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linker p450

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https://www.readbyqxmd.com/read/27814979/improving-the-activity-of-surface-displayed-cytochrome-p450-enzymes-by-optimizing-the-outer-membrane-linker
#1
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...
November 1, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27781345/immobilization-of-a-bacterial-cytochrome-p450-monooxygenase-system-on-a-solid-support
#2
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
#3
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)...
2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27050842/potent-and-selective-human-neuronal-nitric-oxide-synthase-inhibition-by-optimization-of-the-2-aminopyridine-based-scaffold-with-a-pyridine-linker
#4
Heng-Yen Wang, Yajuan Qin, Huiying Li, Linda J Roman, Pavel Martásek, Thomas L Poulos, Richard B Silverman
Neuronal nitric oxide synthase (nNOS) is an important therapeutic target for the treatment of various neurodegenerative disorders. A major challenge in the design of nNOS inhibitors focuses on potency in humans and selectivity over other NOS isoforms. Here we report potent and selective human nNOS inhibitors based on the 2-aminopyridine scaffold with a central pyridine linker. Compound 14j, the most promising inhibitor in this study, exhibits excellent potency for rat nNOS (Ki = 16 nM) with 828-fold n/e and 118-fold n/i selectivity with a Ki value of 13 nM against human nNOS with 1761-fold human n/e selectivity...
May 26, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27049848/a-fluorescent-readout-for-the-oxidation-state-of-electron-transporting-proteins-in-cell-free-settings
#5
Sergii Pochekailov, Rebecca R Black, Venkata Pramod Chavali, Arjun Khakhar, Georg Seelig
Pathways involving sequential electron transfer between multiple proteins are ubiquitous in nature. Here, we demonstrate a new class of fluorescent protein-based reporters for monitoring electron transport through such multistage cascades, specifically those involving ferredoxin-like electron transporters. We created protein fusions between mammalian Adrenodoxin (Adx) and plant Ferredoxin (Fdx) with fluorescent proteins of different colors and found that the fluorescence of such fusions is highly sensitive to the redox state of the electron transporter...
July 15, 2016: ACS Synthetic Biology
https://www.readbyqxmd.com/read/26972311/a-rationally-designed-connector-for-assembly-of-protein-functionalized-dna-nanostructures
#6
Katja J Koßmann, Cornelia Ziegler, Alessandro Angelin, Rebecca Meyer, Marc Skoupi, Kersten S Rabe, Christof M Niemeyer
We report on the rational engineering of the binding interface of the self-ligating HaloTag protein to generate an optimized linker for DNA nanostructures. Five amino acids positioned around the active-site entry channel for the chlorohexyl ligand (CH) of the HaloTag protein were exchanged for positively charged lysine amino acids to produce the HOB (halo-based oligonucleotide binder) protein. HOB was genetically fused with the enzyme cytochrome P450 BM3, as well as with BMR, the separated reductase domain of BM3...
June 16, 2016: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/26235815/photo-initiated-crosslinking-extends-mapping-of-the-protein-protein-interface-to-membrane-embedded-portions-of-cytochromes-p450-2b4-and-b%C3%A2
#7
Tomáš Ječmen, Renata Ptáčková, Věra Černá, Helena Dračínská, Petr Hodek, Marie Stiborová, Jiří Hudeček, Miroslav Šulc
Protein-protein interactions play a central role in the regulation of many biochemical processes (e.g. the system participating in enzyme catalysis). Therefore, a deeper understanding of protein-protein interactions may contribute to the elucidation of many biologically important mechanisms. For this purpose, it is necessary to establish the composition and stoichiometry of supramolecular complexes and to identify the crucial portions of the interacting molecules. This study is devoted to structure-functional relationships in the microsomal Mixed Function Oxidase (MFO) complex, which is responsible for biotransformation of many hydrophobic endogenous compounds and xenobiotics...
November 1, 2015: Methods: a Companion to Methods in Enzymology
https://www.readbyqxmd.com/read/26177696/design-and-improvement-of-artificial-redox-modules-by-molecular-fusion-of-flavodoxin-and-flavodoxin-reductase-from-escherichia-coli
#8
Patrick J Bakkes, Stefan Biemann, Ansgar Bokel, Marc Eickholt, Marco Girhard, Vlada B Urlacher
A variety of fusion proteins between the versatile redox partners flavodoxin (FldA) and flavodoxin reductase (Fpr) from Escherichia coli was constructed with the aim to improve the electron transfer properties. The order in which FldA and Fpr were fused and the linker region between them was varied in a systematic manner. A simple molecular tool, designated "DuaLinX", was developed that facilitated the parallel introduction of flexible glycine-rich and rigid proline-rich linkers between the fusion partners in a single cloning event...
2015: Scientific Reports
https://www.readbyqxmd.com/read/25638375/quantification-of-interactions-between-cytochrome-p450-2b4-and-cytochrome-b5-in-a-functional-membrane-complex
#9
Tomáš Ječmen, Renata Ptáčková, Daniel Kavan, Věra Cerná, Petr Hodek, Marie Stiborová, Jiří Hudeček, Miroslav Sulc
OBJECTIVES: The mammalian mixed function oxidase (MFO) system participates in hydroxylation of many hydrophobic endogenous compounds as well as xenobiotics such as drugs and carcinogens. This biotransformation system, located in a membrane of endoplasmic reticulum, consists of cytochrome P-450 (P450), NADPH:P450 oxidoreductase and a facultative component, cytochrome b5. The knowledge of the interactions among the individual components of the MFO system is essential to understand the relationships between the structure and function of this system that finally dictate a qualitative and quantitative pattern of produced metabolites (e...
2014: Neuro Endocrinology Letters
https://www.readbyqxmd.com/read/25079257/aflatoxin-and-deconstruction-of-type-i-iterative-polyketide-synthase-function
#10
REVIEW
Craig A Townsend
In this viewpoint highlights are drawn from a deep analysis of the multifaceted problem of aflatoxin biosynthesis, one of the most highly rearranged polyketide natural products known. Fundamental chemical insights have emerged into how cytochrome P450-mediated skeletal rearrangements occur through probable cationic intermediates and oxidative dearomatizations, which are applicable more widely in natural product catabolism. So to where current experimental methods have failed in our hands, bioinformatic tools and fresh experimental strategies have been developed to identify linker regions in large, polydomain proteins and guide the dissection and reassembly of their component parts...
October 2014: Natural Product Reports
https://www.readbyqxmd.com/read/25005689/p-link-a-method-for-generating-multicomponent-cytochrome-p450-fusions-with-variable-linker-length
#11
Ketaki D Belsare, Anna Joëlle Ruff, Ronny Martinez, Amol V Shivange, Hemanshu Mundhada, Dirk Holtmann, Jens Schrader, Ulrich Schwaneberg
Fusion protein construction is a widely employed biochemical technique, especially when it comes to multi-component enzymes such as cytochrome P450s. Here we describe a novel method for generating fusion proteins with variable linker lengths, protein fusion with variable linker insertion (P-LinK), which was validated by fusing P450cin monooxygenase (CinA) to the flavodoxin shuttle protein (CinC). CinC was fused to the C terminus of CinA through a series of 16 amino acid linkers of different lengths in a single experiment employing 3 PCR amplifications...
July 2014: BioTechniques
https://www.readbyqxmd.com/read/24292786/synthesis-and-structure-activity-relationship-of-naphtho-1-2-b-furan-2-carboxamide-derivatives-as-melanin-concentrating-hormone-receptor-1-antagonists
#12
Chae Jo Lim, Jun Young Choi, Byung Ho Lee, Kwang-Seok Oh, Kyu Yang Yi
The discovery that novel naphtho[1,2-b]furan-2-carboxamides containing linked piperidinylphenylacetamide groups serve as melanin concentrating hormone receptor 1 (MCH-R1) antagonists is described. An extensive structure-activity relationship (SAR) study, probing members of this family that contain a variety of aryl and heteroaryl groups at C-5 of the naphtho[1,2-b]furan-2-carboxamide skeleton and having different chain linker lengths, led to the identification of the 5-(4-pyridinyl) substituted analog 10b as a highly potent MCH-R1 antagonist with an IC50 value of 3 nM...
2013: Chemical & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/24040392/fine-tuning-of-spatial-arrangement-of-enzymes-in-a-pcna-mediated-multienzyme-complex-using-a-rigid-poly-l-proline-linker
#13
Tomoaki Haga, Hidehiko Hirakawa, Teruyuki Nagamune
Inspired by natural multienzyme complexes, many types of artificial multienzyme complexes have recently been constructed. We previously constructed a self-assembled complex of a bacterial cytochrome P450 and its ferredoxin and ferredoxin reductase partners using heterotrimerization of proliferating cell nuclear antigen (PCNA) from Sulfolobus solfataricus. In this study, we inserted different peptide linkers between ferredoxin and the PCNA subunit, and examined the effect on activity of the self-assembled multienzyme complex...
2013: PloS One
https://www.readbyqxmd.com/read/24038207/highly-efficient-c-h-oxidative-activation-by-a-porous-mn-iii-porphyrin-metal-organic-framework-under-mild-conditions
#14
Ming-Hua Xie, Xiu-Li Yang, Yabing He, Jian Zhang, Banglin Chen, Chuan-De Wu
A simple strategy to rationally immobilize metalloporphyrin sites into porous mixed-metal-organic framework (M'MOF) materials by a metalloligand approach has been developed to mimic cytochrome P450 monooxygenases in a biological system. The synthesized porous M'MOF of [Zn2 (MnOH-TCPP)(DPNI)]⋅0.5 DMF⋅EtOH⋅5.5 H2 O (CZJ-1; CZJ=Chemistry Department of Zhejiang University; TCPP=tetrakis(4-carboxyphenyl)porphyrin); DPNI=N,N'-di(4-pyridyl)-1,4,5,8-naphthalenetetracarboxydiimide) has the type of doubly interpenetrated cubic α-Po topology in which the basic Zn2 (COO)4 paddle-wheel clusters are bridged by metalloporphyrin to form two-dimensional sheets that are further bridged by the organic pillar linker DPNI to form a three-dimensional porous structure...
October 11, 2013: Chemistry: a European Journal
https://www.readbyqxmd.com/read/24036972/structure-and-function-of-cytochrome-p450s-in-insect-adaptation-to-natural-and-synthetic-toxins-insights-gained-from-molecular-modeling
#15
REVIEW
Mary A Schuler, May R Berenbaum
Over evolutionary time, insect herbivores have adapted to the presence of natural toxins and more recently to synthetic insecticides in or on the plants they consume. Biochemical analyses and molecular modeling of the cytochrome P450 monooxygenases (P450s) that metabolize these compounds have provided insight into the many variations affecting their catalytic activity. Phylogenetically distinct P450s may metabolize similar substrates, and phylogenetically similar P450s may metabolize different substrates; as well, some P450s process broad arrays of both phytochemicals and synthetic insecticides, while closely related P450s are restricted to a narrow range of phytochemicals...
September 2013: Journal of Chemical Ecology
https://www.readbyqxmd.com/read/22878120/cytochrome-b-5-forms-homomeric-complexes-in-living-cells
#16
Karl-Heinz Storbeck, Amanda C Swart, Nicolaas Lombard, Craig V Adriaanse, Pieter Swart
Cytochrome b(5) (cyt-b(5)) is a ubiquitous hemoprotein also associated with microsomal cytochrome P450 17α-hydroxylase/17,20 lyase (CYP17A1). In the steroidogenic pathway CYP17A1 catalyses the metabolism of pregnenolone, yielding both glucocorticoid and androgen precursors. While not affecting the 17α-hydroxylation of pregnenolone, cyt-b(5) augments the 17,20 lyase reaction of 17-hydroxypregnenolone, catalyzing the formation of DHEA, through direct protein-protein interactions. In this study, multimeric complex formation of cyt-b(5) and the possible regulatory role of these complexes were investigated...
November 2012: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/22752008/in-vitro-characterization-of-the-drug-drug-interaction-potential-of-catabolites-of-antibody-maytansinoid-conjugates
#17
John A Davis, Dan A Rock, Larry C Wienkers, Josh T Pearson
The in vitro characterization of the inhibition potential of four representative maytansinoid species observed upon hepatic and/or tumor in vivo processing of antibody-maytansine conjugates (AMCs) with cleavable and noncleavable linkers is reported. We investigated the free maytansinoid species N(2')-deacetyl-N(2')-(3-mercapto-1-oxopropyl)-maytansine (DM1), (S)-methyl-DM1, and N(2')-deacetyl-N(2')-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4) as representative cleavable linker catabolites and Lysine-N(ε)-N-succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate-DM1 (Lys-MCC-DM1) as the representative noncleavable linker catabolite...
October 2012: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/22411763/factors-that-restrict-the-cell-permeation-of-cyclic-prodrugs-of-an-opioid-peptide-part-3-synthesis-of-analogs-designed-to-have-improved-stability-to-oxidative-metabolism
#18
Rebecca Nofsinger, Tarra Fuchs-Knotts, Ronald T Borchardt
Previously, our laboratory reported that cyclic peptide prodrugs of the opioid peptide H-Tyr-D-Ala-Gly-Phe-D-Leu-OH (DADLE) are metabolized by cytochrome P450 (CYP450) enzymes, which limits their systemic exposure after oral dosing to animals. In an attempt to design more metabolically stable cyclic prodrugs of DADLE, we synthesized analogs of DADLE cyclized with a coumarinic acid linker (CA; CA-DADLE), which contained modifications in the amino acid residues known to be susceptible to CYP450 oxidation. Metabolic stability and metabolite identification studies of CA-DADLE and its analogs were then compared using rat liver microsomes (RLM), guinea pig liver microsomes (GPLM), and human liver microsomes (HLM), as well as recombinant human recombinant cytochrome P450 3A4 (hCYP3A4)...
September 2012: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/22038382/novel-iron-sulfur-containing-nadph-reductase-from-nocardia-farcinica-ifm10152-and-fusion-construction-with-cyp51-lanosterol-demethylase
#19
Kwon-Young Choi, Eun-Ok Jung, Da-Hye Jung, Bishnu Prasad Pandey, Nahum Lee, Hyungdon Yun, Hyung-Yun Park, Byung-Gee Kim
CYP51, a sterol 14α-demethylase, is one of the key enzymes involved in sterol biosynthesis and requires electrons transferred from its redox partners. A unique CYP51 from Nocardia farcinica IFM10152 forms a distinct cluster with iron-sulfur containing NADPH-P450 reductase (FprD) downstream of CYP51. Previously, sequence alignment of nine reductases from N. farcinica revealed that FprC, FprD, and FprH have an additional sequence at their N-termini that has very high identity with iron-sulfur clustered ferredoxin G (FdxG)...
March 2012: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/21328910/-mass-spectrometric-identification-of-interaction-sites-between-cytochrome-p450-2b4-and-nadph-cytochrome-p450-reductase
#20
A V Ivanov, A T Kopylov, V G Zgoda, I Iu Toropygin, E V Khriapova, Iu D Ivanov
We determined the interaction sites of the cytochrome P450's protein-partners: 2B4 (d-2B4) and NADPH-cytochrome P450 of reductase (d-Fp). While in operation, these proteins are forming the complexes. We used 4-4'-dithio(bisphenyl)azide linker for non-specific covalent coupling of d-2B4 complexes with d-Fp in Emulgen-913-monomerized system. Covalently-linked peptides in this complex were identified with ESI-MS/MS. Several sites of these proteins' binding with each other were revealed. Based on them, a model of intermolecular protein interactions was created...
January 2010: Biomedit︠s︡inskai︠a︡ Khimii︠a︡
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