Biochemical Journal (BIOCHEM J)

Publisher: Biochemical Society (Great Britain), Portland Press

Journal description

The Biochemical Journal publishes over 7000 pages of high-quality scientific information every year. The papers are carefully selected by an international editorial board to cover all aspects of biochemistry, and cell and molecular biology. The journal features regular papers, authoritative reviews, research communications (short articles reporting novel and significant findings) and correspondence.

Current impact factor: 4.40

Impact Factor Rankings

2016 Impact Factor Available summer 2017
2014 / 2015 Impact Factor 4.396
2013 Impact Factor 4.779
2012 Impact Factor 4.654
2011 Impact Factor 4.897
2010 Impact Factor 5.016
2009 Impact Factor 5.155
2008 Impact Factor 4.371
2007 Impact Factor 4.009
2006 Impact Factor 4.1
2005 Impact Factor 4.224
2004 Impact Factor 4.278
2003 Impact Factor 4.101
2002 Impact Factor 4.589
2001 Impact Factor 4.326
2000 Impact Factor 4.28
1999 Impact Factor 4.349
1998 Impact Factor 3.855
1997 Impact Factor 3.579
1996 Impact Factor 3.687
1995 Impact Factor 4.159
1994 Impact Factor 4.262
1993 Impact Factor 3.659
1992 Impact Factor 3.716

Impact factor over time

Impact factor

Additional details

5-year impact 4.66
Cited half-life >10.0
Immediacy index 0.89
Eigenfactor 0.06
Article influence 1.75
Website Biochemical Journal website
Other titles Biochemical journal (London, England: 1984), Biochemical journal
ISSN 0264-6021
OCLC 10379627
Material type Periodical, Internet resource
Document type Journal / Magazine / Newspaper, Internet Resource

Publisher details

Portland Press

  • Pre-print
    • Author cannot archive a pre-print version
  • Post-print
    • Author cannot archive a post-print version
  • Restrictions
    • 6 months embargo
  • Conditions
    • On author's personal website or institutional repository
    • Accepted version may be placed on PubMed Central and Europe PMC after 12 months from publication
    • Must link to journal website
    • Published source must be acknowledged ('The final version of record is available at [insert Journals URL]')
    • Publisher's version/PDF cannot be used
    • Must link to journal website, e.g. with a DOI
  • Classification

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Historically, drugs used in the treatment of cancers also tend to cause damage to healthy cells while affecting cancer cells. Therefore, the identification of novel agents that act specifically against cancer cells remains a high priority in the search for new therapies. In contrast to normal cells, most cancer cells contain multiple centrosomes which are associated with genome instability and tumorigenesis. Cancer cells can avoid multipolar mitosis, which can cause cell death, by clustering the extra centrosomes into two spindle poles, thereby enabling bipolar division. Kinesin-like protein KIFC1 plays a critical role in centrosome clustering in cancer cells, but is not essential for normal cells. Therefore, targeting KIFC1 may provide novel insight into selectively killing of cancer cells. In the present study, we identified a small molecule KIFC1 inhibitor, SR31527, which inhibited microtubule-stimulated KIFC1 ATPase activity with an IC50 value of 6.6 µM. By using bio-layer interferometry technology, we further demonstrated that SR31527 bound directly to KIFC1 with high affinity ( Kd = 25.4 nM). Our results from computational modeling and STD-NMR experiment suggested that SR31527 bound to a novel allosteric site of KIFC1 that appears suitable for developing selective inhibitors of KIFC1. Importantly, SR31527 prevented bipolar clustering of extra-centrosomes in triple negative breast cancer (TNBC) cells and significantly reduced TNBC cell colony formation and viability, but was less toxic to normal fibroblasts. Therefore, SR31527 provides a valuable tool for studying the biological function of KIFC1 and serves as a potential lead for the development of novel therapeutic agents for breast cancer treatment.
    No preview · Article · Feb 2016 · Biochemical Journal
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    ABSTRACT: Lonidamine (LND) is an anti-tumour drug particularly effective at selectively sensitising tumours to chemotherapy, hyperthermia and radiotherapy, although its precise mode of action remains unclear. It has been reported to perturb the bioenergetics of cells by inhibiting glycolysis and mitochondrial respiration, while indirect evidence suggests it may also inhibit L-lactic acid efflux from cells mediated by members of the proton-linked monocarboxylate transporter (MCT) family and also pyruvate uptake into the mitochondria by the mitochondrial pyruvate carrier (MPC). Here we test these possibilities directly. We demonstrate that LND potently inhibits MPC activity in isolated rat liver mitochondria (Ki 2.5 μM) and cooperatively inhibits L-lactate transport by MCT1, MCT2 andMCT4 expressed in Xenopus laevis oocytes with K0.5 and Hill Coefficient values of 36-40 μM and 1.65-1.85. In rat heart mitochondria LND inhibited the MPC with similar potency and uncoupled oxidation of pyruvate was inhibited more effectively (IC50 ~7 μM) than other substrates including glutamate (IC50 ~20 μM). In isolated DB-1 melanoma cells 1-10 μM LND increased L-lactate output, consistent with MPC inhibition, but higher concentrations (150 μM) decreased L-lactate output while increasing intracellular [L-lactate] > five-fold, consistent with MCT inhibition. We conclude that MPC inhibition is the most sensitive anti-tumour target for LND, with additional inhibitory effects on MCT-mediated L-lactic acid efflux and glutamine/glutamate oxidation. Together these actions can account for published data on the selective tumour effects of LND on L-lactate, intracellular pH (pHi) and ATP levels that can be partially mimicked by the established MPC and MCT inhibitor α-cyano-4-hydroxycinnamate.
    No preview · Article · Feb 2016 · Biochemical Journal
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    ABSTRACT: The sodium/iodide symporter (NIS) is an integral membrane protein that plays a crucial role in iodide accumulation, especially in the thyroid. As for many other membrane proteins, its intracellular sorting and distribution have a tremendous effect on its function, and constitute an important aspect of its regulation. Many small sequences have been shown to contribute to protein trafficking along the sorting or endocytic pathways. Using bioinformatics tools, we identified such potential sites on human NIS (tyrosine-based motifs, SH2-, SH3- and PDZ-binding motifs, and diacidic, dibasic and dileucine motifs) and analyzed their roles using mutagenesis. We found that several of these sites play a role in protein stability and/or targeting to the membrane. Aside from the mutation at position 178 (SH2 plus tyrosine-based motif) that affects iodide uptake, the most drastic effect is associated with the mutation of an internal PDZ-binding motif at position 121 that completely abolishes NIS expression at the plasma membrane. Mutating the sites located on the C-terminus domain of the protein has no effect except the creation of a diacidic motif that decreases total NIS protein level without affecting its expression at the plasma membrane.
    No preview · Article · Feb 2016 · Biochemical Journal

  • No preview · Article · Feb 2016 · Biochemical Journal
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    ABSTRACT: AMP-activated protein kinase (AMPK) is a metabolic stress-sensing kinase. We previously showed that glucose deprivation induces autophosphorylation of AMPKβ at threonine-148 (Thr-148), which prevents the binding of AMPK to glycogen. Furthermore, in MIN6 cells, AMPKβ1 binds to R6 (PPP1R3D), a glycogen-targeting subunit of protein phosphatase 1 (PP1), thereby regulating the glucose-induced inactivation of AMPK. Here, we further investigated the interaction of R6 with AMPKβ and the possible dependency on Thr-148 phosphorylation status. Yeast two-hybrid analyses and co-immunoprecipitation of the overexpressed proteins in HEK293T cells revealed that both AMPKβ1 and β2 wild-type (WT) isoforms bind to R6. The AMPKβ/R6 interaction was stronger with the muscle-specific β2-WT and required association with the substrate-binding motif of R6. When HEK293T cells or C2C12 myotubes were cultured in high-glucose medium, AMPKβ2-WT and R6 weakly interacted. In contrast, glycogen depletion significantly enhanced this protein interaction. Mutation of AMPKβ2 Thr-148 prevented the interaction with R6 irrespective of the intracellular glycogen content. Treatment with the AMPK activator oligomycin enhanced AMPKβ2/R6 interaction in conjunction with increased Thr-148 phosphorylation in cells grown in low glucose medium. These data are in accordance with R6 binding directly to AMPKβ2 when both proteins detach from the diminishing glycogen particle, which is simultaneous to increased AMPKβ2 Thr-148 autophosphorylation. Such model points to a possible control of AMPK by PP1-R6 upon glycogen depletion in muscle.
    No preview · Article · Feb 2016 · Biochemical Journal
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    ABSTRACT: For successful infection and propagation viruses must overcome many obstacles such as the immune system and entry into their host cells. The human immunodeficiency virus (HIV), utilizes its trimeric envelope protein gp160, specifically the gp41 subunit, to enter its host cell. During this process, a gp41-central coiled-coil is formed from three N and three C terminal heptad repeats, termed the six helix bundle, which drives membrane fusion. Recently, T-cell suppression has been reported as an additional function for several regions of gp41 by interfering with the T-cell receptor signaling cascade. One of these regions encompasses the conserved pocket binding domain that is situated in the C terminal heptad repeat and stabilizes six-helix bundle formation. This could indicate that the pocket binding domain plays a role in T-cell suppression in addition to its role in membrane fusion. To investigate this dual function, we used two independent cell cultures coupled with biophysical techniques. The data reveal that the pocket binding domain mediates T-cell suppression by stabilizing a T-cell receptor binding conformation in the membrane. Moreover, we show that the clinically used HIV fusion inhibitor T-20 did not show suppressive abilities, in contrast to the potent fusion inhibitor C34. In addition, by focusing on six helix bundle conformation post its assembly, we shed light on a mechanism by which gp41's function alternates from membrane fusion facilitation to suppression of T-cell receptor activation.
    No preview · Article · Jan 2016 · Biochemical Journal
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    ABSTRACT: Members of the poly-ADP-ribose polymerase (PARP) family catalyse the ADP-ribosylation of target proteins and are known to play important roles in many cellular processes, including DNA repair, differentiation and transcription. The majority of PARPs exhibit mono-ADP-ribosyltransferase activity rather than poly-ADP-ribose polymer activity; however, little is known about their biological activity. In this study we report that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly-ADP-ribose polymerase (TIPARP), mono-ADP-ribosylates and positively regulates liver X receptor a (LXRa) and LXRb activity. Overexpression of TIPARP enhanced LXR-reporter gene activity. TIPARP knockdown or deletion reduced LXR regulated target gene expression levels in HepG2 cells and in Tiparp(-/-) mouse embryonic fibroblasts, respectively. Deletion and mutagenesis studies showed that TIPARP's zinc-finger and catalytic domains were required to enhance LXR activity. Protein interaction studies using TIPARP and LXRα/β peptide arrays revealed that LXRs interacted with an N-terminal sequence (a.a. 209-236) of TIPARP, which also overlapped with a putative coactivator domain of TIPARP (a.a. 200-225). Immunofluorescence studies showed that TIPARP and LXRαor LXRβ co-localized in the nucleus. In vitro ribosylation assays provided evidence that TIPARP mono-ADP-ribosylated both LXRα and LXRβ. Co-immunoprecipitation studies revealed that ADP-ribosylase Macrodomain 1 (MACROD1), but not MACROD2, interacted with LXRs in a TIPARP-dependent manner. This was complemented by reporter gene studies showing that MACROD1, but not MACROD2, prevented the TIPARP-dependent increase in LXR activity. GW3965-dependent increases in hepatic Srebp1 mRNA and protein expression levels were reduced in Tiparp(-/-) mice compared with Tiparp(+/+) mice. Taken together, these data identify a new mechanism of LXR regulation that involves TIPARP, ADP-ribosylation and MACROD1.
    No preview · Article · Jan 2016 · Biochemical Journal
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    ABSTRACT: In plants, the last step in the biosynthesis of the osmoprotectant glycine betaine (GB) is the NAD(+)-dependent oxidation of betaine aldehyde (BAL) catalyzed by some ALDH10 enzymes that exhibit betaine aldehyde dehydrogenase (BADH) activity. Given the irreversibility of the reaction, the short-term regulation of these enzymes is of great physiological relevance to avoid adverse NAD(+)/NADH ratio decreases. We here report that the Spinacia oleracea betaine aldehyde dehydrogenase ( So BADH) is reversibly and partially inactivated by BAL in the absence of NAD(+) in a time- and concentration-dependent mode. Crystallographic evidence indicates that the non-essential Cys(450) ( So BADH numbering) forms a thiohemiacetal with BAL, totally blocking the productive binding of the aldehyde. Interestingly, in contrast with Cys(450) the catalytic cysteine (Cys(291)) did not react with BAL in the absence of NAD(+). The trimethylammonium group of BAL binds in the same position in the inactivating or productive modes. Accordingly, BAL does not inactivate the C450S So BADH mutant and the degree of inactivation of the A441I and A441C mutants corresponds to their very different ability to bind the trimethylammonium group. Cys(450) and the neighboring residues that participate in stabilization of the thiohemiacetal are strictly conserved in plant ALDH10 enzymes with proven or predicted BADH activity, suggesting that inactivation by BAL is a common feature of them. Under osmotic stress conditions, this novel partial and reversible covalent regulatory mechanism may contribute to prevent NAD(+) exhaustion, while still permitting the synthesis of high amounts of GB and avoiding the accumulation of the toxic BAL.
    No preview · Article · Jan 2016 · Biochemical Journal
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    ABSTRACT: The membrane topology of vitamin K epoxide hydrolase (VKOR) is controversial with data supporting both a three transmembrane and a four transmembrane model. The positioning of the transmembrane domains and the loops between these domains is critical if we are to understand the mechanism of vitamin K oxidation and its recycling by members of the thioredoxin family of proteins and the mechanism of action of warfarin, an inhibitor of VKOR. Here we show that both mammalian VKOR isoforms adopt the same topology, with the large loop between transmembrane one and two facing the lumen of the endoplasmic reticulum (ER). We used a redox sensitive GFP fused to the N- or C- terminus to show that these regions face the cytosol, and introduction of glycosylation sites along with mixed disulfide formation with thioredoxin like transmembrane protein (TMX) to demonstrate ER localisation of the major loop. The topology is identical to the bacterial homologue from Synechococcus sp., for which the structure and mechanism of recycling has been characterized. Our results provide a resolution to the membrane topology controversy and support previous results suggesting a role for members of the ER protein disulfide isomerase family in recycling VKOR.
    No preview · Article · Jan 2016 · Biochemical Journal
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    ABSTRACT: GABAB receptor mediates slow and prolonged synaptic inhibition in the central nervous system, which represents an interesting target for the treatment of various CNS diseases and disorders. Till now, only one activator of GABAB receptor, baclofen, is on the market for the treatment of spasticity. Inhibitors of GABAB receptor such as antagonists show anti-absence seizure activity and pro-cognitive properties. In a search for the allosteric compounds of GABAB receptor, whereas several positive allosteric modulators (PAMs) have been developed, only recently the first negative allosteric modulator (NAM), CLH304a (also named as Compound 14), has been reported. Here we provide further information on the mechanism of action of CLH304a, and also show the possibility to design more NAMs such asCLH391 and CLH393, based on the structure of CLH304a. We first show that CLH304a inhibits the native GABAB receptor activity in cultured cerebellar granule neurons. We then show that CLH304a has inverse agonist property and non-competitively inhibits the effect of agonist, indicating that it binds at a different site than GABA. GABAB receptor is a mandatory heterodimer made of GB1subunits where agonists bind, and GB2 subunits that activates G proteins. By using various combinations made of wild type and/or mutated of GB1 and GB2, we show that CLH304a acts on the heptahelical domain of GB2. These data revealed the possibility to design innovative NAMs acting in the HD of GB2, offering novel possibilities for therapeutic intervention based on GABAB receptor inhibition.
    No preview · Article · Jan 2016 · Biochemical Journal
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    ABSTRACT: The structural maintenance of chromosome (SMC) proteins are fundamental to chromosome organization. They share a characteristic domain structure, featuring a central SMC hinge domain that is critical for forming SMC dimers and interacting with nucleic acids. The structural maintenance of chromosomes flexible hinge domain containing 1 (Smchd1) is a noncanonical member of the SMC family. While it has been well established that Smchd1 serves crucial roles in epigenetic silencing events implicated in development and disease, much less is known about the structure and function of Smchd1 protein. Recently, we demonstrated that the C-terminal hinge domain of Smchd1 forms a nucleic acid-binding homodimer, however, it is unclear how the protomers are assembled within the hinge homodimer and how the full-length Smchd1 protein is organised with respect to the hinge region. Here, by employing small-angle X-ray scattering (SAXS) we demonstrate that the hinge domain of Smchd1 likely adopts an unconventional homodimeric arrangement augmented by a coiled-coil formed between the two monomers. Such a dimeric structure differs markedly from that of archetypical SMC proteins, raising the possibility that Smchd1 binds chromatin in an unconventional manner.
    Preview · Article · Jan 2016 · Biochemical Journal
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    ABSTRACT: The extracellular matrix of articular cartilage is structurally specialized for efficient absorption of mechanical impact. In particular, giant aggregates of the large chondroitin sulfate proteoglycan, aggrecan, with the glycosaminoglycan, hyaluronan, allow cartilage to resist compressive load. Proteolysis of aggrecan by members of the proteinase family ADAMTS (A disintegrin-like and metalloproteinase domain with thrombospondin type 1 motif), was identified as an early step in the inexorable destruction of cartilage in osteoarthritis (OA). Of the investigated proteinases, ADAMTS5 has emerged as a principal mediator of aggrecan loss in OA, convincingly so in mouse models, and with high probability in humans. ADAMTS5 has a bipartite organization, comprising a proteinase domain and an ancillary domain containing exosites for interaction with aggrecan and other substrates. In a recent issue of this journal, Santamaria et al. characterized anti-ADAMTS5 monoclonal antibodies isolated from a phage display library. By blocking the catalytic site of the ADAMTS5 immunogen with a synthetic inhibitor, the authors of the paper biased selection of antibodies to the ancillary domain. This work, together with other antibodies targeting ADAMTS5, offers diverse, high-affinity and, as far as can be determined, selective aggrecanase inhibitors. Mapping of their epitopes provided novel insights into ADAMTS5 interactions with aggrecan. These monoclonal antibodies deserve continued investigation for potential arthritis therapy, although their successful use will require a comprehensive understanding of the physiological roles of ADAMTS5, and its regulation, intrinsic properties and intermolecular interactions.
    No preview · Article · Jan 2016 · Biochemical Journal

  • No preview · Article · Dec 2015 · Biochemical Journal

  • No preview · Article · Dec 2015 · Biochemical Journal
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    ABSTRACT: The chemokine receptor CX3CR1 has been implicated as an attractive therapeutic target in several diseases, including atherosclerosis and diabetes. However, there has been a lack of non-peptide CX3CR1 inhibitors to substantiate these findings. A selective small molecule inhibitor of CX3CR1, AZD8797, was recently reported and we present here an in-depth in vitro characterisation of that molecule. In a flow adhesion assay, AZD8797 antagonized the natural ligand, fractalkine (CX3CL1) in both human whole blood and in a B lymphocyte cell line with IC50 values of 300 and 6 nM, respectively. AZD8797 also prevented G-protein activation in a [(35)S]-GTPγS accumulation assay. In contrast, dynamic mass redistribution (DMR) experiments revealed a weak Gαi dependent AZD8797 agonism. Additionally, AZD8797 positively modulated the CX3CL1 response at sub-micro molar concentrations in a β-arrestin recruitment assay. In equilibrium saturation binding experiments, AZD8797 reduced the maximal binding of [(125)I]-CX3CL1 without affecting Kd. Kinetic experiments, determining the kon and koff of AZD8797, demonstrated that this was not an artefact of irreversible or insurmountable binding, thus a true non-competitive mechanism. Finally we show that both AZD8797 and GTPγS increase the rate with which CX3CL1 dissociates from CX3CR1 in a similar manner, indicating a connection between AZD8797 and the CX3CR1 bound G-protein. Collectively, these data show that AZD8797 is a non-competitive allosteric modulator of CX3CL1, binding CX3CR1 and effecting G protein signalling and β-arrestin recruitment in a biased way.
    No preview · Article · Dec 2015 · Biochemical Journal