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Pavlo Bielytskyi, Daniel Gräsing, Kaustubh R Mote, Karthick Babu Sai Sankar Gupta, Shimon Vega, P K Madhu, A Alia, Jörg Matysik
In the present study, we exploit the light-induced hyperpolarization occurring on 13 C nuclei due to the solid-state photochemically induced dynamic nuclear polarization (photo-CIDNP) effect to boost the NMR signal intensity of selected protons via inverse cross-polarization. Such hyperpolarization transfer is implemented into 1 H-detected two-dimensional 13 C-1 H correlation magic-angle-spinning (MAS) NMR experiment to study protons in frozen photosynthetic reaction centers (RCs). As a first trial, the performance of such an experiment is tested on selectively 13 C labeled RCs from the purple bacteria of Rhodobacter sphaeroides...
June 8, 2018: Journal of Magnetic Resonance
Paula Pluta, Pietro Roversi, Ganeko Bernardo-Seisdedos, Adriana L Rojas, Jonathan B Cooper, Shuang Gu, Richard W Pickersgill, Oscar Millet
Human porphobilinogen deaminase (PBGD), the third enzyme in the heme pathway, catalyzes four times a single reaction to convert porphobilinogen into hydroxymethylbilane. Remarkably, PBGD employs a single active site during the process, with a distinct yet chemically equivalent bond formed each time. The four intermediate complexes of the enzyme have been biochemically validated and they can be isolated but they have never been structurally characterized other than the apo- and holo-enzyme bound to the cofactor...
June 14, 2018: Biochimica et Biophysica Acta
Yan Li, Ying Ru Loh, Alvin W Hung, CongBao Kang
Zika virus (ZIKV) protease is a two-component complex in which NS3 contains the catalytic triad and NS2B cofactor region is important for protease folding and activity. A protease construct-eZiPro lacking the transmembrane domains of NS2B was designed. Structural study on eZiPro reveals that the Thr-Gly-Lys-Arg (TGKR) sequence at the C-terminus of NS2B binds to the active site after cleavage. Another bZiPro construct only contains NS2B cofactor region and the N-terminus of NS3 without any artificial linker or protease cleavage site, giving rise to an empty pocket accessible to substrate and inhibitor binding...
June 13, 2018: Biochemical and Biophysical Research Communications
Unekwu M Yakubu, Kevin A Morano
Cellular protein homeostasis (proteostasis) is maintained by a broad network of proteins involved in synthesis, folding, triage, repair and degradation. Chief among these are molecular chaperones and their cofactors that act as powerful protein remodelers. The growing realization that many human pathologies are fundamentally diseases of protein misfolding (proteopathies) has generated interest in understanding how the proteostasis network impacts onset and progression of these diseases. In this minireview, we highlight recent progress in understanding the enigmatic Hsp110 class of heat shock protein that acts as both a potent nucleotide exchange factor to regulate activity of the foldase Hsp70, and as a passive chaperone capable of recognizing and binding cellular substrates on its own, and its integration into the proteostasis network...
June 1, 2018: Biological Chemistry
Vanya Icheva, Martina Nowak-Machen, Ulrich Budde, Karl Jaschonek, Felix Neunhoeffer, Matthias Kumpf, Michael Hofbeck, Christian Schlensak, Gesa Wiegand
BACKGROUND: Cardiac surgery of the newborn and infant with complex congenital heart disease (CHD) is associated with a high rate of intraoperative bleeding complications. CHD-related anatomic features such as valve stenoses or patent arterial ducts can lead to enhanced shear stress in blood stream and thus cause acquired von Willebrand syndrome (aVWS). OBJECTIVE: To evaluate the intraoperative incidence and impact of aVWS after cardiopulmonary bypass (CPB) in neonates and infants with complex CHD...
June 16, 2018: Journal of Thrombosis and Haemostasis: JTH
Franz Schaefer, Gianluigi Ardissino, Gema Ariceta, Fadi Fakhouri, Marie Scully, Nicole Isbel, Åsa Lommelé, Varant Kupelian, Christoph Gasteyger, Larry A Greenbaum, Sally Johnson, Masayo Ogawa, Christoph Licht, Johan Vande Walle, Véronique Frémeaux-Bacchi
Atypical hemolytic uremic syndrome (aHUS) is a rare, genetic, life-threatening disease. The Global aHUS Registry collects real-world data on the natural history of the disease. Here we characterize end-stage renal disease (ESRD)-free survival, the rate of thrombotic microangiopathy, organ involvement and the genetic background of 851 patients in the registry, prior to eculizumab treatment. A sex-specific difference was apparent according to age at initial disease onset as the ratio of males to females was 1...
June 12, 2018: Kidney International
Shan Chen, Jonatan C Campillo-Brocal, Per Berglund, Maria Svedendahl Humble
The amine transaminase from Vibrio fluvialis (Vf-ATA) is an attractive enzyme with applications within Biocatalysis for the preparation of chiral amines. Various catalytic properties of Vf-ATA have been investigated, but a biophysical characterization of its stability has been lacking. Today, the industrial application of Vf-ATA is limited by its low operational stability. In order to enhance the knowledge regarding the structural stability of ATAs, general characterizations of different ATAs are required. In this work, the stability of Vf-ATA was explored...
June 12, 2018: Journal of Biotechnology
Eva-Maria Weick, M Rhyan Puno, Kurt Januszyk, John C Zinder, Michael A DiMattia, Christopher D Lima
The ribonucleolytic RNA exosome interacts with RNA helicases to degrade RNA. To understand how the 3' to 5' Mtr4 helicase engages RNA and the nuclear exosome, we reconstituted 14-subunit Mtr4-containing RNA exosomes from Saccharomyces cerevisiae, Schizosaccharomyces pombe, and human and show that they unwind structured substrates to promote degradation. We loaded a human exosome with an optimized DNA-RNA chimera that stalls MTR4 during unwinding and determined its structure to an overall resolution of 3.45 Å by cryoelectron microscopy (cryo-EM)...
June 14, 2018: Cell
Natercia Bras, Pedro Fernandes, Maria João Ramos
Liver's glycogen phosphorylase (GP) is a key enzyme to human health, as its increased activity is associated with type 2 diabetes. The GP catalytic mechanism has been explored by quantum mechanics/molecular mechanics methods. Herein, we propose a mechanism that proceeds via three steps: i) it begins with a H transfer from the phosphate group of the pyridoxal 5'-phosphate (HPO42--PLP) cofactor to the phosphate substrate; ii) then, the glycosidic linkage is cleaved through protonation of the glycosidic oxygen atom by an hydroxyl of the inorganic phosphate group; and iii) an oxygen atom of the phosphate performs a nucleophilic attack on the anomeric carbon of glucose, concomitantly with the return of a proton from phosphate to PO43--PLP, which finally leads to the formation of the glucose-1-phosphate product and recovers the initial state of the PLP cofactor...
June 15, 2018: ChemMedChem
Giuseppe Grasso
Amyloid-β peptide (Aβ) accumulation and aggregation have been considered for many years the main cause of Alzheimer's disease (AD), and therefore have been the principal target of investigation as well as of the proposed therapeutic approaches (Grasso [2011] Mass Spectrom Rev. 30: 347-365). However, the amyloid cascade hypothesis, which considers Aβ accumulation the only causative agent of the disease, has proven to be incomplete if not wrong. In recent years, actors such as metal ions, oxidative stress, and other cofactors have been proposed as possible co-agents or, in some cases, main causative factors of AD...
June 15, 2018: Mass Spectrometry Reviews
Claus Nielsen, Morten Steen Nørby, Jacob Kongsted, Ilia A Solov'yov
The magnetic compass sense utilized by migratory birds for long-distance navigation functions only once light of a certain wavelength is present. This piece of evidence fits partially with the popular hypothesis of chemical magnetoreception in cryptochrome proteins, located in the bird retina. According to this hypothesis a magnetosensitive radical pair is produced after photoexcitation of an FAD co-factor inside cryptochrome, and as such the absorption properties of FAD is of crucial importance for cryptochrome activation...
June 15, 2018: Journal of Physical Chemistry Letters
Eric J Moore, Viktoria Steck, Priyanka Bajaj, Rudi Fasan
Hemoproteins have recently emerged as promising biocatalysts for promoting a variety of carbene transfer reactions including cyclopropanation and Y-H insertion (Y = N, S, Si, B). For these and synthetic carbene transfer catalysts alike, achieving high chemoselectivity toward cyclopropanation in olefin substrates bearing unprotected Y-H groups has proven remarkably challenging due to competition from the more facile carbene Y-H insertion reaction. In this report, we describe the development of a novel artificial metalloenzyme based on an engineered myoglobin incorporating a serine-ligated Co-porphyrin cofactor that is capable of offering high selectivity toward olefin cyclopropanation over N-H and Si-H insertion...
June 15, 2018: Journal of Organic Chemistry
Marta A Uzarska, Jonathan Przybyla-Toscano, Farah Spangar, Flavien Zannini, Roland Lill, Ulrich Mühlenhoff, Nicolas Rouhier
Numerous proteins require iron‑sulfur (Fe-S) clusters as cofactors for their function. Their biogenesis is a multi-step process occurring in the cytosol and mitochondria of all eukaryotes and additionally in plastids of photosynthetic eukaryotes. A basic model of Fe-S protein maturation in mitochondria has been obtained based on studies achieved in mammals and yeast, yet some molecular details, especially of the late steps, still require investigation. In particular, the late-acting biogenesis factors in plant mitochondria are poorly understood...
June 11, 2018: Biochimica et Biophysica Acta
Christopher A Lopez, Eric P Skaar
Transition metals are required cofactors for many proteins that are critical for life, and their concentration within cells is carefully maintained to avoid both deficiency and toxicity. To defend against bacterial pathogens, vertebrate immune proteins sequester metals, in particular zinc, iron, and manganese, as a strategy to limit bacterial acquisition of these necessary nutrients in a process termed "nutritional immunity." In response, bacteria have evolved elegant strategies to access metals and counteract this host defense...
June 13, 2018: Cell Host & Microbe
Joseph H Lynch, Na Sa, Sompop Saeheng, Nadia Raffaelli, Sanja Roje
The flavin cofactors FMN and FAD are required for a wide variety of biological processes, however, little is known about their metabolism. Here, we report the cloning and biochemical characterization of the Saccharomyces cerevisiae pyrophosphatase Fpy1p. Genetic and functional studies suggest that Fpy1p may play a key role in flavin metabolism and is the first-reported non-Nudix superfamily enzyme to display FAD pyrophosphatase activity. Characterization of mutant yeast strains found that deletion of fpy1 counteracts the adverse effects that are caused by deletion of flx1, a known mitochondrial FAD transporter...
2018: PloS One
Milda Mickute, Milda Nainyte, Lina Vasiliauskaite, Alexandra Plotnikova, Viktoras Masevicius, Saulius Klimašauskas, Giedrius Vilkaitis
S-adenosyl-L-methionine-dependent 2'-O-methylati-on of the 3'-terminal nucleotide plays important roles in biogenesis of eukaryotic small non-coding RNAs, such as siRNAs, miRNAs and Piwi-interacting RNAs (piRNAs). Here we demonstrate that, in contrast to Mg2+/Mn2+-dependent plant and bacterial homologues, the Drosophila DmHen1 and human HsHEN1 piRNA methyltransferases require cobalt cations for their enzymatic activity in vitro. We also show for the first time the capacity of the animal Hen1 to catalyse the transfer of a variety of extended chemical groups from synthetic analogues of the AdoMet cofactor onto a wide range (22-80 nt) of single-stranded RNAs permitting their 3'-terminal functionalization and labelling...
June 13, 2018: Nucleic Acids Research
Katarina Kopcova, Ludmila Blascakova, Tibor Kozar, Daniel Jancura, Marian Fabian
Second-derivative absorption spectroscopy was employed to monitor the response of effective symmetry of cytochromes a and a3 to the redox and ligation states of bovine cytochrome c oxidase (CcO). The Soret band , * electronic transitions were used to display the changes in symmetry of these chromophores induced by the reduction of CcO inhibited by the exogenous ligands and during the catalytic turnover. Second derivative of the difference absorption spectra revealed only a single Soret band for the oxidized cytochromes a, a3 and cyanide-ligated a3...
June 14, 2018: Biochemistry
Maryam Gulshan, Keisuke Yaku, Keisuke Okabe, Arshad Mahmood, Tsutomu Sasaki, Masashi Yamamoto, Keisuke Hikosaka, Isao Usui, Tadahiro Kitamura, Kazuyuki Tobe, Takashi Nakagawa
Nicotinamide adenine dinucleotide (NAD) is an important cofactor that regulates various biological processes, including metabolism and gene expression. As a coenzyme, NAD controls mitochondrial respiration through enzymes of the tricarboxylic acid (TCA) cycle, β-oxidation, and oxidative phosphorylation and also serves as a substrate for posttranslational protein modifications, such as deacetylation and ADP-ribosylation by sirtuins and poly(ADP-ribose) polymerase (PARP), respectively. Many studies have demonstrated that NAD levels decrease with aging and that these declines cause various aging-associated diseases...
June 14, 2018: Aging Cell
Mario Mastrangelo
This review offers an update on a group of inborn errors of metabolism causing severe epilepsy with the onset in pediatric age (but also other neurological manifestations such as developmental delay or movement disorders) with available effective or potentially effective treatments. The main pathogenic and clinical features and general recommendations for the diagnostic and therapeutic workup of the following disorders are discussed: vitamin B6 -dependent epilepsies, cerebral folate deficiency, congenital disorders of serine metabolism, biotinidase deficiency, inborn errors of creatine metabolism, molybdenum cofactor deficiency, and glucose transporter 1 deficiency...
January 2018: Journal of Pediatric Neurosciences
Ellen E Gillis, Krystal N Brinson, Olga Rafikova, Wei Chen, Jacqueline B Musall, David G Harrison, Jennifer C Sullivan
We previously published that female spontaneously hypertensive rats (SHR) have significantly greater nitric oxide (NO) bioavailability and NO synthase (NOS) enzymatic activity in the renal inner medulla compared to age-matched males, although the mechanism responsible remains unknown.  Tetrahydrobiopterin (BH4 ) is a critical cofactor required for NO generation, and decreases in BH4 as the result of increases in oxidative stress have been implicated in the pathogenesis of hypertension.  As male SHR are known to have higher levels of oxidative stress compared to female SHR, we hypothesized that relative BH4 deficiency induced by oxidative stress in male SHR results in lower levels of NOS activity in renal inner medulla compared to females...
June 13, 2018: Bioscience Reports
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