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    Systems analysis of metabolism in platelet concentrates during storage in platelet additive solution.
    Biochem J 2018 Jun 18. Epub 2018 Jun 18.
    Center for Systems Biology, University of Iceland, Sturlugata 8, Reykjavík, 101, Iceland
    Platelets deteriorate over time when stored within blood banks through a biological process known as platelet storage lesion (PSL). Here we describe the refinement of biochemical network of platelet metabolism iAT-PLT-636 and its application to describe and investigate changes in metabolism during platelet storage. Changes to extracellular acetate and citrate were measured in buffy coat and apheresis platelet units over 10 days of storage in the platelet additive solution T-Sol. Read More

    Characterization of the PLP-dependent Transaminase Initiating Azasugar Biosynthesis.
    Biochem J 2018 Jun 15. Epub 2018 Jun 15.
    Chemistry, University of Florida, Box 117200, Gainesville, Florida, 32611, United States
    Biosynthesis of the azasugar 1-deoxynojirimycin (DNJ) critically involves a transamination in the first committed step. Here we identify the azasugar biosynthetic cluster signature in SC2 ( ), homologous to that reported in FZB42 ( ) and report the characterization of the aminotransferase GabT1 (named from ). GabT1 from exhibits a specific activity of 4. Read More

    Binding mode of AIF(370-394) peptide to CypA: insights from NMR, label-free and molecular docking studies.
    Biochem J 2018 Jun 11. Epub 2018 Jun 11.
    Istituto di Biostrutture e Bioimmagini (IBB), CNR, Naples, Tennessee, 80134, Italy
    The complex formation between the proteins Apoptosis Inducing Factor (AIF) and Cyclophilin A (CypA) following oxidative stress in neuronal cells has been suggested as a main target for reverting ischemia-stroke damage. Recently, a peptide encompassing AIF residues 370-394 has been developed to target the AIF-binding site on CypA, to prevent the association between the two proteins and suppress glutamate-induced cell death in neuronal cells. Using a combined approach based on NMR spectroscopy, synthesis and testing of all Ala-scan mutants of the peptide and molecular docking/molecular dynamics, we have generated a detailed model of the AIF(370-394)/CypA complex. Read More

    CRISPR base editors: genome editing without double-stranded breaks.
    Biochem J 2018 Jun 11;475(11):1955-1964. Epub 2018 Jun 11.
    Laboratory for Genome Engineering, Biological and Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia
    The CRISPR (clustered regularly interspaced short palindromic repeat)/Cas9 adaptive immunity system has been harnessed for genome editing applications across eukaryotic species, but major drawbacks, such as the inefficiency of precise base editing and off-target activities, remain. A catalytically inactive Cas9 variant (dead Cas9, dCas9) has been fused to diverse functional domains for targeting genetic and epigenetic modifications, including base editing, to specific DNA sequences. As base editing does not require the generation of double-strand breaks, dCas9 and Cas9 nickase have been used to target deaminase domains to edit specific loci. Read More

    Autophagy in cancer: a complex relationship.
    Biochem J 2018 Jun 11;475(11):1939-1954. Epub 2018 Jun 11.
    Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, U.S.A.
    Macroautophagy is the process by which cells package and degrade cytosolic components, and recycle the breakdown products for future use. Since its initial description by Christian de Duve in the 1960s, significant progress has been made in understanding the mechanisms that underlie this vital cellular process and its specificity. Furthermore, macroautophagy is linked to pathologic conditions such as cancer and is being studied as a therapeutic target. Read More

    Probing the specificity of CYP112 in bacterial gibberellin biosynthesis
    Biochem J 2018 06 6. Epub 2018 Jun 6.
    Biochemistry, Biophysics, & Molecular Biology, Iowa State University, 4216 Mol. Biol. Bldg., Ames, Iowa, 50011, United States
    Biosynthesis of the gibberellin A (GA) plant hormones evolved independently in plant-associated fungi and bacteria. While the relevant enzymes have distinct evolutionary origins, the pathways proceed via highly similar reactions. One particularly complex transformation involves combined demethylation and λ-lactone ring formation, catalyzed in bacteria by the cytochrome P450 CYP112 in three individual steps, which involves large structural changes in the transition from substrate to product, with further divergence in the recently demonstrated use of two separate mechanistic routes. Read More

    Trade-offs with stability modulate innate and mutationally acquired drug-resistance in bacterial dihydrofolate reductase enzymes.
    Biochem J 2018 Jun 5. Epub 2018 Jun 5.
    Maharaja Sayajirao University, Baroda, India.
    Structural stability is a major constraint on the evolution of protein sequences. However, under strong directional selection, mutations that confer novel phenotypes but compromise structural stability of proteins may be permissible. During the evolution of antibiotic resistance, mutations that confer drug resistance often have pleiotropic effects on the structure and function of antibiotic-target proteins, usually essential metabolic enzymes. Read More

    Effect of the actin- and calcium-regulating activities of ITPKB on the metastatic potential of lung cancer cells.
    Biochem J 2018 Jun 5. Epub 2018 Jun 5.
    Institut für Biochemie und Signaltransduktion, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, HAMBURG, 20246, Germany
    Inositol-1,4,5-trisphosphate 3-kinase-A (ITPKA) exhibits oncogenic activity in lung cancer cells by regulating Ins(1,4,5)P-mediated calcium release and cytoskeletal dynamics. Since in normal cells ITPKA is mainly expressed in the brain, it is an excellent target for selected therapy of lung cancer. However, ITPKB is strongly expressed in normal lung tissue but is down-regulated in lung cancer cells by miR-375, assuming that ITPKB might have tumor suppressor activity. Read More

    Crystal structures of the kinase domain of PpkA, a key regulatory component of T6SS, reveal a general inhibitory mechanism.
    Biochem J 2018 Jun 1. Epub 2018 Jun 1.
    Department of Microbiology, Nanjing Agricultural University, 1 Weigang, Nanjing, 210095, China
    The type VI secretion system (T6SS) is a versatile and widespread export system found in many Gram-negative bacteria that delivers effector proteins into target cells. The functions of T6SSs are tightly regulated by diverse mechanisms at multiple levels, including posttranslational modification through threonine phosphorylation via the Ser/Thr protein kinase (STPK) PpkA. Here, we identified that PpkA is essential for T6SS secretion in since its deletion eliminated the secretion of hemolysin coregulated protein (Hcp), while the periplasmic and transmembrane portion of PpkA was found to be disposable for T6SS secretion. Read More

    Molecular insights of inhibition in sickle hemoglobin polymerization upon glutathionylation: hydrogen/deuterium exchange mass spectrometry and molecular dynamics simulation based approach.
    Biochem J 2018 Jun 1. Epub 2018 Jun 1.
    Division of Molecular Medicine, St John's Research Institute, 100 Feet Road, Koramangala, Bangalore, 560034, India
    In sickle cell anemia, polymerization of hemoglobin in its deoxy state leads to the formation of insoluble fibres that result in sickling of red blood cells. Stereo-specific binding of isopropyl group of βVal6, the mutated amino acid residue of a tetrameric sickle hemoglobin molecule (HbS), with hydrophobic groove of another HbS tetramer initiates the polymerization. Glutathionylation of βCys93 in HbS was reported to inhibit the polymerization. Read More

    DIS3 isoforms vary in their endoribonuclease activity and are differentially expressed within haematological cancers.
    Biochem J 2018 May 25. Epub 2018 May 25.
    Brighton & Sussex Medical School, University of Sussex, Medical Research Building, Falmer, Brighton, BN1 9PS, United Kingdom
    DIS3 is the catalytic subunit of the exosome, a protein complex involved in the 3' to 5' degradation of RNAs. DIS3 is a highly conserved exoribonuclease, also known as Rrp44. Global sequencing studies have identified DIS3 as being mutated in a range of cancers, with a considerable incidence in multiple myeloma. Read More

    Who does TORC2 talk to?
    Biochem J 2018 May 24;475(10):1721-1738. Epub 2018 May 24.
    Nutrition and Metabolism, South Australian Health and Medical Research Institute, North Terrace, Adelaide, South Australia 5000, Australia
    The target of rapamycin (TOR) is a protein kinase that, by forming complexes with partner proteins, governs diverse cellular signalling networks to regulate a wide range of processes. TOR thus plays central roles in maintaining normal cellular functions and, when dysregulated, in diverse diseases. TOR forms two distinct types of multiprotein complexes (TOR complexes 1 and 2, TORC1 and TORC2). Read More

    Global conformational changes in IgG-Fc upon mutation of the FcRn binding site are not associated with altered antibody-dependent effector functions.
    Biochem J 2018 May 24. Epub 2018 May 24.
    School of Science, RMIT University, Bundoora, Australia
    Antibody engineering is important for many diagnostic and clinical applications of monoclonal antibodies. We recently reported a series of Fc mutations targeting the neonatal Fc receptor (FcRn) site on a Lewis Y binding IgG1, hu3S193. The hu3S193 variants displayed shortened half-lives and may have potential for radioimaging or radiotherapy of Lewis Y positive tumors. Read More

    SINHCAF/FAM60A and SIN3A specifically repress HIF 2α expression.
    Biochem J 2018 May 21. Epub 2018 May 21.
    Biochemistry-IIB, University of Liverpool, Biosciences building, Liverpool, L697ZB, United Kingdom
    The SIN3A-HDAC complex is a master transcriptional repressor, required for development but often deregulated in disease. Here, we report that the recently identified new component of this complex, SINHCAF/FAM60A, links the SIN3A-HDAC co-repressor complex function to the hypoxia response. We show that SINHCAF specifically repress HIF 2α mRNA and protein expression, via its interaction with the transcription factor SP1, and recruitment of HDAC1 to the HIF 2α promoter. Read More

    Spotlight on the transglutaminase 2 gene: a focus on genomic and transcriptional aspects.
    Biochem J 2018 May 15;475(9):1643-1667. Epub 2018 May 15.
    Department of Biomedical Sciences and Specialist Surgery, Section of Biochemistry, Molecular Biology and Medical Genetics, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy
    The type 2 isoenzyme is the most widely expressed transglutaminase in mammals displaying several intra- and extracellular activities depending on its location (protein modification, modulation of gene expression, membrane signalling and stabilization of cellular interactions with the extracellular matrix) in relation to cell death, survival and differentiation. In contrast with the appreciable knowledge about the regulation of the enzymatic activities, much less is known concerning its inducible expression, which is altered in inflammatory and neoplastic diseases. In this context, we first summarize the gene's basic features including single-nucleotide polymorphism characterization, epigenetic DNA methylation and identification of regulatory regions and of transcription factor-binding sites at the gene promoter, which could concur to direct gene expression. Read More

    The new normal of structure/function studies in the era of CRISPR/Cas9.
    Biochem J 2018 May 15;475(9):1635-1642. Epub 2018 May 15.
    Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA 19104, U.S.A.
    Major advances in gene-editing technologies have enabled the rapid dissection of proteins in complex biological systems, facilitating biological experiments to complement biochemical studies with purified components. In this editorial, we highlight CRISPR/Cas9-based strategies to rapidly manipulate endogenous genes - strategies that have already transformed functional studies of proteins in metazoan systems. We further describe emerging tools using a catalytically dead version of Cas9 (dCas9) that do not cleave DNA, but can alter gene expression and/or local chromatin states, edit single nucleotide bases, and permit the visualization of specific genomic loci. Read More

    Structural and ligand binding analysis of the YAP-binding domain of transcription factor TEAD4.
    Biochem J 2018 May 14. Epub 2018 May 14.
    EXPERIMENTAL THERAPEUTICS CENTRE, 31 Biopolis Way Nanos #03-01, Singapore, 138669, Singapore
    The oncoprotein YAP requires the TEAD family of transcription factors for the upregulation of genes important for cell proliferation. Disrupting YAP-TEAD interaction is an attractive strategy for cancer therapy. Targeting TEADs using small molecules that either bind to the YAP-binding pocket or the palmitate-binding pocket is proposed to the disrupt YAP-TEAD interaction. Read More

    Identification of a Wells-Dawson polyoxometalate-based AP-2γ inhibitor with pro-apoptotic activity.
    Biochem J 2018 Jun 11;475(11):1965-1977. Epub 2018 Jun 11.
    Faculty of Health Sciences, University of Macau, Macau, China
    AP-2 gamma (AP-2γ) is a transcription factor that plays pivotal roles in breast cancer biology. To search for small molecule inhibitors of AP-2γ, we performed a high-throughput fluorescence anisotropy screen and identified a polyoxometalate compound with Wells-Dawson structure K[PMoO] (Dawson-POM) that blocks the DNA-binding activity of AP-2γ. We showed that this blocking activity is due to the direct binding of Dawson-POM to AP-2γ. Read More

    Anti-sigma factor YlaD regulates transcriptional activity of sigma factor YlaC and sporulation via manganese-dependent redox-sensing molecular switch in .
    Biochem J 2018 May 14. Epub 2018 May 14.
    School of Biological Sciences, Seoul National University, Shillim-dong, Gwanak-gu, Seoul, 151-742, Korea (South), Republic of
    YlaD, a membrane-anchored anti-sigma factor of , contains a HXCXXC motif that functions as a redox-sensing domain and belongs to one of the zinc-coordinated anti-sigma factor families. Despite previously showing that the YlaC transcription is controlled by YlaD, experimental evidence of how the YlaC-YlaD interaction is affected by active cysteines and/or metal ions is lacking. Here, we showed that the P promoter is autoregulated solely by YlaC. Read More

    An allostatic mechanism for M2 pyruvate kinase as an amino-acid sensor.
    Biochem J 2018 May 31;475(10):1821-1837. Epub 2018 May 31.
    Centre for Translational and Chemical Biology, School of Biological Sciences, University of Edinburgh, Michael Swann Building, Max Born Crescent, Edinburgh EH9 3BF, U.K.
    We have tested the effect of all 20 proteinogenic amino acids on the activity of the M2 isoenzyme of pyruvate kinase (M2PYK) and show that, within physiologically relevant concentrations, phenylalanine, alanine, tryptophan, methionine, valine, and proline act as inhibitors, while histidine and serine act as activators. Size exclusion chromatography has been used to show that all amino acids, whether activators or inhibitors, stabilise the tetrameric form of M2PYK. In the absence of amino-acid ligands an apparent tetramer-monomer dissociation is estimated to be ∼0. Read More

    Cancer stem cells (CSCs): metabolic strategies for their identification and eradication.
    Biochem J 2018 May 9;475(9):1611-1634. Epub 2018 May 9.
    Translational Medicine, School of Environment and Life Sciences, Biomedical Research Centre (BRC), University of Salford, Greater Manchester, U.K.
    Phenotypic and functional heterogeneity is one of the most relevant features of cancer cells within different tumor types and is responsible for treatment failure. Cancer stem cells (CSCs) are a population of cells with stem cell-like properties that are considered to be the root cause of tumor heterogeneity, because of their ability to generate the full repertoire of cancer cell types. Moreover, CSCs have been invoked as the main drivers of metastatic dissemination and therapeutic resistance. Read More

    ApoE isoforms and carboxyl-terminal-truncated apoE4 forms affect neuronal BACE1 levels and Aβ production independently of their cholesterol efflux capacity.
    Biochem J 2018 May 31;475(10):1839-1859. Epub 2018 May 31.
    Institute of Biosciences and Applications, National Center for Scientific Research 'Demokritos', Agia Paraskevi, Athens 15341, Greece
    The β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) initiates the production of amyloid-β peptide (Aβ), which is central to the pathogenesis of Alzheimer's disease (AD). Changes in brain cholesterol homeostasis have been suggested to affect Aβ metabolism. Cholesterol homeostasis is maintained in the brain by apolipoprotein E (apoE). Read More

    The Parkinson's disease VPS35[D620N] mutation enhances LRRK2-mediated Rab protein phosphorylation in mouse and human.
    Biochem J 2018 Jun 6;475(11):1861-1883. Epub 2018 Jun 6.
    MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.
    Missense mutations in the LRRK2 (Leucine-rich repeat protein kinase-2) and VPS35 genes result in autosomal dominant Parkinson's disease. The VPS35 gene encodes for the cargo-binding component of the retromer complex, while LRRK2 modulates vesicular trafficking by phosphorylating a subgroup of Rab proteins. Pathogenic mutations in LRRK2 increase its kinase activity. Read More

    Inhibition of FOXO1 transcription factor in primary human adipocytes mimics the insulin-resistant state of type 2 diabetes.
    Biochem J 2018 May 31;475(10):1807-1820. Epub 2018 May 31.
    Department of Clinical and Experimental Medicine, Linköping University, SE-58185 Linköping, Sweden
    Type 2 diabetes is characterized by insulin resistance in the expanding adipose tissue of obesity. The insulin resistance manifests in human adipocytes as system-wide impairment of insulin signalling. An exception is the regulation of transcription factor FOXO1 (forkhead box protein O1), which is phosphorylated downstream of mTORC2 (mammalian/mechanistic target of rapamycin in complex with raptor) and is therefore not exhibiting impaired response to insulin. Read More

    The type IV pilus assembly motor PilB is a robust hexameric ATPase with complex kinetics.
    Biochem J 2018 Jun 15;475(11):1979-1993. Epub 2018 Jun 15.
    Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, U.S.A.
    The bacterial type IV pilus (T4P) is a versatile nanomachine that functions in pathogenesis, biofilm formation, motility, and horizontal gene transfer. T4P assembly is powered by the motor ATPase PilB which is proposed to hydrolyze ATP by a symmetrical rotary mechanism. This mechanism, which is deduced from the structure of PilB, is untested. Read More

    A phosphatidic acid-binding protein is important for lipid homeostasis and adaptation to anaerobic biofilm conditions in .
    Biochem J 2018 Jun 6;475(11):1885-1907. Epub 2018 Jun 6.
    Institute of Microbiology, Technische Universität Braunschweig, Spielmannstraße 7, D-38106 Braunschweig, Germany
    A quantitative proteomics approach revealed increased abundance of the so-far uncharacterized protein PA3911 in anaerobic biofilms grown under conditions of the cystic fibrosis lung. Physiological relevance of ORF PA3911 was demonstrated, , using phenotype microarray experiments. The mutant strain showed increased susceptibility in the presence of antimicrobials (minocycline, nafcillin, oxacillin, chloramphenicol and thiamphenicol), enhanced twitching motility and significantly impaired biofilm formation. Read More

    The functional principle of eukaryotic molybdenum insertases.
    Biochem J 2018 May 24;475(10):1739-1753. Epub 2018 May 24.
    Department of Plant Biology, Braunschweig University of Technology, 38106 Braunschweig, Germany
    The molybdenum cofactor (Moco) is a redox-active prosthetic group found in the active site of Moco-dependent enzymes, which are vitally important for life. Moco biosynthesis involves several enzymes that catalyze the subsequent conversion of GTP into cyclic pyranopterin monophosphate (cPMP), molybdopterin (MPT), adenylated MPT (MPT-AMP), and finally Moco. While the underlying principles of cPMP, MPT, and MPT-AMP formation are well understood, the molybdenum insertase (Mo-insertase)-catalyzed final Moco maturation step is not. Read More

    Regulation of the metabolism of apolipoprotein M and sphingosine 1-phosphate by hepatic PPARγ activity.
    Biochem J 2018 Apr 30. Epub 2018 Apr 30.
    Department of Clinical Laboratory Medicine, The University of Tokyo, Graduate School of Medicine, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
    Apolipoprotein M (apoM) is a carrier and a modulator of sphingosine 1-phosphate (S1P), an important multi-functional bioactive lipid. Since PPARγ is reportedly associated with the function and metabolism of S1P, we investigated the modulation of apoM/S1P homeostasis by PPARγ. First, we investigated the modulation of apoM and S1P homeostasis by the overexpression or knockdown of PPARγ in HepG2 cells and found that both the overexpression and the knockdown of PPARγ decreased apoM expression and S1P synthesis. Read More

    Elevation of cytosolic Ca in response to energy deficiency in plants: the general mechanism of adaptation to low oxygen stress.
    Biochem J 2018 Apr 23;475(8):1411-1425. Epub 2018 Apr 23.
    Department of Plant Science, University of Manitoba, Winnipeg, MB, Canada R3T 2N2.
    Ca can be released from cell compartments to the cytosol during stress conditions. We discuss here the causes of Ca release under conditions of ATP concentration decline that result in the suppression of ATPases and activation of calcium ion channels. The main signaling and metabolic consequences of Ca release are considered for stressed plant cells. Read More

    TFE-induced local unfolding and fibrillation of SOD1: bridging the experiment and simulation studies.
    Biochem J 2018 May 18;475(10):1701-1719. Epub 2018 May 18.
    Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
    Misfolding and aggregation of Cu, Zn Superoxide dismutase (SOD1) is involved in the neurodegenerative disease, amyotrophic lateral sclerosis. Many studies have shown that metal-depleted, monomeric form of SOD1 displays substantial local unfolding dynamics and is the precursor for aggregation. Here, we have studied the structure and dynamics of different apo monomeric SOD1 variants associated with unfolding and aggregation in aqueous trifluoroethanol (TFE) through experiments and simulation. Read More

    Stereochemistry as a determining factor for the effect of a cell-penetrating peptide on cellular viability and epithelial integrity.
    Biochem J 2018 May 24;475(10):1773-1788. Epub 2018 May 24.
    Center for Biopharmaceuticals and Biobarriers in Drug Delivery, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
    Cell-penetrating peptides (CPPs) comprise efficient peptide-based delivery vectors. Owing to the inherent poor enzymatic stability of peptides, CPPs displaying partial or full replacement of l-amino acids with the corresponding d-amino acids might possess advantages as delivery vectors. Thus, the present study aims to elucidate the membrane- and metabolism-associated effects of l-Penetratin (l-PEN) and its corresponding all-d analog (d-PEN). Read More

    Insulin-induced exocytosis regulates the cell surface level of low-density lipoprotein-related protein-1 in Müller Glial cells.
    Biochem J 2018 May 15;475(9):1669-1685. Epub 2018 May 15.
    Universidad Nacional de Córdoba, Facultad de Ciencias Químicas, Departamento de Bioquímica Clínica, Córdoba, Argentina
    Low-density lipoprotein (LDL) receptor-related protein-1 (LRP1) is expressed in retinal Müller glial cells (MGCs) and regulates intracellular translocation to the plasma membrane (PM) of the membrane proteins involved in cellular motility and activity. Different functions of MGCs may be influenced by insulin, including the removal of extracellular glutamate in the retina. In the present work, we investigated whether insulin promotes LRP1 translocation to the PM in the Müller glial-derived cell line MIO-M1 (human retinal Müller glial cell-derived cell line). Read More

    MPC1 is essential for PGC-1α-induced mitochondrial respiration and biogenesis.
    Biochem J 2018 May 18;475(10):1687-1699. Epub 2018 May 18.
    Department of Biochemistry and Molecular Biology, Integrated Genomic Research Center for Metabolic Regulation, Institute of Genetic Science, College of Medicine, Yonsei University, Seoul 03722, Korea
    Mitochondrial pyruvate carrier (MPC), which is essential for mitochondrial pyruvate usage, mediates the transport of cytosolic pyruvate into mitochondria. Low MPC expression is associated with various cancers, and functionally associated with glycolytic metabolism and stemness. However, the mechanism by which MPC expression is regulated is largely unknown. Read More

    Residues contributing to drug transport by ABCG2 are localised to multiple drug-binding pockets.
    Biochem J 2018 May 4;475(9):1553-1567. Epub 2018 May 4.
    School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, U.K.
    Multidrug binding and transport by the ATP-binding cassette transporter ABCG2 is a factor in the clinical resistance to chemotherapy in leukaemia, and a contributory factor to the pharmacokinetic profiles of many other prescribed drugs. Despite its importance, the structural basis of multidrug transport, i.e. Read More

    Deregulation of LIMD1-VHL-HIF-1α-VEGF pathway is associated with different stages of cervical cancer.
    Biochem J 2018 May 31;475(10):1793-1806. Epub 2018 May 31.
    Department of Oncogene Regulation, Chittaranjan National Cancer Institute, Kolkata, India.
    To understand the mechanism of cellular stress in basal-parabasal layers of normal cervical epithelium and during different stages of cervical carcinoma, we analyzed the alterations (expression/methylation/copy number variation/mutation) of HIF-1α and its associated genes LIMD1, VHL and VEGF in disease-free normal cervix ( = 9), adjacent normal cervix of tumors ( = 70), cervical intraepithelial neoplasia (CIN;  = 32), cancer of uterine cervix (CACX;  = 174) samples and two CACX cell lines. In basal-parabasal layers of normal cervical epithelium, LIMD1 showed high protein expression, while low protein expression of VHL was concordant with high expression of HIF-1α and VEGF irrespective of HPV-16 (human papillomavirus 16) infection. This was in concordance with the low promoter methylation of LIMD1 and high in VHL in the basal-parabasal layers of normal cervix. Read More

    Nucleic acid-induced potentiation of matrix metalloproteinase-9 enzymatic activity.
    Biochem J 2018 May 9;475(9):1597-1610. Epub 2018 May 9.
    Department of Anesthesiology, University of Wisconsin, School of Medicine and Public Health, Madison, WI 53705, U.S.A.
    Matrix metalloproteinases (MMPs) play varied roles in normal biology and diseases where, depending on the context, both inhibition and enhancement of the enzymatic activity may be beneficial. However, there are very few reports of positive modulators of MMP activity. We report that polynucleotides, including single-stranded DNA, RNA, and even double-stranded DNA, bind to and enhance the enzymatic activity of MMP9. Read More

    Cytosolic reverse CrAT activity in cardiac tissue: potential importance for fuel selection.
    Biochem J 2018 04 9;475(7):1267-1269. Epub 2018 Apr 9.
    Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada
    The movement of lipids across mitochondrial membranes represents a rate-limiting step in fatty acid oxidation within the heart. A key regulatory point in this process is flux through carnitine palmitoyltransferase-I (CPT-I), an enzyme located on the outer mitochondrial membrane. Malonyl-CoA (M-CoA) is a naturally occurring inhibitor of CPT-I; therefore, the abundance of M-CoA has long been considered a major regulator of fatty acid oxidation. Read More

    Extracellular ATP activates hyaluronan synthase 2 () in epidermal keratinocytes via P2Y, Ca signaling, and MAPK pathways.
    Biochem J 2018 May 24;475(10):1755-1772. Epub 2018 May 24.
    Institute of Biomedicine, University of Eastern Finland, FI-70211 Kuopio, Finland.
    Extracellular nucleotides are used as signaling molecules by several cell types. In epidermis, their release is triggered by insults such as ultraviolet radiation, barrier disruption, and tissue wounding, and by specific nerve terminals firing. Increased synthesis of hyaluronan, a ubiquitous extracellular matrix glycosaminoglycan, also occurs in response to stress, leading to the attractive hypothesis that nucleotide signaling and hyaluronan synthesis could also be linked. Read More

    NLRP3 regulates macrophage M2 polarization through up-regulation of IL-4 in asthma.
    Biochem J 2018 Apr 6. Epub 2018 Apr 6.
    the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
    Activation of nucleotide binding oligomerization domain (Nod)-like receptor (NLR) protein 3 (NLRP3) inflammasome received substantial attention recently in inflammatory diseases. Macrophages contribute to allergic inflammation in asthma. This study was aimed to investigate the effect of NLRP3 inflammasome on the polarization of macrophages. Read More

    Structural insights into the nanomolar affinity of RING E3 ligase ZNRF1 for Ube2N and its functional implications.
    Biochem J 2018 May 9;475(9):1569-1582. Epub 2018 May 9.
    Department of Biochemistry, Bose Institute, P-1/12 CIT Scheme VIIM, Kolkata 700054, India
    RING (eally nteresting ew ene) domains in ubiquitin RING E3 ligases exclusively engage ubiquitin (Ub)-loaded E2s to facilitate ubiquitination of their substrates. Despite such specificity, all RINGs characterized till date bind unloaded E2s with dissociation constants (s) in the micromolar to the sub-millimolar range. Here, we show that the RING domain of E3 ligase ZNRF1, an essential E3 ligase implicated in diverse cellular pathways, binds Ube2N with a of ∼50 nM. Read More

    Deubiquitinating enzyme USP9X regulates cellular clock function by modulating the ubiquitination and degradation of a core circadian protein BMAL1.
    Biochem J 2018 Apr 30;475(8):1507-1522. Epub 2018 Apr 30.
    Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu 215123, China
    Living organisms on the earth maintain a roughly 24 h circadian rhythm, which is regulated by circadian clock genes and their protein products. Post-translational modifications of core clock proteins could affect the circadian behavior. Although ubiquitination of core clock proteins was studied extensively, the reverse process, deubiquitination, has only begun to unfold and the role of this regulation on circadian function is not completely understood. Read More

    A plasmid borne, functionally novel glycoside hydrolase family 30 subfamily 8 endoxylanase from solventogenic .
    Biochem J 2018 May 4;475(9):1533-1551. Epub 2018 May 4.
    Department of Chemistry, Physics and Geology, Winthrop University, Rock Hill, SC, U.S.A.
    Glycoside hydrolase family 30 subfamily 8 (GH30-8) β-1,4-endoxylanases are known for their appendage-dependent function requiring recognition of an α-1,2-linked glucuronic acid (GlcA) common to glucuronoxylans for hydrolysis. Structural studies have indicated that the GlcA moiety of glucuronoxylans is coordinated through six hydrogen bonds and a salt bridge. These GlcA-dependent endoxylanases do not have significant activity on xylans that do not bear GlcA substitutions such as unsubstituted linear xylooligosaccharides or cereal bran arabinoxylans. Read More

    The Gcn2-eIF2α pathway connects iron and amino acid homeostasis in .
    Biochem J 2018 Apr 30;475(8):1523-1534. Epub 2018 Apr 30.
    Instituto de Biología Molecular y Celular de Plantas, Universidad Politécnica de Valencia-Consejo Superior de Investigaciones Científicas, Edificio 8E, Camino de Vera s/n, 46022 Valencia, Spain
    In eukaryotic cells, amino acid biosynthesis is feedback-inhibited by amino acids through inhibition of the conserved protein kinase Gcn2. This decreases phosphorylation of initiation factor eIF2α, resulting in general activation of translation but inhibition of translation of mRNA for transcription factor (TF) Gcn4 in yeast or ATF4 in mammals. These TFs are positive regulators of amino acid biosynthetic genes. Read More

    Protein CoAlation and antioxidant function of coenzyme A in prokaryotic cells.
    Biochem J 2018 Jun 6;475(11):1909-1937. Epub 2018 Jun 6.
    Department of Structural and Molecular Biology, University College London, London WC1E 6BT, U.K.
    In all living organisms, coenzyme A (CoA) is an essential cofactor with a unique design allowing it to function as an acyl group carrier and a carbonyl-activating group in diverse biochemical reactions. It is synthesized in a highly conserved process in prokaryotes and eukaryotes that requires pantothenic acid (vitamin B5), cysteine and ATP. CoA and its thioester derivatives are involved in major metabolic pathways, allosteric interactions and the regulation of gene expression. Read More

    Biological role of site-specific O-glycosylation in cell adhesion activity and phosphorylation of osteopontin.
    Biochem J 2018 May 9;475(9):1583-1595. Epub 2018 May 9.
    Department of Biochemistry, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, Fukushima 960-1295, Japan
    Osteopontin (OPN) is an extracellular glycosylated phosphoprotein that promotes cell adhesion by interacting with several integrin receptors. We previously reported that an OPN mutant lacking five O-glycosylation sites (Thr/Thr/Thr/Thr/Thr) in the threonine/proline-rich region increased cell adhesion activity and phosphorylation compared with the wild type. However, the role of O-glycosylation in cell adhesion activity and phosphorylation of OPN remains to be clarified. Read More

    Metabolic regulation of photosynthetic membrane structure tunes electron transfer function.
    Biochem J 2018 Apr 5;475(7):1225-1233. Epub 2018 Apr 5.
    Department of Molecular Biology and Biotechnology, University of Sheffield, Firth Court, Western Bank, Sheffield S10 2TN, U.K.
    The photosynthetic chloroplast thylakoid membrane of higher plants is a complex three-dimensional structure that is morphologically dynamic on a timescale of just a few minutes. The membrane dynamics are driven by the phosphorylation of light-harvesting complex II (LHCII) by the STN7 kinase, which controls the size of the stacked grana region relative to the unstacked stromal lamellae region. Here, I hypothesise that the functional significance of these membrane dynamics is in controlling the partition of electrons between photosynthetic linear and cyclic electron transfer (LET and CET), which determines the ratio of NADPH/ATP produced. Read More

    Intersectin goes nuclear: secret life of an endocytic protein.
    Biochem J 2018 Apr 27;475(8):1455-1472. Epub 2018 Apr 27.
    Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
    Intersectin 1-short (ITSN1-s) is a 1220 amino acid ubiquitously expressed scaffold protein presenting a multidomain structure that allows to spatiotemporally regulate the functional interaction of a plethora of proteins. Besides its well-established role in endocytosis, ITSN1-s is involved in the regulation of cell signaling and is implicated in tumorigenesis processes, although the signaling pathways involved are still poorly understood. Here, we identify ITSN1-s as a nucleocytoplasmic trafficking protein. Read More

    Cystathionine β-lyase is involved in d-amino acid metabolism.
    Biochem J 2018 Apr 23;475(8):1397-1410. Epub 2018 Apr 23.
    Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
    Non-canonical d-amino acids play important roles in bacteria including control of peptidoglycan metabolism and biofilm disassembly. Bacteria appear to produce non-canonical d-amino acids to adapt to various environmental changes, and understanding the biosynthetic pathways is important. We identified novel amino acid racemases possessing the ability to produce non-canonical d-amino acids in and in our previous study, whereas the biosynthetic pathways of these d-amino acids still remain unclear. Read More

    Matrix-bound AGEs enhance TGFβ2-mediated mesenchymal transition of lens epithelial cells via the noncanonical pathway: implications for secondary cataract formation.
    Biochem J 2018 Apr 23;475(8):1427-1440. Epub 2018 Apr 23.
    Department of Ophthalmology, University of Colorado School of Medicine, Aurora, CO 80045, U.S.A.
    Advanced glycation end products (AGEs) are post-translational modifications formed from the reaction of reactive carbonyl compounds with amino groups in proteins. Our laboratory has previously shown that AGEs in extracellular matrix (ECM) proteins promote TGFβ2 (transforming growth factor-beta 2)-mediated epithelial-to-mesenchymal transition (EMT) of lens epithelial cells (LECs), which could play a role in fibrosis associated with posterior capsule opacification. We have also shown that αB-crystallin plays an important role in TGFβ2-mediated EMT of LECs. Read More

    Gtgen3A, a novel plant GH3 β-glucosidase, modulates gentio-oligosaccharide metabolism in .
    Biochem J 2018 Apr 16;475(7):1309-1322. Epub 2018 Apr 16.
    Iwate Biotechnology Research Center, Kitakami, Iwate 024-0003, Japan.
    Gentiobiose, a β-1,6-linked glycosyl-disaccharide, accumulates abundantly in Gentianaceae and is involved in aspects of plant development, such as fruits ripening and release of bud dormancy. However, the mechanisms regulating the amount of gentio-oligosaccharide accumulation in plants remain obscure. The present study aimed to identify an enzyme that modulates gentio-oligosaccharide amount in gentian (). Read More

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