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Kell K Andersen, Brian Stougaard Vad, Carsten Scavenius, Jan Johannes Enghild, Daniel Erik Otzen
Infection by the opportunistic pathogen Pseudomonas aeruginosa (PA) is accompanied by the secretion of virulence factors such as the secondary metabolite rhamnolipid (RL) as well as an array of bacterial enzymes, including the protease elastase. The human immune system tries to counter this via defensive proteins such as human lysozyme (HLZ). HLZ targets the bacterial cell wall but may also have other antimicrobial activities. The enzyme contains four disulfide bonds and shows high thermodynamic stability and resistance to proteolytic attack...
December 8, 2016: Biochemistry
Jonathan L Sanchez, Zachary Romero, Angelica Quinones, Kristiane R Torgeson, Nancy C Horton
Infection with human parvovirus B19 (B19V) has been associated with a myriad of illnesses, including erythema infectiosum (Fifth disease), hydrops fetalis, arthropathy, hepatitis, cardiomyopathy and also possibly the triggering of any number of different autoimmune diseases. B19V NS1 is a multi-domain protein that plays a critical role in viral replication, with predicted nuclease, helicase, and gene transactivation activities. Herein we investigate the biochemical activities of the nuclease domain (residues 2-176) of B19V NS1 (NS1-nuc) in sequence-specific DNA binding of the viral origin of replication sequences, as well as those of promoter sequences including the viral p6 and the human p21, TNFα, and IL-6 promoters previously identified in NS1-dependent transcriptional transactivation...
November 4, 2016: Biochemistry
Lukas Hofmann, Yaroslav Tsybovsky, Nathan S Alexander, Darwin Babino, Nicole Yishi Leung, Craig Montell, Surajit Banerjee, Johannes von Lintig, Krzysztof Palczewski
The 11-cis-retinylidene chromophore of visual pigments isomerizes upon interaction with a photon, initiating a downstream cascade of signaling events that ultimately lead to visual perception. 11-cis-Retinylidene is regenerated through the enzymatic transformations collectively called visual cycle. The first and rate-limiting enzymatic reaction within this cycle, i.e. the reduction of all-trans-retinal to all-trans-retinol, is catalyzed by retinol dehydrogenases. Here, we solved the structure of Drosophila melanogaster photoreceptor retinol dehydrogenase (PDH) isoform C (PDHc) that belongs to the short-chain dehydrogenase/reductase (SDR) family...
November 3, 2016: Biochemistry
Hong Qiu Smith, Thomas James Smith
Glutamate dehydrogenase (GDH) catalyzes the oxidative deamination of L-glutamate and in animals is highly regulated. GDH in Hyperinsulinism/hyperammonemia syndrome (HHS) patients lack GTP inhibition resulting in hypersecretion of insulin upon protein consumption. This suggests insulin secretion could be stimulated with GDH activators. A high throughput screen yielded one potent activator N1-[4-(2-aminopyrimidin-4-yl)phenyl]-3-(trifluoromethyl)benzene-1-sulfonamide (75-E10). 75-E10 is ~1,000 fold more efficacious than the synthetic activator, BCH, and is at least as effective as ADP...
November 3, 2016: Biochemistry
Dipanwita Batabyal, Ariel Lewis-Ballester, Syun-Ru Yeh, Thomas L Poulos
The camphor monooxygenase, cytochrome P450cam, exhibits a strict requirement for its own redox partner, putidaredoxin (Pdx), a two iron-sulfur ferredoxin. The closest homolog to P450cam is CYP101D1 which is structurally very similar, uses a similar redox partner, and exhibits nearly identical enzymatic properties in the monooxygenation of camphor to give the same single 5-exo-hydroxy camphor product. However, CYP101D1 does not strictly require its own ferredoxin (Arx) for activity since Pdx can support CYP101D1 catalysis but Arx cannot support P450cam catalysis...
November 3, 2016: Biochemistry
Per Eugen Kristiansen, Cecilia Persson, Virginia Fuochi, Anders Pedersen, Göran B Karlsson, Jon Nissen-Meyer, Camilla Oppegård
The class IId bacteriocin lactococcin A and the pediocin-like bacteriocins induce membrane leakage and cell death by specifically binding the mannose phophotransferase system (man-PTS) on their target cells. The bacteriocins' cognate immunity proteins that protect the producer cell from its own bacteriocin recognize and bind to the bacteriocin-man-PTS complex and thereby block membrane leakage. In this study, we have determined the three-dimensional structure of the lactococcin A immunity protein (LciA) by the use of nuclear magnetic resonance spectroscopy...
November 3, 2016: Biochemistry
Sydney P Thomas, Eunji Kim, Jin-Soo Kim, Ronald T Raines
Ribonuclease inhibitor (RNH1) is a cytosolic protein that binds with femtomolar affinity to human ribonuclease 1 (RNase 1) and homologous secretory ribonucleases. RNH1 contains 32 cysteine residues and has been implicated as an anti-oxidant. Here, we use CRISPR-Cas9 to knockout RNH1 in HeLa cells. We find that cellular RNH1 affords marked protection from the lethal ribonucleolytic activity of RNase 1 but not from oxidants. We conclude that RNH1 protects cytosolic RNA from invading ribonucleases.
November 2, 2016: Biochemistry
Jiangchuan Shen, Hui Peng, Yixiang Zhang, Jonathan C Trinidad, David Peter Giedroc
Recent studies implicate hydrogen sulfide (H2S) oxidation as an important aspect of bacterial antibiotic resistance and sulfide homeostasis. The cst operon of the major human pathogen Staphylococcus aureus is induced by exogenous H2S stress and encodes enzymes involved in sulfide oxidation, including a Group I flavoprotein disulfide oxidoreductase sulfide:quinone oxidoreductase (SQR). In this work, we show that S. aureus SQR catalyzes the two-electron oxidation of sodium sulfide (Na2S) into sulfane sulfur (S0) when provided FAD and a water soluble quinone acceptor...
November 2, 2016: Biochemistry
Jonathan Musila, Holly R Ellis
The flavin reductase of the alkanesulfonate monooxygenase system (SsuE) contains a conserved π-helix located at the tetramer interface that originates from the insertion of Tyr118 in the α4-helix of SsuE. Although the presence of π-helices provide an evolutionary gain of function, the defined role of these discrete secondary structures remains largely unexplored. The Tyr118 residue that generated the π-helix in SsuE was substituted for Ala to evaluate the functional role of this distinctive structural feature...
November 2, 2016: Biochemistry
Lakshmi S Pidugu, Joshua W Flowers, Christopher T Coey, Edwin Pozharski, Marc M Greenberg, Alexander C Drohat
Thymine DNA glycosylase (TDG) is a base excision repair enzyme with key functions in epigenetic regulation. Performing a critical step in a pathway for active DNA demethylation, TDG removes 5-formylcytosine and 5-carboxylcytosine, oxidized derivatives of 5-methylcytosine that are generated by TET (ten-eleven translocation) enzymes. We determined a crystal structure of TDG bound to DNA with a noncleavable (2'-fluoroarabino) analogue of 5-formyldeoxycytidine flipped into its active site, revealing how it recognizes and hydrolytically excises fC...
November 2, 2016: Biochemistry
Olesya Levsh, Ying-Chih Chiang, Chun Fai Tung, Joseph P Noel, Yi Wang, Jing-Ke Weng
Hydroxycinnamoyl-CoA:shikimate hydroxycinnamoyltransferase (HCT) is an essential acyltransferase that mediates flux through plant phenylpropanoid metabolism by catalyzing a reaction between p-coumaroyl-CoA and shikimate, yet it also exhibits broad substrate permissiveness in vitro. How do enzymes like HCT avoid functional derailment by cellular metabolites that qualify as non-native substrates? Here, we combine X-ray crystallography and molecular dynamics to reveal distinct dynamic modes of HCT under native and non-native catalysis...
November 2, 2016: Biochemistry
Hristina Rumenova Zhekova, Chunfeng Zhao, Paul P M Schnetkamp, Sergei Yu Noskov
NCKX1-5 are proteins involved in the K(+) dependent Na(+)/Ca(2+) exchange in various signal tissues. Here we present a homology model of NCKX2 based on the crystal structure of the NCX_Mj transporter found in Methanoccocus jannaschii. Molecular dynamics simulations were performed on the resultant wild type NCKX2 model and two mutants (D548N and D575N) loaded with either 4Na(+) or 1Ca(2+)-1K(+) ions, in line with the experimentally observed transport stoichiometry. The selectivity of the active site in the wild type NCKX2 for Na(+), K(+), and Li(+) as well as the electrostatic interactions of the positive Na(+) ions in the negatively charged active site of the wild type NCKX2 and the two mutants were evaluated from Free Energy Perturbation calculations...
November 2, 2016: Biochemistry
Tathyana M Amorim Franco, Subray Hegde, John S Blanchard
The biosynthetic pathway of the branched-chain amino acids is essential for Mycobacterium tuberculosis growth and survival. We report here the kinetic and chemical mechanism of the pyridoxal 5'-phosphate (PLP)-dependent branched-chain aminotransferase, IlvE, from M. tuberculosis (MtIlvE). This enzyme is responsible for the final step of the synthesis of the branched-chain amino acids isoleucine, leucine, and valine. As seen in other aminotransferases, MtIlvE displays a ping-pong kinetic mechanism. pK values were identified from the pH dependence on V as well as V/K, indicating that the phosphate ester of the PLP cofactor, and the α-amino group from l-glutamate and the active site Lys204, play roles in acid-base catalysis and binding, respectively...
November 2, 2016: Biochemistry
Satyabrata Pany, Youngki You, Joydip Das
Curcumin is a polyphenolic nutraceutical that acts on multiple biological targets, including protein kinase C (PKC). PKC is a family of serine/threonine kinases central to intracellular signal transduction. We have recently shown that curcumin selectively inhibits PKCα, but not PKCε, in CHO-K1 cells [Pany, S. (2016) Biochemistry 55, 2135-2143]. To understand which domain(s) of PKCα is responsible for curcumin binding and inhibitory activity, we made several domain-swapped mutants in which the C1 (combination of C1A and C1B) and C2 domains are swapped between PKCα and PKCε...
November 2, 2016: Biochemistry
Elena Sugrue, Paul D Carr, Colin Scott, Colin J Jackson
The desolvation of ionizable residues in the active sites of enzymes and the subsequent effects on catalysis and thermostability have been studied in model systems, yet little about how enzymes can naturally evolve to include active sites with highly reactive and desolvated charges is known. Variants of triazine hydrolase (TrzN) with significant differences in their active sites have been isolated from different bacterial strains: TrzN from Nocardioides sp. strain MTD22 contains a catalytic glutamate residue (Glu241) that is surrounded by hydrophobic and aromatic second-shell residues (Pro214 and Tyr215), whereas TrzN from Nocardioides sp...
November 2, 2016: Biochemistry
Florian Baier, Janine N Copp, Nobuhiko Tokuriki
The sequence and functional diversity of enzyme superfamilies has expanded through billions of years of evolution from a common ancestor. Understanding how protein sequence and functional "space" has expanded, at both the evolutionary and molecular level, is central to biochemistry, molecular and evolutionary biology. Integrative approaches that examine protein sequence, structure, and function have begun to provide comprehensive views of the functional diversity and evolutionary relationships within enzyme superfamilies...
November 1, 2016: Biochemistry
Wynton D McClary, John P Sumida, Michele Scian, Lorela Paço, William M Atkins
Cytochrome P4503A4 (CYP3A4) is a peripheral membrane protein that plays a major role in enzymatic detoxification of many drugs and toxins. CYP3A4 has an integral membrane N-terminal helix and a localized patch comprised of the G' and F' helix regions that are embedded in the membrane, but the effects of membrane composition on CYP3A4 function are unknown. Here, circular dichroism and differential scanning calorimetry were used to compare the stability of CYP3A4 in lipid bilayer nanodiscs with varying ratios of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine to 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)...
November 1, 2016: Biochemistry
Purva P Bhojane, Michael R Duff, Khushboo Bafna, Gabriella P Rimmer, Pratul K Agarwal, Elizabeth E Howell
Folate, or vitamin B9, is an important compound in one-carbon metabolism. Previous studies have found weaker binding of dihydrofolate to dihydrofolate reductase in the presence of osmolytes. In other words, osmolytes are more difficult to remove from the dihydrofolate solvation shell than water; this shifts the equilibrium toward the free ligand and protein species. This study uses vapor-pressure osmometry to explore the interaction of folate with the model osmolyte, glycine betaine. This method yields a preferential interaction potential (μ23/RT value)...
November 1, 2016: Biochemistry
Ryo Amano, Kenta Takada, Yoichiro Tanaka, Yoshikazu Nakamura, Gota Kawai, Tomoko Kozu, Taiichi Sakamoto
AML1 (RUNX1) protein is an essential transcription factor involved in the development of hematopoietic cells. Several genetic aberrations that disrupt the function of AML1 have been frequently observed in human leukemia. AML1 contains a DNA-binding domain known as the Runt domain (RD), which recognizes the RD-binding double-stranded DNA element of target genes. In this study, we identified high-affinity RNA aptamers that bind to RD by systematic evolution of ligands by exponential enrichment. The binding assay using surface plasmon resonance indicated that a shortened aptamer retained the ability to bind to RD when 1 M potassium acetate was used...
November 1, 2016: Biochemistry
Jing Liu, Vinodh B Kurella, Louis Lecour, Tomas Vanagunas, David K Worthylake
IQGAP1 is a multi-domain scaffold protein involved in many cellular processes. We have determined the crystal structure of an N-terminal fragment spanning residues 1-191 (CHDF hereafter) which contains the entire calponin homology domain. The structure of the CHDF is very similar to other Type 3 calponin homology domains like those from calponin, Vav, and the yeast IQGAP1 ortholog Rng2. However, in the crystal two CHDF molecules form a "head-to-head" or parallel dimer through mostly hydrophobic interactions...
October 31, 2016: Biochemistry
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