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    The inositol requiring Enzyme 1 (IRE1α) RNAse inhibitor, 4µ8C, is also a potent cellular antioxidant.
    Biochem J 2018 Feb 20. Epub 2018 Feb 20.
    School of Pharmacy, University of Lincoln, Lincoln, United Kingdom
    Inositol Requiring Enzyme 1 alpha (IRE1α) is an ER-transmembrane endonuclease that is activated in response to ER stress as part of the unfolded protein response (UPR). Chronic activation of the UPR has been implicated in the pathogenesis of many common disease including diabetes, cancer and neurological pathologies such as Huntington's and Alzheimer's disease. 7-hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde (4µ8C) is widely used as a specific inhibitor of IRE1α ribonuclease activity in mechanistic studies (IC50 of 6. Read More

    Phosphorylation of BACH1 switches its function from transcription factor to mitotic chromosome regulator and promotes its interaction with HMMR.
    Biochem J 2018 Feb 19. Epub 2018 Feb 19.
    Department of Biochemistry, Tohoku University Graduate School of Medicine, Seiryo-machi 2-1, Sendai, 9808575, Japan
    The transcription repressor BACH1 performs mutually independent dual roles in transcription regulation as well as chromosome alignment during mitosis by supporting polar ejection force of mitotic spindle. We now found that the mitotic spindles became oblique relative to the adhesion surface following endogenous BACH1 depletion in HeLa cells. This spindle orientation rearrangement was rescued by re-expression of BACH1 depending on its interactions with HMMR and CRM1, both of which are required for the positioning of mitotic spindle, but independently of its DNA binding activity. Read More

    Amplification of PIP3 signalling by macropinocytic cups.
    Biochem J 2018 Feb 14;475(3):643-648. Epub 2018 Feb 14.
    MRC Laboratory of Molecular Biology, Francis Crick Ave., Cambridge CB1 0QH, U.K.
    In a role distinct from and perhaps more ancient than that in signal transduction, PIP3 and Ras help to spatially organize the actin cytoskeleton into macropinocytic cups. These large endocytic structures are extended by actin polymerization from the cell surface and have at their core an intense patch of active Ras and PIP3, around which actin polymerizes, creating cup-shaped projections. We hypothesize that active Ras and PIP3 self-amplify within macropinocytic cups, in a way that depends on the structural integrity of the cup. Read More

    Molecular mechanisms of missense mutations that generate ectopic N-glycosylation sites in coagulation factor VIII.
    Biochem J 2018 Feb 14. Epub 2018 Feb 14.
    Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio, 44195, United States
    N-glycosylation is a common posttranslational modification of secreted and membrane proteins, catalyzed by the two enzymatic isoforms of the oligosaccharyltransferase, STT3A and STT3B. Missense mutations are the most common mutations in inherited diseases, however, missense mutations that generate extra, non-native N-glycosylation sites have not been well characterized. Coagulation factor VIII (FVIII) contains five consensus N-glycosylation sites outside its functionally dispensable B domain. Read More

    Thioredoxin regulates G6PDH activity by changing redox states of OpcA in the nitrogen-fixing cyanobacteriumsp. PCC 7120.
    Biochem J 2018 Feb 13. Epub 2018 Feb 13.
    Laboratory for Chemistry and Life Science, Tokyo Institute of Technology, Nagatsuta 4259-R1-8, Midori-Ku, Yokohama, 226-8503, Japan
    Glucose 6-phosphate dehydrogenase (G6PDH) catalyzes the first reaction in the oxidative pentose phosphate pathway. In green plant chloroplasts, G6PDH is a unique redox-regulated enzyme, since it is inactivated under the reducing conditions. This regulation is accomplished using a redox-active cysteine pair, which is conserved in plant G6PDH. Read More

    Biodiversity of CS-proteoglycan sulphation motifs: chemical messenger recognition modules with roles in information transfer, control of cellular behaviour and tissue morphogenesis.
    Biochem J 2018 Feb 9;475(3):587-620. Epub 2018 Feb 9.
    School of Biosciences, Cardiff University, Cardiff CF10 1AX, Wales, U.K.
    Chondroitin sulphate (CS) glycosaminoglycan chains on cell and extracellular matrix proteoglycans (PGs) can no longer be regarded as merely hydrodynamic space fillers. Overwhelming evidence over recent years indicates that sulphation motif sequences within the CS chain structure are a source of significant biological information to cells and their surrounding environment. CS sulphation motifs have been shown to interact with a wide variety of bioactive molecules, e. Read More

    Identification of progesterone receptor membrane component-1 as an interaction partner and possible regulator of fatty acid 2-hydroxylase.
    Biochem J 2018 Feb 9. Epub 2018 Feb 9.
    Institute of Biochemistry and Molecular Biology, University of Bonn, Nussallee 11, Bonn, 53115, Germany
    The fatty acid 2-hydroxylase (FA2H) is essential for synthesis of 2-hydroxylated fatty acids in myelinating and other cells and deficiency of this enzyme causes a complicated form of hereditary spastic paraplegia also known as fatty acid hydroxylase-associated neurodegeneration. Despite its important role in sphingolipid metabolism, regulation of FA2H and its interaction with other proteins involved in the same or other metabolic pathways is poorly understood. To identify potential interaction partners of the enzyme, quantitative mass-spectrometry using stable isotope labeling of cells was combined with formaldehyde cross-linking and proximity biotinylation, respectively. Read More

    Functional role of highly-conserved residues of the N-terminal tail and first transmembrane segment of a P4-ATPase.
    Biochem J 2018 Feb 7. Epub 2018 Feb 7.
    Bioquímica y Farmacología Molecular, INSTITUTO DE PARASITOLOGIA Y BIOMEDICINA LOPEZ-NEYRA, IPBLN-CSIC, Avda del Conocimiento, Armilla (GRANADA), 18016, Spain
    The P4 family of P-type ATPases (P4-ATPases) plays an important role in maintaining phospholipid asymmetry in eukaryotic cell membranes.miltefosine transporter (LMT) is a plasma membrane (PM) P4-ATPase that catalyses translocation into the parasite of the leishmanicidal drug miltefosine as well as phosphatidylcholine and phosphatidylethanolamine analogues. In this study, we analysed the role, in LMT, of a series of highly-conserved amino acids previously non-described in the N-terminal region of P4-ATPases. Read More

    Cardiomyocyte diffusible redox mediators control Trypanosoma cruzi infection: role of parasite mitochondrial iron superoxide dismutase.
    Biochem J 2018 Feb 7. Epub 2018 Feb 7.
    Uruguay, Departamento de Bioquímica, Facultad de Medicina, Avenida General Flores 2125, Montevideo, 11800, Uruguay
    Chagas disease (CD), caused by the protozoa, is a chronic illness in which parasites persist in the host-infected tissues for years.invasion in cardiomyocytes elicits the production of pro-inflammatory mediators (TNF-α, IL-1β, IFNγ; nitric oxide (NO)) leading to mitochondrial dysfunction with increase superoxide radical (O), hydrogen peroxide (HO) and peroxynitrite generation. We hypothesize that these redox-mediators may control parasite proliferation through the induction of intracellular amastigote programmed cell death (PCD). Read More

    Cytosolic Carnitine Acetyltransferase as a Source of Cytosolic Acetyl-CoA: A Possible Mechanism for Regulation of Cardiac Energy Metabolism.
    Biochem J 2018 Feb 7. Epub 2018 Feb 7.
    University of Alberta, Edmonton, Canada
    The role of carnitine acetyltransferase (CrAT) in regulating cardiac energy metabolism is poorly understood.  CrAT modulates mitochondrial acetyl-CoA/CoA ratios, thus regulating pyruvate dehydrogenase activity and glucose oxidation.  Here we propose that cardiac CrAT also provides cytosolic acetyl-CoA for the production of malonyl-CoA, a potent inhibitor of fatty acid oxidation. Read More

    Metabolic profiling of visceral adipose tissue from obese subjects with or without metabolic syndrome.
    Biochem J 2018 Feb 8. Epub 2018 Feb 8.
    Experimental Medicine and Surgery, University of Rome "Tor Vergata", Via Montpellier, 1, Rome, 00133, Italy
    Obesity represents one of the most complex public health challenges and has recently reached epidemic proportions.  Obesity is also considered to be primarily responsible for the rising prevalence of metabolic syndrome, defined as the coexistence in the same individual of several risk factors for atherosclerosis, including dyslipidaemia, hypertension and hyperglycaemia, as well as for cancer. Additionally, the presence of three of the five risk factors (abdominal obesity, low HDL cholesterol, high triglycerides, high fasting glucose and high blood pressure) characterizes metabolic syndrome, which has serious clinical consequences. Read More

    Methionine Sulfoxide Reductase B3 Requires Resolving Cysteine Residues for full Activity and can act as a Stereospecific Methionine Oxidase.
    Biochem J 2018 Feb 2. Epub 2018 Feb 2.
    Institute of Molecular Cell and Systems Biology, University of Glasgow, Davidsion Building, University Avenue, Glasgow, G12 8QQ, United Kingdom
    The oxidation of methionine residues in proteins occurs during oxidative stress and can lead to an alteration in protein function.  The enzyme methionine sulfoxide reductase reverses this modification.  Here we characterise the mammalian enzyme methionine sulfoxide reductase B3. Read More

    Molecular control of stomatal development.
    Biochem J 2018 Jan 31;475(2):441-454. Epub 2018 Jan 31.
    Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield S10 2TN, U.K.
    Plants have evolved developmental plasticity which allows the up- or down-regulation of photosynthetic and water loss capacities as new leaves emerge. This developmental plasticity enables plants to maximise fitness and to survive under differing environments. Stomata play a pivotal role in this adaptive process. Read More

    Mechanistic insight into the allosteric regulation ofaspartate kinase.
    Biochem J 2018 Jan 30. Epub 2018 Jan 30.
    State Key Laboratory of Biotherapy, Sichuan University, No.17, south renmin road,Wuhou District, Chengdu, 610041, China
    In plants and microorganisms, aspartate kinase (AK) catalyzes an initial commitment step of the aspartate family amino acids biosynthesis. Due to various structural organization, AKs from different species show tremendous diversity and complex allosteric controls. We report the crystal structure of AK from(PaAK), a typical α2β2 hetero-tetrameric enzyme, in complex with inhibitory effectors. Read More

    A plastidial pantoate transporter with a potential role in pantothenate synthesis.
    Biochem J 2018 Jan 30. Epub 2018 Jan 30.
    Horticultural Sciences, University of Florida, Gainesville, Florida, FL 32611, United States
    The pantothenate (vitamin B) synthesis pathway in plants is not fully defined because the sub-cell-ular site of its ketopantoate → pantoate reduction step is unclear. However, the pathway is known to be split between cytosol, mit-o-chondria, and potentially plastids, and inferred to involve mitochondrial or plast-idial transport of ketopantoate or pantoate. No proteins that mediate these transport steps have been identified. Read More

    Crystal structure of thermospermine synthase fromand substrate discriminatory features of plant aminopropyltransferases.
    Biochem J 2018 Jan 24. Epub 2018 Jan 24.
    Synchrotron Radiation Research Section of the Macromolecular Crystallography Laboratory, National Cancer Institute, South Cass Avenue 9700, Bldg 202, Rm Q-141, Argonne, Illinois, 60439, United States.
    Polyamines are linear polycationic compounds that play a crucial role in the growth and development of higher plants. One triamine (spermidine, SPD) and two tetraamine isomers (spermine, SPM, and thermospermine, TSPM) are obtained by the transfer of the aminopropyl group from decarboxylated S-adenosylmethionine to putrescine and SPD. These reactions are catalyzed by the specialized aminopropyltransferases. Read More

    Topoisomerases as anticancer targets.
    Biochem J 2018 Jan 23;475(2):373-398. Epub 2018 Jan 23.
    Department of Pharmacology, University of Minnesota Medical School, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, U.S.A.
    Many cancer type-specific anticancer agents have been developed and significant advances have been made toward precision medicine in cancer treatment. However, traditional or nonspecific anticancer drugs are still important for the treatment of many cancer patients whose cancers either do not respond to or have developed resistance to cancer-specific anticancer agents. DNA topoisomerases, especially type IIA topoisomerases, are proved therapeutic targets of anticancer and antibacterial drugs. Read More

    CMS-G fromis maintained in natural populations despite containing an atypical cytochromeoxidase.
    Biochem J 2018 Jan 22. Epub 2018 Jan 22.
    Evo-Eco-Paleo, Univ. Lille, Bât. SN2 F, Villeneuve d'Asq, 59655, France.
    While mitochondrial mutants of the respiratory machinery are rare and often lethal, Cytoplasmic Male Sterility (CMS), a mitochondrially inherited trait that results in pollen abortion is frequently encountered in wild populations. It generates a breeding system called gynodioecy. Inssp. Read More

    Globular C1 q receptor (p33) binds and stabilizes pro-inflammatory MCP-1: a novel mechanism for regulation of MCP-1 production and function.
    Biochem J 2018 Jan 22. Epub 2018 Jan 22.
    Experimental Medical Science, Lund University, Lund, Sweden.
    The protein gC1qR, also named p33, was originally identified as a binding partner of the globular heads of C1q in the complement system. gC1qR/p33 is abundantly expressed in many cell types but the functional importance of this protein is not completely understood. Here, we investigate the impact of gC1qR/p33 on the production and function of the pathophysiologically important chemokine MCP-1 and the underlying molecular mechanisms. Read More

    Restricted HIV-1 Env Glycan Engagement by Lectin-Reengineered DAVEI Protein Chimera is sufficient for Lytic Inactivation of the Virus.
    Biochem J 2018 Jan 17. Epub 2018 Jan 17.
    Drexel University, 245 north 15th street, room 11311, philadelphia, Pennsylvania, 19102, United States
    We previously reported first generation recombinant DAVEI construct, a dual action virus entry inhibitor composed of cyanovirin-N (CVN) fused to a membrane proximal external region (MPER) or its derivative peptide Trp3. DAVEI exhibits potent and irreversible inactivation of HIV-1 viruses by dual engagement of gp120 and gp41. However, the promiscuity of CVN to associate with multiple glycosylation sites in gp120 and its multivalency limit current understanding of the molecular arrangement of the DAVEI molecules on trimeric spike. Read More

    Structural and functional characterisation of the cytochrome P450 enzyme CYP268A2 from.
    Biochem J 2018 Feb 16;475(4):705-722. Epub 2018 Feb 16.
    Department of Chemistry, School of Physical Sciences, University of Adelaide, Adelaide, SA 5005, Australia
    Members of the cytochrome P450 monooxygenase family CYP268 are found across a broad range ofspecies including the pathogens,,, andCYP268A2, from, which is the first member of this family to be studied, was purified and characterised. CYP268A2 was found to bind a variety of substrates with high affinity, including branched and straight chain fatty acids (C10-C12), acetate esters, and aromatic compounds. The enzyme was also found to bind phenylimidazole inhibitors but not larger azoles, such as ketoconazole. Read More

    Structural insights into the catalytic mechanism of cysteine (hydroxyl) lyase from the hydrogen sulfide-producing oral pathogen,.
    Biochem J 2018 Feb 16;475(4):733-748. Epub 2018 Feb 16.
    Department of Structural Biology, School of Pharmacy, Iwate Medical University, Yahaba, Iwate 028-3694, Japan.
    Hydrogen sulfide (HS) plays important roles in the pathogenesis of periodontitis. Oral pathogens typically produce HS from l-cysteine in addition to pyruvate and [Formula: see text] However,fromsubsp.ATCC 25586 encodes a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the production of HS and l-serine from l-cysteine and HO, an unusual cysteine (hydroxyl) lyase reaction (β-replacement reaction). Read More

    Propionate enters GABAergic neurons, inhibits GABA transaminase, causes GABA accumulation and lethargy in a model of propionic acidemia.
    Biochem J 2018 Feb 16;475(4):749-758. Epub 2018 Feb 16.
    Norwegian Defense Research Establishment, Kjeller, Norway
    Propionic acidemia is the accumulation of propionate in blood due to dysfunction of propionyl-CoA carboxylase. The condition causes lethargy and striatal degeneration with motor impairment in humans. How propionate exerts its toxic effect is unclear. Read More

    Mobilization of a splicing factor through a nuclear kinase-kinase complex.
    Biochem J 2018 Feb 14;475(3):677-690. Epub 2018 Feb 14.
    Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0636, U.S.A.
    The splicing of mRNA is dependent on serine-arginine (SR) proteins that are mobilized from membrane-free, nuclear speckles to the nucleoplasm by the Cdc2-like kinases (CLKs). This movement is critical for SR protein-dependent assembly of the macromolecular spliceosome. Although CLK1 facilitates such trafficking through the phosphorylation of serine-proline dipeptides in the prototype SR protein SRSF1, an unrelated enzyme known as SR protein kinase 1 (SRPK1) performs the same function but does not efficiently modify these dipeptides in SRSF1. Read More

    Extracellular ATP activates store-operated Caentry in white adipocytes: functional evidence for STIM1 and ORAI1.
    Biochem J 2018 Feb 14;475(3):691-704. Epub 2018 Feb 14.
    Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, University of Gothenburg, Göteborg, Sweden
    In the present study, we have applied ratiometric measurements of intracellular Caconcentrations ([Ca]) to show that extracellularly applied ATP (adenosine triphosphate) (100 µM) stimulates store-operated Caentry (SOCE) in 3T3-L1 adipocytes. ATP produced a rapid increase in [Ca]consisting of an initial transient elevation followed by a sustained elevated phase that could be observed only in the presence of extracellular CaGene expression data and [Ca]recordings with uridine-5'-triphosphate or with the phospholipase C (PLC) inhibitor U73122 demonstrated the involvement of purinergic P2Y2 receptors and the PLC/inositol trisphosphate pathway. The [Ca]elevation produced by reintroduction of a Ca-containing intracellular solution to adipocytes exposed to ATP in the absence of Cawas diminished by known SOCE antagonists. Read More

    Silencing carboxylesterase 1 in human THP-1 macrophages perturbs genes regulated by PPARγ/RXR and RAR/RXR: down-regulation of CYP27A1-LXRα signaling.
    Biochem J 2018 Feb 9;475(3):621-642. Epub 2018 Feb 9.
    Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, PO Box 6100, Mississippi State, MS 39762, U.S.A.
    Macrophage foam cells store excess cholesterol as cholesteryl esters, which need to be hydrolyzed for cholesterol efflux. We recently reported that silencing expression of carboxylesterase 1 (CES1) in human THP-1 macrophages [CES1KD (THP-1 cells with CES1 expression knocked down) macrophages] reduced cholesterol uptake and decreased expression of CD36 and scavenger receptor-A in cells loaded with acetylated low-density lipoprotein (acLDL). Here, we report that CES1KD macrophages exhibit reduced transcription of cytochrome P45027A1 () in nonloaded and acLDL-loaded cells. Read More

    Adipose depot-specific effects of ileal interposition surgery in UCD-T2D rats: unexpected implications for obesity and diabetes.
    Biochem J 2018 Feb 14;475(3):649-662. Epub 2018 Feb 14.
    Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, U.S.A.
    Ileal interposition (IT) surgery delays the onset of diabetes in a rat model of type-2 diabetes (UCD-T2DM). Here, to gain a deeper understanding of the molecular events underlying the effects of IT surgery, we examined the changes in the proteome of four white adipose depots (retroperitoneal, mesenteric, inguinal, and epididymal) and plasma-free fatty acid profile in pre-diabetic rats 1.5 months following IT or sham surgery. Read More

    Adhesion/growth-regulatory galectins tested in combination: evidence for formation of hybrids as heterodimers.
    Biochem J 2018 Jan 10. Epub 2018 Jan 10.
    Department of Biochemistry, University of Minnesota Medical School, 6-155 Jackson Hall, 321 Church Street, MINNEAPOLIS, 55455-0347, United States
    The delineation of the physiological significance of protein (lectin)-glycan recognition and the structural analysis of individual lectins have directed our attention to studying them in combination. In this report, we tested the hypothesis of hybrid formation by using binary mixtures of homodimeric galectins-1 and -7 as well as a proteolytically truncated version of chimera-type galectin-3. Initial supportive evidence is provided by affinity chromatography using resin-presented galectin-7. Read More

    Revisiting paradigms of Casignaling protein kinase regulation in plants.
    Biochem J 2018 Jan 5;475(1):207-223. Epub 2018 Jan 5.
    Department of Plant Biology, University of Illinois, Urbana, IL 61801, U.S.A.
    Calcium (Ca) serves as a universal second messenger in eukaryotic signal transduction. Understanding the Caactivation kinetics of Casensors is critical to understanding the cellular signaling mechanisms involved. In this review, we discuss the regulatory properties of two sensor classes: the Ca-dependent protein kinases (CPKs/CDPKs) and the calcineurin B-like (CBL) proteins that control the activity of CBL-interacting protein kinases (CIPKs) and identify emerging topics and some foundational points that are not well established experimentally. Read More

    Back to the future: new target-validated Rab antibodies for evaluating LRRK2 signalling in cell biology and Parkinson's disease.
    Biochem J 2018 Jan 5;475(1):185-189. Epub 2018 Jan 5.
    Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, U.K.
    The addition of phosphate groups to substrates allows protein kinases to regulate a myriad of biological processes, and contextual analysis of protein-bound phosphate is important for understanding how kinases contribute to physiology and disease. Leucine-rich repeat kinase 2 (LRRK2) is a Ser/Thr kinase linked to familial and sporadic cases of Parkinson's disease (PD). Recent work established that multiple Rab GTPases are physiological substrates of LRRK2, with Rab10 in particular emerging as a human substrate whose site-specific phosphorylation mirrors hyperactive LRRK2 lesions associated with PD. Read More

    Stromal cell-derived factor-1 (CXCL12) activates integrins by direct binding to an allosteric ligand-binding site (site 2) of integrins without CXCR4.
    Biochem J 2018 Feb 16;475(4):723-732. Epub 2018 Feb 16.
    Department of Dermatology, Biochemistry and Molecular Medicine, University of California Davis School of Medicine, Sacramento, CA 95817, U.S.A.
    Leukocyte arrest on the endothelial cell surface during leukocyte extravasation is induced by rapid integrin activation by chemokines. We recently reported that fractalkine induces integrin activation without its receptor CX3CR1 through binding to the allosteric site (site 2) of integrins. Peptides from site 2 bound to fractalkine and suppressed integrin activation by fractalkine. Read More

    Insights into the effect of minor groove interactions and metal cofactors on mutagenic replication by human DNA polymerase β.
    Biochem J 2018 Feb 9;475(3):571-585. Epub 2018 Feb 9.
    Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, U.S.A.
    DNA polymerases accommodate various base-pair conformations in the event of incorrect insertions. In particular, Watson-Crick-like dG:dTTP base pair has been observed at the insertion site of human DNA polymerase β (pol β). A potential factor contributing to the diverse conformations of base-pair mismatches is minor groove interactions. Read More

    Search of multiple hot spots on the surface of peptidyl-tRNA hydrolase: structural, binding and antibacterial studies.
    Biochem J 2018 Feb 9;475(3):547-560. Epub 2018 Feb 9.
    Department of Biophysics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110 029, India
    Peptidyl-tRNA hydrolase (Pth) catalyzes the breakdown of peptidyl-tRNA into peptide and tRNA components. Pth from(Pth) was cloned, expressed, purified and crystallized in a native unbound (Pth-N) state and in a bound state with the phosphate ion and cytosine arabinoside (cytarabine) (Pth-C). Structures ofPth-N andPth-C were determined at 1. Read More

    Controlling of-alkylpolyamine analogue metabolism by selective deuteration.
    Biochem J 2018 Feb 14;475(3):663-676. Epub 2018 Feb 14.
    School of Pharmacy, University of Eastern Finland, Biocenter Kuopio, Yliopistonranta 1B, FI-70210 Kuopio, Finland
    Replacing protium with deuterium is an efficient method to modulate drug metabolism.-alkylated polyamine analogues are polyamine antimetabolites with proven anticancer efficacy. We have characterized earlier the preferred metabolic routes of,-diethylspermine (DESpm),-benzyl--ethylspermine (BnEtSpm) and,-dibenzylspermine (DBSpm) by human recombinant spermine oxidase (SMOX) and acetylpolyamine oxidase (APAO). Read More

    Synergistic drug combination GC7/DFMO suppresses hypusine/spermidine-dependent eIF5A activation and induces apoptotic cell death in neuroblastoma.
    Biochem J 2018 Jan 31;475(2):531-545. Epub 2018 Jan 31.
    Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, U.S.A.
    The eukaryotic initiation factor 5A (eIF5A), which contributes to several crucial processes during protein translation, is the only protein that requires activation by a unique post-translational hypusine modification. eIF5A hypusination controls cell proliferation and has been linked to cancer. eIF5A hypusination requires the enzymes deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase and uniquely depends on the polyamine (PA) spermidine as the sole substrate. Read More

    Mechanism of prostaglandin E-induced transcriptional up-regulation of Oncostatin-M by CREB and Sp1.
    Biochem J 2018 Jan 31;475(2):477-494. Epub 2018 Jan 31.
    Department of Biophysics, Molecular Biology and Bioinformatics, University of Calcutta, 92 A.P.C. Road, Kolkata 700009, India
    Oncostatin-M (OSM) is a pleotropic cytokine belonging to the interleukin-6 family. Differential expression of OSM in response to varying stimuli and exhibiting repertoire of functions in different cells renders it challenging to study the mechanism of its expression. Prostaglandin E(PGE) transcriptionally increasedlevels. Read More

    The hydrophobic region of theperoxin 14: requirements for association with a glycosome mimetic membrane.
    Biochem J 2018 Jan 31;475(2):511-529. Epub 2018 Jan 31.
    Institute of Parasitology, Macdonald Campus of McGill University, Ste-Anne-de-Bellevue, QC, Canada
    Protein import into theglycosome requires docking of the cargo-loaded peroxin 5 (PEX5) receptor to the peroxin 14 (PEX14) bound to the glycosome surface. To examine the LdPEX14-membrane interaction, we purifiedpromastigote glycosomes and determined the phospholipid and fatty acid composition. These membranes contained predominately phosphatidylethanolamine, phosphatidylcholine, and phosphatidylglycerol (PG) modified primarily with C18 and C22 unsaturated fatty acid. Read More

    Identification of a second binding site on the TRIM25 B30.2 domain.
    Biochem J 2018 Jan 23;475(2):429-440. Epub 2018 Jan 23.
    The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
    Theetinoic acid-nducibleene-(RIG-I) receptor recognizes short 5'-di- and triphosphate base-paired viral RNA and is a critical mediator of the innate immune response against viruses such as influenza A, Ebola, HIV and hepatitis C. This response is reported to require an orchestrated interaction with thepartiteotif 25 (TRIM25) B30.2 protein-interaction domain. Read More

    Ezrin-anchored PKA phosphorylates serine 369 and 373 on connexin 43 to enhance gap junction assembly, communication, and cell fusion.
    Biochem J 2018 Jan 31;475(2):455-476. Epub 2018 Jan 31.
    UMR-S 1180, Inserm, Univ. Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
    A limited number of human cells can fuse to form multinucleated syncytia. In the differentiation of human placenta, mononuclear cytotrophoblasts fuse to form an endocrinologically active, non-proliferative, multinucleated syncytium. This syncytium covers the placenta and manages the exchange of nutrients and gases between maternal and fetal circulation. Read More

    Genetic dissection of cyclic pyranopterin monophosphate biosynthesis in plant mitochondria.
    Biochem J 2018 Jan 31;475(2):495-509. Epub 2018 Jan 31.
    John Innes Centre, Norwich NR4 7UH, U.K.
    Mitochondria play a key role in the biosynthesis of two metal cofactors, iron-sulfur (FeS) clusters and molybdenum cofactor (Moco). The two pathways intersect at several points, but a scarcity of mutants has hindered studies to better understand these links. We screened a collection of sirtinol-resistantmutants for lines with decreased activities of cytosolic FeS enzymes and Moco enzymes. Read More

    Therapeutic targeting of non-coding RNAs in cancer.
    Biochem J 2017 Dec 14;474(24):4219-4251. Epub 2017 Dec 14.
    Institute of Macromolecular Chemistry, Czech Academy of Sciences, Prague, Czech Republic.
    The majority of the human genome encodes RNAs that do not code for proteins. These non-coding RNAs (ncRNAs) affect normal expression of the genes, including oncogenes and tumour suppressive genes, which make them a new class of targets for drug development in cancer. Although microRNAs (miRNAs) are the most studied regulatory ncRNAs to date, and miRNA-targeted therapeutics have already reached clinical development, including the mimics of the tumour suppressive miRNAs miR-34 and miR-16, which reached phase I clinical trials for the treatment of liver cancer and mesothelioma, the importance of long non-coding RNAs (lncRNAs) is increasingly being recognised. Read More

    Assaying kinase activity of the TPL-2/NF-κB1 p105/ABIN-2 complex using an optimal peptide substrate.
    Biochem J 2018 Jan 11;475(1):329-340. Epub 2018 Jan 11.
    Immune Cell Signalling Laboratory, The Francis Crick Institute, London NW1 1AT, U.K.
    The MKK1/2 kinase tumour progression locus 2 (TPL-2) is critical for the production of tumour necrosis factor alpha (TNFα) in innate immune responses and a potential anti-inflammatory drug target. Several earlier pharmaceutical company screens with the isolated TPL-2 kinase domain have identified small-molecule inhibitors that specifically block TPL-2 signalling in cells, but none of these have progressed to clinical development. We have previously shown that TPL-2 catalytic activity regulates TNF production by macrophages while associated with NF-κB1 p105 and ABIN-2, independently of MKK1/2 phosphorylation via an unknown downstream substrate. Read More

    Multiple substitutions lead to increased loop flexibility and expanded specificity incarbapenemase OXA-239.
    Biochem J 2018 Jan 11;475(1):273-288. Epub 2018 Jan 11.
    Department of Chemistry, Grand Valley State University, Allendale, MI 49401, U.S.A.
    OXA-239 is a class D carbapenemase isolated from anstrain found in Mexico. This enzyme is a variant of OXA-23 with three amino acid substitutions in or near the active site. These substitutions cause OXA-239 to hydrolyze late-generation cephalosporins and the monobactam aztreonam with greater efficiency than OXA-23. Read More

    An unusual diphosphatase from the PhnP family cleaves reactive FAD photoproducts.
    Biochem J 2018 Jan 11;475(1):261-272. Epub 2018 Jan 11.
    Horticultural Sciences Department, University of Florida, Gainesville, FL, U.S.A.
    Flavins are notoriously photolabile, but while the photoproducts derived from the-alloxazine ring are well known the other photoproducts are not. In the case of FAD, typically the main cellular flavin, the other photoproducts are predicted to include four- and five-carbon sugars linked to ADP. These FAD photoproducts were shown to be potent glycating agents, more so than ADP-ribose. Read More

    Functional characterization of the Ca-ATPase SMA1 from.
    Biochem J 2018 Jan 11;475(1):289-303. Epub 2018 Jan 11.
    Université Grenoble Alpes, F-38054 Grenoble, France
    is a parasite that causes bilharzia, a neglected tropical disease affecting hundreds of millions of people each year worldwide. In 2012,had been identified as the only invertebrate possessing two SERCA-type Ca-ATPases, SMA1 and SMA2. However, our analysis of recent genomic data shows that the presence of two SERCA pumps is rather frequent in parasitic flatworms. Read More

    JMJD6 induces HOTAIR, an oncogenic lincRNA, by physically interacting with its proximal promoter.
    Biochem J 2018 Jan 15;475(1):355-371. Epub 2018 Jan 15.
    National Institute of Biomedical Genomics, Kalyani 741251, India
    Using microarray analysis, we found that HOX transcript antisense intergenic RNA (HOTAIR) is up-regulated by Jumonji domain containing-6 (JMJD6), a bifunctional lysyl hydroxylase and arginine demethylase. In breast cancer, both JMJD6 and HOTAIR RNAs increase tumor growth and associate with poor prognosis but no molecular relationship between them is known. We show that overexpression of JMJD6 increased HOTAIR expression and JMJD6 siRNAs suppressed it in ER+ MCF-7, triple negative MDA-MB-231 and non-breast cancer HEK 293 cells. Read More

    The stress sigma factor of RNA polymerase RpoS/σis a solvent-exposed open molecule in solution.
    Biochem J 2018 Jan 15;475(1):341-354. Epub 2018 Jan 15.
    Laboratoire Systèmes Macromoléculaires et Signalisation, Département de Microbiologie, Institut Pasteur, 25 rue du Docteur Roux, 75015 Paris, France
    In bacteria, one primary and multiple alternative sigma (σ) factors associate with the RNA polymerase core enzyme (E) to form holoenzymes (Eσ) with different promoter recognition specificities. The alternative σ factor RpoS/σis produced in stationary phase and under stress conditions and reprograms global gene expression to promote bacterial survival. To date, the three-dimensional structure of a full-length free σ factor remains elusive. Read More

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