential for enzymatic synthesis. Application development of class I CYPs is hampered by their dependence on two redox partners (a ferredoxin and ferredoxin reductase), slowing catalysis compared to self-sufficient CYPs such as CYP102A1 (P450BM3). Previous attempts to address this have fused all three components in several permutations and geometries, with much reduced activity compared to the native system...
October 21, 2016: Catalysis Science & Technology
https://www.readbyqxmd.com/read/28874838/structural-determinants-of-5-6-epoxyeicosatrienoic-acid-binding-to-and-activation-of-trpv4-channel
#7
Alejandro Berna-Erro, Mercè Izquierdo-Serra, Romina V Sepúlveda, Fanny Rubio-Moscardo, Pau Doñate-Macián, Selma A Serra, Julia Carrillo-Garcia, Alex Perálvarez-Marín, Fernando González-Nilo, José M Fernández-Fernández, Miguel A Valverde
TRPV4 cation channel activation by cytochrome P450-mediated derivatives of arachidonic acid (AA), epoxyeicosatrienoic acids (EETs), constitute a major mechanisms of endothelium-derived vasodilatation. Besides, TRPV4 mechano/osmosensitivity depends on phospholipase A2 (PLA2) activation and subsequent production of AA and EETs. However, the lack of evidence for a direct interaction of EETs with TRPV4 together with claims of EET-independent mechanical activation of TRPV4 has cast doubts on the validity of this mechanism...
September 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28852040/engineering-of-versatile-redox-partner-fusions-that-support-monooxygenase-activity-of-functionally-diverse-cytochrome-p450s
#8
Patrick J Bakkes, Jan L Riehm, Tanja Sagadin, Ansgar Rühlmann, Peter Schubert, Stefan Biemann, Marco Girhard, Michael C Hutter, Rita Bernhardt, Vlada B Urlacher
Most bacterial cytochrome P450 monooxygenases (P450s or CYPs) require two redox partner proteins for activity. To reduce complexity of the redox chain, the Bacillus subtilis flavodoxin YkuN (Y) was fused to the Escherichia coli flavodoxin reductase Fpr (R), and activity was tuned by placing flexible (GGGGS)n or rigid ([E/L]PPPP)n linkers (n = 1-5) in between. P-linker constructs typically outperformed their G-linker counterparts, with superior performance of YR-P5, which carries linker ([E/L]PPPP)5. Molecular dynamics simulations demonstrated that ([E/L]PPPP)n linkers are intrinsically rigid, whereas (GGGGS)n linkers are highly flexible and biochemical experiments suggest a higher degree of separation between the fusion partners in case of long rigid P-linkers...
August 29, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28799023/expression-of-cholesterol-hydroxylase-lyase-system-proteins-in-yeast-s-cerevisiae-cells-as-a-self-processing-polyprotein
#9
Vera S Efimova, Ludmila V Isaeva, Desislava S Makeeva, Mikhail A Rubtsov, Ludmila A Novikova
2A peptide discovered in Picornaviridae is capable of self-cleavage providing an opportunity to carry out synthesis of several proteins using one transcript. Dissociation in the 2A sequence during translation leads to the individual proteins formation. We constructed cDNA including genes of the bovine cholesterol hydroxylase/lyase (CHL) system proteins-cytochrome P450scc (CYP11A1), adrenodoxin (Adx) and adrenodoxin reductase (AdR), that are fused into a single ORF using FMDV 2A nucleotide sequences. The constructed vectors direct the expression of cDNA encoding polyprotein P450scc-2A-Adx-2A-AdR (CHL-2A) in Escherichia coli and Saccharomyces cerevisiae...
October 2017: Molecular Biotechnology
https://www.readbyqxmd.com/read/28734977/modulation-of-the-interaction-between-human-p450-3a4-and-b-megaterium-reductase-via-engineered-loops
#10
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...
January 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28405004/engineered-p450-biocatalysts-show-improved-activity-and-regio-promiscuity-in-aromatic-nitration
#11
Ran Zuo, Yi Zhang, Chao Jiang, John C Hackett, Rosemary Loria, Steven D Bruner, Yousong Ding
Nitroaromatics are among the most important and commonly used chemicals but their production often suffers from multiple unsolved challenges. We have previously described the development of biocatalytic nitration processes driven by an engineered P450 TxtE fusion construct. Herein we report the creation of improved nitration biocatalysts through constructing and characterizing fusion proteins of TxtE with the reductase domain of CYP102A1 (P450BM3, BM3R). The majority of constructs contained variable linker length while one was rationally designed for optimizing protein-protein interactions...
April 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28377716/human-cytochrome-p450-3a4-as-a-biocatalyst-effects-of-the-engineered-linker-in-modulation-of-coupling-efficiency-in-3a4-bmr-chimeras
#12
Danilo Degregorio, Serena D'Avino, Silvia Castrignanò, Giovanna Di Nardo, Sheila J Sadeghi, Gianluca Catucci, Gianfranco Gilardi
Human liver cytochrome P450 3A4 is the main enzyme involved in drug metabolism. This makes it an attractive target for biocatalytic applications, such as the synthesis of pharmaceuticals and drug metabolites. However, its poor solubility, stability and low coupling have limited its application in the biotechnological context. We previously demonstrated that the solubility of P450 3A4 can be increased by creating fusion proteins between the reductase from Bacillus megaterium BM3 (BMR) and the N-terminally modified P450 3A4 (3A4-BMR)...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28355486/molecular-recognition-in-mitochondrial-cytochromes-p450-that-catalyze-the-terminal-steps-of-corticosteroid-biosynthesis
#13
COMPARATIVE STUDY
Hwei-Ming Peng, Richard J Auchus
The mitochondrial cytochromes P450 11B1 and P450 11B2 are responsible for the final stages of cortisol and aldosterone synthesis, respectively. Dysregulation of both enzymes has been implicated in secondary forms of hypertension. Molecular recognition of the cytochromes P450 with their corresponding redox partner is a key step in the catalytic cycle, yet the precise nature of the interaction of P450 11B1 or P450 11B2 with their proximal partner, adrenodoxin (Adx), is still unknown. Here, we obtained P450 11B1·Adx2 and P450 11B2·Adx2 complexes using the zero-length cross-linker ethyl-3-[3-(dimethylamino)propyl]carbodiimide, which formed best under low-ionic strength conditions...
May 2, 2017: Biochemistry
https://www.readbyqxmd.com/read/28300390/recruitment-and-regulation-of-the-non-ribosomal-peptide-synthetase-modifying-cytochrome-p450-involved-in-nikkomycin-biosynthesis
#14
Courtney E Wise, Thomas M Makris
The β-hydroxylation of l-histidine is the first step in the biosynthesis of the imidazolone base of the antifungal drug nikkomycin. The cytochrome P450 (NikQ) hydroxylates the amino acid while it is appended via a phosphopantetheine linker to the non-ribosomal peptide synthetase (NRPS) NikP1. The latter enzyme is comprised of an MbtH and single adenylation and thiolation domains, a minimal composition that allows for detailed binding and kinetics studies using an intact and homogeneous NRPS substrate. Electron paramagnetic resonance studies confirm that a stable complex is formed with NikQ and NikP1 when the amino acid is tethered...
May 19, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28204885/de-bugging-and-maximizing-plant-cytochrome-p450-production-in-escherichia-coli-with-c-terminal-gfp-fusions
#15
Ulla Christensen, Dario Vazquez-Albacete, Karina M Søgaard, Tonja Hobel, Morten T Nielsen, Scott James Harrison, Anders Holmgaard Hansen, Birger Lindberg Møller, Susanna Seppälä, Morten H H Nørholm
Cytochromes P450 (CYP) are attractive enzyme targets in biotechnology as they catalyze stereospecific C-hydroxylations of complex core skeletons at positions that typically are difficult to access by chemical synthesis. Membrane bound CYPs are involved in nearly all plant pathways leading to the formation of high-value compounds. In the present study, we systematically maximize the heterologous expression of six different plant-derived CYP genes in Escherichia coli, using a workflow based on C-terminal fusions to the green fluorescent protein...
May 2017: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/28131847/inhibition-of-11%C3%AE-hydroxysteroid-dehydrogenase-2-by-the-fungicides-itraconazole-and-posaconazole
#16
Katharina R Beck, Murielle Bächler, Anna Vuorinen, Sandra Wagner, Muhammad Akram, Ulrich Griesser, Veronika Temml, Petra Klusonova, Hideaki Yamaguchi, Daniela Schuster, Alex Odermatt
Impaired 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2)-dependent cortisol inactivation can lead to electrolyte dysbalance, hypertension and cardiometabolic disease. Furthermore, placental 11β-HSD2 essentially protects the fetus from high maternal glucocorticoid levels, and its impaired function has been associated with altered fetal growth and a higher risk for cardio-metabolic diseases in later life. Despite its important role, 11β-HSD2 is not included in current off-target screening approaches. To identify potential 11β-HSD inhibitors among approved drugs, a pharmacophore model was used for virtual screening, followed by biological assessment of selected hits...
April 15, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28054175/directed-accumulation-of-less-toxic-pimaricin-derivatives-by-improving-the-efficiency-of-a-polyketide-synthase-dehydratase-domain
#17
Zhen Qi, Yucong Zhou, Qianjin Kang, Chunyan Jiang, Jianting Zheng, Linquan Bai
Pimaricin is an important polyene antifungal antibiotic that binds ergosterol and extracts it from fungal membranes. In previous work, two pimaricin derivatives (1 and 2) with improved pharmacological activities and another derivative (3) that showed no antifungal activity were produced by the mutant strain of Streptomyces chattanoogensis, in which the P450 monooxygenase gene scnG has been inactivated. Furthermore, inactivation of the DH12 dehydratase domain of the pimaricin polyketide synthases (PKSs) resulted in specific accumulation of the undesired metabolite 3, suggesting that improvement of the corresponding dehydratase activity may reduce or eliminate the accumulation of 3...
March 2017: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/27814979/improving-the-activity-of-surface-displayed-cytochrome-p450-enzymes-by-optimizing-the-outer-membrane-linker
#18
Paul Quehl, Jan Schüürmann, Joel Hollender, Joachim Jose
Anchorage of recombinant proteins onto the outer membrane of gram-negative bacteria is an attractive solution for protein library screening and whole cell biocatalysis if a membrane environment is required or mass transfer into the cell is limiting. Autotransporters have been successfully applied for surface display of various heterologous proteins. Still, many underlying parameters for achieving active enzymes are not known. Here, we systematically tested different linkers between passenger and the membrane embedded β-barrel of the autotransporter...
January 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27781345/immobilization-of-a-bacterial-cytochrome-p450-monooxygenase-system-on-a-solid-support
#19
Cheau Yuaan Tan, Hidehiko Hirakawa, Risa Suzuki, Tomoaki Haga, Fumiya Iwata, Teruyuki Nagamune
Bacterial cytochrome P450s (P450s), which catalyze regio- and stereoselective oxidations of hydrocarbons with high turnover rates, are attractive biocatalysts for fine chemical production. Enzyme immobilization is needed for cost-effective industrial manufacturing. However, immobilization of P450s is difficult because electron-transfer proteins are involved in catalysis and anchoring these can prevent them from functioning as shuttle molecules for carrying electrons. We studied a heterotrimeric protein-mediated co-immobilization of a bacterial P450, and its electron-transfer protein and reductase...
October 26, 2016: Angewandte Chemie
https://www.readbyqxmd.com/read/27240349/transcriptome-and-difference-analysis-of-fenpropathrin-resistant-predatory-mite-neoseiulus-barkeri-hughes
#20
Lin Cong, Fei Chen, Shijiang Yu, Lili Ding, Juan Yang, Ren Luo, Huixia Tian, Hongjun Li, Haoqiang Liu, Chun Ran
Several fenpropathrin-resistant predatory mites have been reported. However, the molecular mechanism of the resistance remains unknown. In the present study, the Neoseiulus barkeri (N. barkeri) transcriptome was generated using the Illumina sequencing platform, 34,211 unigenes were obtained, and 15,987 were manually annotated. After manual annotation, attentions were attracted to resistance-related genes, such as voltage-gated sodium channel (VGSC), cytochrome P450s (P450s), and glutathione S-transferases (GSTs)...
May 27, 2016: International Journal of Molecular Sciences
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