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Qingfei Zheng, Yukang Gong, Yujiao Guo, Zhixiong Zhao, Zhuhua Wu, Zixuan Zhou, Dandan Chen, Lifeng Pan, Wen Liu
Here, we provide structural insights into PyrE3, a flavin-dependent [4 + 2] cyclase that catalyzes trans-decalin formation in the biosynthesis of pyrroindomycins. PyrE3 shares an architecture/domain organization head-to-tail similarity with the members of the family of para-hydroxybenzoate hydroxylase (pHBH)-fold monooxygenases, and possesses a flavin adenine dinucleotide (FAD)-binding domain, a middle domain, and a C-terminal thioredoxin-like domain. The FAD-binding domain forms a central hub of the protein structure, and binds with FAD in a "closed" conformation of pHBH-fold family monooxygenases known for their highly dynamic catalytic processes...
April 2, 2018: Cell Chemical Biology
Bu-Yeo Kim, Hye-Sun Lim, Yoonju Kim, Yu Jin Kim, Imhoi Koo, Soo-Jin Jeong
Despite many efforts to alleviate the pathological conditions of Alzheimer's disease (AD), effective therapeutic drugs have not been developed, mainly because of the lack of molecular information about AD and animal models. We observed the reciprocal regulation of AD-associated genes (AD genes) and their related functions. Upregulated AD genes were positioned in central regions in the protein-protein interaction network and were involved in inflammation and DNA repair pathways. Downregulated AD genes positioned in the periphery of the network were associated with metabolic pathways...
April 14, 2018: Molecular Neurobiology
Anya Kalsbeek, Jenna Veenstra, Jason Westra, Craig Disselkoen, Kristin Koch, Katelyn A McKenzie, Jacob O'Bott, Jason Vander Woude, Karen Fischer, Greg C Shearer, William S Harris, Nathan L Tintle
Recent analyses have suggested a strong heritable component to circulating fatty acid (FA) levels; however, only a limited number of genes have been identified which associate with FA levels. In order to expand upon a previous genome wide association study done on participants in the Framingham Heart Study Offspring Cohort and FA levels, we used data from 2,400 of these individuals for whom red blood cell FA profiles, dietary information and genotypes are available, and then conducted a genome-wide evaluation of potential genetic variants associated with 22 FAs and 15 FA ratios, after adjusting for relevant dietary covariates...
2018: PloS One
Joana Reis, Nicola Manzella, Fernando Cagide, Jeanne Mialez-Perez, Eugenio Uriarte, Angelo Parini, Fernanda M Borges, Claudia Binda
Monoamine oxidase B (MAO-B) is a validated drug target for Parkinson's disease. Chromone derivatives were identified as novel potent and reversible MAO-B inhibitors and herewith we report on a crystallographic and biochemical analysis to investigate their inhibition mechanism. The crystal structures of human MAO-B in complex with three chromone analogs bearing different substituents on the exocyclic aromatic ring (determined at 1.6-1.8 Å resolution) showed that they all bind in the active site cavity of the protein with the chromone moiety located in front of the FAD cofactor...
April 12, 2018: Journal of Medicinal Chemistry
Yan Wang, Min Sun, Jinping Qiao, Jin Ouyang, Na Na
The role of the coenzyme flavin adenine dinucleotide (FAD) in the catalytic oxidation of glucose was elucidated by MS using a new extraction and ionization method. By a multiphase flow of liquid-gas, extractive electrospray ionization was achieved, and this technique (MF-EESI) decreased the salt-matrix interference effectively, avoided salt crystallizations at the capillary tip and increased ionization efficiency by a concentric-sprayed solvent. Notably, two intermediate complexes of FAD-glucose have been observed and differentiated for the first time using this MF-EESI technique...
January 21, 2018: Chemical Science
Jane A Armstrong, Nicole J Cash, Yulin Ouyang, Jack C Morton, Michael Chvanov, Diane Latawiec, Muhammad Awais, Alexei V Tepikin, Robert Sutton, David N Criddle
Mitochondrial dysfunction lies at the core of acute pancreatitis (AP). Diverse AP stimuli induce Ca2+ -dependent formation of the mitochondrial permeability transition pore (MPTP), a solute channel modulated by cyclophilin D (CypD), whose formation causes ATP depletion and necrosis. Oxidative stress reportedly triggers MPTP formation and is elevated in clinical AP, but how reactive oxygen species influence cell death is unclear. Here, we assessed potential MPTP involvement in oxidant-induced effects on pancreatic acinar cell bioenergetics and fate...
April 6, 2018: Journal of Biological Chemistry
Ryota Miyazaki, Tomohiko Yamazaki, Keiichi Yoshimatsu, Katsuhiro Kojima, Ryutaro Asano, Koji Sode, Wakako Tsugawa
Glucoside 3‑dehydrogenase (G3DH) is a flavin adenine dinucleotide (FAD)-containing oxidoreductase that catalyzes the oxidation of the hydroxy group on the C-3 position of pyranose and shows broad substrate specificity by oxidizing many saccharides. Due to unique site specificity and wide substrate specificity, G3DHs can be used for synthesis of sugar derivatives, anodic catalysis in biofuel cells, multi-sugar analysis using enzyme electrode, and for enzymatic detection of 1,5‑anhydro‑d‑glucitol, a clinical marker for diabetes...
March 7, 2018: Bioelectrochemistry
Michel Oelschlägel, Juliane Zimmerling, Dirk Tischler
Styrene is one of the most produced and processed chemicals worldwide and is released into the environment during widespread processing. But, it is also produced from plants and microorganisms. The natural occurrence of styrene led to several microbiological strategies to form and also to degrade styrene. One pathway designated as side-chain oxygenation has been reported as a specific route for the styrene degradation among microorganisms. It comprises the following enzymes: styrene monooxygenase (SMO; NADH-consuming and FAD-dependent, two-component system), styrene oxide isomerase (SOI; cofactor independent, membrane-bound protein) and phenylacetaldehyde dehydrogenase (PAD; NAD+ -consuming) and allows an intrinsic cofactor regeneration...
2018: Frontiers in Microbiology
Marina V Serebryakova, Yulia V Bertsova, Svyatoslav S Sokolov, Alexander A Kolesnikov, Alexander A Baykov, Alexander V Bogachev
One of the three domains of kinetoplastid NADH:fumarate oxidoreductase (FRD) is homologous to bacterial flavin transferase that catalyzes transfer of FMN residue from FAD to threonine in flavoproteins. Leptomonas pyrrhocoris FRD produced in yeast cells, which lack flavin transferase gene in their proteome, reduces fumarate in the presence of NADH and contains an FMN residue covalently linked to a Ser9 residue. The conserved flavinylation motif of FRD, D3 (g/s)x(s/t)(s/g)AS9 , is similar to the Dxx(s/t)gAT motif recognized by flavin transferase in prokaryotic proteins...
April 2, 2018: Biochimie
Jessica Petri, Yosuke Shimaki, Wanting Jiao, Hannah R Bridges, Euan R Russell, Emily J Parker, David Aragão, Gregory M Cook, Yoshio Nakatani
Type II NADH:quinone oxidoreductase (NDH-2) is a proposed drug-target of major pathogenic microorganisms such as Mycobacterium tuberculosis and Plasmodium falciparum. Many NDH-2 inhibitors have been identified, but rational drug development is impeded by the lack of information regarding their mode of action and associated inhibitor-bound NDH-2 structure. We have determined the crystal structure of NDH-2 complexed with a quinolone inhibitor 2-heptyl-4-hydroxyquinoline-N-oxide (HQNO). HQNO is nested into the slot-shaped tunnel of the Q-site, in which the quinone-head group is clamped by Q317 and I379 residues, and hydrogen-bonds to FAD...
April 2, 2018: Biochimica et Biophysica Acta
Michael S Wolfe
Genetics strongly implicate the amyloid β-peptide (Aβ) in the pathogenesis of Alzheimer's disease. Dominant missense mutation in the presenilins and the amyloid precursor protein (APP) cause early-onset familial Alzheimer's disease (FAD). As presenilin is the catalytic component of the γ-secretase protease complex that produces Aβ from APP, mutation of the enzyme or substrate that produce Aβ leads to FAD. However, the mechanism by which presenilin mutations cause FAD has been controversial, with gain of function and loss of function offered as binary choices...
April 4, 2018: Neurochemical Research
Kechinyere C Iheduru-Anderson, Monika M Wahi
INTRODUCTION: Successful transition to practice of internationally educated nurses (IENs) can critically affect quality of care. The aim of this study was to characterize the facilitators and barriers to transition of Nigerian IENs (NIENs) to the United States health care setting. METHOD: Using a descriptive phenomenology approach, 6 NIENs were interviewed about their transitional experiences in the United States. Thematic methods were used for data analysis. RESULTS: The three major themes identified from the participants' stories were "fear/anger and disappointment" (FAD), "road/journey to success/overcoming challenges" (RJO), and "moving forward" (MF)...
April 1, 2018: Journal of Transcultural Nursing: Official Journal of the Transcultural Nursing Society
Koryun Hakobyan, Yuri Poghosyan, Aram Kasyan
'Krokodil' is the street name of a new synthetic drug mixture. It is a light brown liquid that is used intravenously without previous purification. Osteonecrosis of the jaw (ONJ) is a common complication among Krokodil users. Krokodil drug-related ONJ presents as alveolar process exposure in the oral cavity. Surgery is the main method for treatment of Krokodil drug-related ONJ patients. In a study by Poghosyan et al., no cases of recurrence were seen after surgery on the maxilla, but 38% of cases (8/21) developed an oroantral communication after surgical treatment for maxillary osteonecrosis (Poghosyan et al...
March 20, 2018: Journal of Cranio-maxillo-facial Surgery
Dirk Tischler, Ringo Schwabe, Lucas Siegel, Kristin Joffroy, Stefan R Kaschabek, Anika Scholtissek, Thomas Heine
Herein we describe the first representative of an E2-type two-component styrene monooxygenase of proteobacteria. It comprises a single epoxidase protein ( Vp StyA1) and a two domain protein ( Vp StyA2B) harboring an epoxidase (A2) and a FAD-reductase (B) domain. It was annotated as Vp StyA1/ Vp StyA2B of Variovorax paradoxus EPS. Vp StyA2B serves mainly as NADH:FAD-oxidoreductase. A K m of 33.6 ± 4.0 µM for FAD and a k cat of 22.3 ± 1.1 s-1 were determined and resulted in a catalytic efficiency ( k cat K m -1 ) of 0...
April 2, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Irene Piaceri, Daniele Imperiale, Enrico Ghidoni, Cristiana Atzori, Silvia Bagnoli, Camilla Ferrari, Silvana Ungari, Luca Ambrogio, Sandro Sorbi, Benedetta Nacmias
BACKGROUND: During the twentieth century, frontotemporal dementia (FTD) was often misdiagnosed, confused with Alzheimer's disease or psychiatric disorders, jeopardizing care and research. OBJECTIVE: To analyze the FTD genes in the DNA samples of patients belonging to families clinically classified as probable Alzheimer's disease (FAD) in the early 1990s and not carrying mutation in the three main genes linked to FAD (Presenilin 1, Presenilin 2, and Amyloid precursor protein)...
2018: Journal of Alzheimer's Disease: JAD
Steinunn Thordardottir, Caroline Graff
This is a brief summary of the findings from the Swedish study on familial Alzheimer's disease (FAD). Similar to other FAD studies, it includes prospective assessments of cognitive function, tissue sampling, and technical analyses such as MRI and PET. This 24-year-old study involves 69 individuals with a 50% risk of inheriting a disease-causing mutation in presenilin 1 (PSEN1 H163Y or I143T), or amyloid precursor protein (the Swedish APP or the arctic APP mutation) who have made a total of 169 visits. Our results show the extraordinary power in this study design to unravel the earliest changes in preclinical AD...
March 29, 2018: Journal of Alzheimer's Disease: JAD
Elena Maklashina, Sany Rajagukguk, T M Iverson, Gary Cecchini
Complex II (SdhABCD) is a membrane-bound component of mitochondrial and bacterial electron transport chains as well as of the TCA cycle. In this capacity, it catalyzes the reversible oxidation of succinate. SdhABCD contains the SDHA protein harboring a covalently bound FAD redox center and the iron-sulfur (Fe-S) protein SDHB, containing three distinct Fe-S centers. When assembly of this complex is compromised, the flavoprotein SDHA may accumulate in the mitochondrial matrix or bacterial cytoplasm. Whether the unassembled SDHA has any catalytic activity, for example, in succinate oxidation, fumarate reduction, reactive oxygen species (ROS) generation, or other off-pathway reactions is not known...
April 2, 2018: Journal of Biological Chemistry
Ae Kyung Park, Gyeong Hweon Lee, Do Wan Kim, Eun Hyuk Jang, Ha Taek Kwon, Young Min Chi
Unsaturated fatty acids are toxic to various bacteria, causing their death or growth inhibition. To prevent this toxicity, unsaturated fatty acids should be converted into saturated fatty acids via hydrogenation reaction, which is the complete reduction of double bonds on the carbon chain. In a recent report, we observed that Stenotrophomonas sp. KCTC 12332 exhibited a high biotransformation activity of oleic acid (OA) in 10-hydroxystearic acid and identified the gene encoding oleate hydratase (OhySt) by complete genomic analysis...
March 30, 2018: Biochemical and Biophysical Research Communications
Habib Diallo, Hasnae Alaoui Mhamdi, Salma Elouarzazi, Mohamed Fadli, Rhizlane Belbaraka
BACKGROUND: Managing metastatic Renal Cell Carcinoma (mRCC) has been revolutionized during the first decade of the 21st century due to the development of targeted therapies. The sunitinib is an oral multi-targeted receptor Tyrosine Kinase Inhibitor (TKI). It became the first targeted therapy as first-line treatment to improve the survival of patients with metastatic kidney cancer. This treatment consists in the oral intake of 50 mg of sunitinib per day in a 6 -week cycle including 4 weeks of treatment intake (the "on" week) followed by a 2-week break (the off week)...
January 2018: Gulf Journal of Oncology
Guang Liu, JingJing Wang, Yi Hou, Yan-Bo Huang, JiaJia Wang, Cunzhi Li, ShiJun Guo, Lin Li, Song-Qing Hu
This study investigated characteristics of recombinant wheat Endoplasmic Reticulum Oxidoreductin 1 (wEro1) and its influence on Chinese steamed bread (CSB) qualities. The purified wEro1 monomer, which contained two conserved redox active motif sites, bound to flavin adenine dinucleotide (FAD) cofactor with a molecular weight of ∼47 kDa. wEro1 catalyzed the reduction of both bound and free FAD, and its reduction activity of free FAD reached 7.8 U/mg. Moreover, wEro1 catalyzed the oxidation of dithiothreitol and wheat protein disulfide isomerase (wPDI)...
August 1, 2018: Food Chemistry
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