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    1979 results match your criteria Annual Review of Biochemistry [Journal]

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    Retrospective on Cholesterol Homeostasis: The Central Role of Scap.
    Annu Rev Biochem 2017 Aug 25. Epub 2017 Aug 25.
    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390; email: ,
    Scap is a polytopic membrane protein that functions as a molecular machine to control the cholesterol content of membranes in mammalian cells. In the 21 years since our laboratory discovered Scap, we have learned how it binds sterol regulatory element-binding proteins (SREBPs) and transports them from the endoplasmic reticulum (ER) to the Golgi for proteolytic processing. Proteolysis releases the SREBP transcription factor domains, which enter the nucleus to promote cholesterol synthesis and uptake. Read More

    Biochemistry of Catabolic Reductive Dehalogenation.
    Annu Rev Biochem 2017 Jun;86:357-386
    Department of Civil and Environmental Engineering and Department of Chemical Engineering, Stanford University, Stanford, California 94305; email: ,
    A wide range of phylogenetically diverse microorganisms couple the reductive dehalogenation of organohalides to energy conservation. Key enzymes of such anaerobic catabolic pathways are corrinoid and Fe-S cluster-containing, membrane-associated reductive dehalogenases. These enzymes catalyze the reductive elimination of a halide and constitute the terminal reductases of a short electron transfer chain. Read More

    A New Facet of Vitamin B12: Gene Regulation by Cobalamin-Based Photoreceptors.
    Annu Rev Biochem 2017 Jun;86:485-514
    Departamento de Genética y Microbiología, Área de Genética, Unidad Asociada al Instituto de Química Física Rocasolano, Consejo Superior de Investigaciones Científicas, Facultad de Biología, Universidad de Murcia, 30100 Murcia, Spain; email:
    Living organisms sense and respond to light, a crucial environmental factor, using photoreceptors, which rely on bound chromophores such as retinal, flavins, or linear tetrapyrroles for light sensing. The discovery of photoreceptors that sense light using 5'-deoxyadenosylcobalamin, a form of vitamin B12 that is best known as an enzyme cofactor, has expanded the number of known photoreceptor families and unveiled a new biological role of this vitamin. The prototype of these B12-dependent photoreceptors, the transcriptional repressor CarH, is widespread in bacteria and mediates light-dependent gene regulation in a photoprotective cellular response. Read More

    A Bright Future for Antibiotics?
    Annu Rev Biochem 2017 Jun;86:567-583
    Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel; email: , ,
    Multidrug resistance is a global threat as the clinically available potent antibiotic drugs are becoming exceedingly scarce. For example, increasing drug resistance among gram-positive bacteria is responsible for approximately one-third of nosocomial infections. As ribosomes are a major target for these drugs, they may serve as suitable objects for novel development of next-generation antibiotics. Read More

    Conceptual and Experimental Tools to Understand Spatial Effects and Transport Phenomena in Nonlinear Biochemical Networks Illustrated with Patchy Switching.
    Annu Rev Biochem 2017 Jun;86:333-356
    Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125; email:
    Many biochemical systems are spatially heterogeneous and exhibit nonlinear behaviors, such as state switching in response to small changes in the local concentration of diffusible molecules. Systems as varied as blood clotting, intracellular calcium signaling, and tissue inflammation are all heavily influenced by the balance of rates of reaction and mass transport phenomena including flow and diffusion. Transport of signaling molecules is also affected by geometry and chemoselective confinement via matrix binding. Read More

    Metabolite Measurement: Pitfalls to Avoid and Practices to Follow.
    Annu Rev Biochem 2017 Jun;86:277-304
    Lewis Sigler Institute for Integrative Genomics and Department of Chemistry, Princeton University, Princeton, New Jersey 08544; email:
    Metabolites are the small biological molecules involved in energy conversion and biosynthesis. Studying metabolism is inherently challenging due to metabolites' reactivity, structural diversity, and broad concentration range. Herein, we review the common pitfalls encountered in metabolomics and provide concrete guidelines for obtaining accurate metabolite measurements, focusing on water-soluble primary metabolites. Read More

    Site-Specific Self-Catalyzed DNA Depurination: A Biological Mechanism That Leads to Mutations and Creates Sequence Diversity.
    Annu Rev Biochem 2017 Jun;86:461-484
    Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544; email: ,
    Self-catalyzed DNA depurination is a sequence-specific physiological mechanism mediated by spontaneous extrusion of a stem-loop catalytic intermediate. Hydrolysis of the 5'G residue of the 5'GA/TGG loop and of the first 5'A residue of the 5'GAGA loop, together with particular first stem base pairs, specifies their hydrolysis without involving protein, cofactor, or cation. As such, this mechanism is the only known DNA catalytic activity exploited by nature. Read More

    Redox-Based Regulation of Bacterial Development and Behavior.
    Annu Rev Biochem 2017 Jun;86:777-797
    Department of Biological Sciences, Columbia University, New York, NY 10027; email:
    Severe changes in the environmental redox potential, and resulting alterations in the oxidation states of intracellular metabolites and enzymes, have historically been considered negative stressors, requiring responses that are strictly defensive. However, recent work in diverse organisms has revealed that more subtle changes in the intracellular redox state can act as signals, eliciting responses with benefits beyond defense and detoxification. Changes in redox state have been shown to influence or trigger chromosome segregation, sporulation, aerotaxis, and social behaviors, including luminescence as well as biofilm establishment and dispersal. Read More

    Mechanisms of Deubiquitinase Specificity and Regulation.
    Annu Rev Biochem 2017 Jun 12;86:159-192. Epub 2017 May 12.
    Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom; email:
    Protein ubiquitination is one of the most powerful posttranslational modifications of proteins, as it regulates a plethora of cellular processes in distinct manners. Simple monoubiquitination events coexist with more complex forms of polyubiquitination, the latter featuring many different chain architectures. Ubiquitin can be subjected to further posttranslational modifications (e. Read More

    Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade.
    Annu Rev Biochem 2017 Jun 12;86:27-68. Epub 2017 May 12.
    Department of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Cambridge CB2 1EW, United Kingdom; email:
    Peptides and proteins have been found to possess an inherent tendency to convert from their native functional states into intractable amyloid aggregates. This phenomenon is associated with a range of increasingly common human disorders, including Alzheimer and Parkinson diseases, type II diabetes, and a number of systemic amyloidoses. In this review, we describe this field of science with particular reference to the advances that have been made over the last decade in our understanding of its fundamental nature and consequences. Read More

    Mechanisms and Functions of Spatial Protein Quality Control.
    Annu Rev Biochem 2017 Jun 10;86:97-122. Epub 2017 May 10.
    Department of Biology, Stanford University, Stanford, California 94305; email: , ,
    A healthy proteome is essential for cell survival. Protein misfolding is linked to a rapidly expanding list of human diseases, ranging from neurodegenerative diseases to aging and cancer. Many of these diseases are characterized by the accumulation of misfolded proteins in intra- and extracellular inclusions, such as amyloid plaques. Read More

    The Evolution of Organellar Coat Complexes and Organization of the Eukaryotic Cell.
    Annu Rev Biochem 2017 Jun 3;86:637-657. Epub 2017 May 3.
    Wellcome Trust Centre for Anti-Infectives Research, School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom; email:
    Eukaryotic cells possess a remarkably diverse range of organelles that provide compartmentalization for distinct cellular functions and are likely responsible for the remarkable success of these organisms. The origins and subsequent elaboration of these compartments represent a key aspect in the transition between prokaryotic and eukaryotic cellular forms. The protein machinery required to build, maintain, and define many membrane-bound compartments is encoded by several paralog families, including small GTPases, coiled-bundle proteins, and proteins with β-propeller and α-solenoid secondary structures. Read More

    Proteasomal and Autophagic Degradation Systems.
    Annu Rev Biochem 2017 Jun 1;86:193-224. Epub 2017 May 1.
    Institute of Biochemistry II, School of Medicine, Goethe University, 60598 Frankfurt am Main, Germany; email:
    Autophagy and the ubiquitin-proteasome system are the two major quality control pathways responsible for cellular homeostasis. As such, they provide protection against age-associated changes and a plethora of human diseases. Ubiquitination is utilized as a degradation signal by both systems, albeit in different ways, to mark cargoes for proteasomal and lysosomal degradation. Read More

    Protein Misfolding Diseases.
    Annu Rev Biochem 2017 Jun 24;86:21-26. Epub 2017 Apr 24.
    Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany; email:
    The majority of protein molecules must fold into defined three-dimensional structures to acquire functional activity. However, protein chains can adopt a multitude of conformational states, and their biologically active conformation is often only marginally stable. Metastable proteins tend to populate misfolded species that are prone to forming toxic aggregates, including soluble oligomers and fibrillar amyloid deposits, which are linked with neurodegeneration in Alzheimer and Parkinson disease, and many other pathologies. Read More

    Oxidative Stress.
    Annu Rev Biochem 2017 Jun 24;86:715-748. Epub 2017 Apr 24.
    Department of Medicine, Emory University, Atlanta, Georgia 30322; email:
    Oxidative stress is two sided: Whereas excessive oxidant challenge causes damage to biomolecules, maintenance of a physiological level of oxidant challenge, termed oxidative eustress, is essential for governing life processes through redox signaling. Recent interest has focused on the intricate ways by which redox signaling integrates these converse properties. Redox balance is maintained by prevention, interception, and repair, and concomitantly the regulatory potential of molecular thiol-driven master switches such as Nrf2/Keap1 or NF-κB/IκB is used for system-wide oxidative stress response. Read More

    Cellular Electron Cryotomography: Toward Structural Biology In Situ.
    Annu Rev Biochem 2017 Jun 19;86:873-896. Epub 2017 Apr 19.
    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125; email: ,
    Electron cryotomography (ECT) provides three-dimensional views of macromolecular complexes inside cells in a native frozen-hydrated state. Over the last two decades, ECT has revealed the ultrastructure of cells in unprecedented detail. It has also allowed us to visualize the structures of macromolecular machines in their native context inside intact cells. Read More

    Extracellular Heme Uptake and the Challenge of Bacterial Cell Membranes.
    Annu Rev Biochem 2017 Jun 19;86:799-823. Epub 2017 Apr 19.
    Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201; email:
    Iron is essential for the survival of most bacteria but presents a significant challenge given its limited bioavailability. Furthermore, the toxicity of iron combined with the need to maintain physiological iron levels within a narrow concentration range requires sophisticated systems to sense, regulate, and transport iron. Most bacteria have evolved mechanisms to chelate and transport ferric iron (Fe(3+)) via siderophore receptor systems, and pathogenic bacteria have further lowered this barrier by employing mechanisms to utilize the host's hemoproteins. Read More

    Teaching Old Dyes New Tricks: Biological Probes Built from Fluoresceins and Rhodamines.
    Annu Rev Biochem 2017 Jun 7;86:825-843. Epub 2017 Apr 7.
    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia 20147; email:
    Small-molecule fluorophores, such as fluorescein and rhodamine derivatives, are critical tools in modern biochemical and biological research. The field of chemical dyes is old; colored molecules were first discovered in the 1800s, and the fluorescein and rhodamine scaffolds have been known for over a century. Nevertheless, there has been a renaissance in using these dyes to create tools for biochemistry and biology. Read More

    Cyclic GMP-AMP as an Endogenous Second Messenger in Innate Immune Signaling by Cytosolic DNA.
    Annu Rev Biochem 2017 Jun 7;86:541-566. Epub 2017 Apr 7.
    Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo 113-0032, Japan; email: ,
    The innate immune system functions as the first line of defense against invading bacteria and viruses. In this context, the cGAS/STING [cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase/STING] signaling axis perceives the nonself DNA associated with bacterial and viral infections, as well as the leakage of self DNA by cellular dysfunction and stresses, to elicit the host's immune responses. In this pathway, the noncanonical cyclic dinucleotide 2',3'-cyclic GMP-AMP (2',3'-cGAMP) functions as a second messenger for signal transduction: 2',3'-cGAMP is produced by the enzyme cGAS upon its recognition of double-stranded DNA, and then the 2',3'-cGAMP is recognized by the receptor STING to induce the phosphorylation of downstream factors, including TBK1 (TANK binding kinase 1) and IRF3 (interferon regulatory factor 3). Read More

    Electric Fields and Enzyme Catalysis.
    Annu Rev Biochem 2017 Jun 24;86:387-415. Epub 2017 Mar 24.
    Department of Chemistry, Stanford University, Stanford, California 94305; email:
    What happens inside an enzyme's active site to allow slow and difficult chemical reactions to occur so rapidly? This question has occupied biochemists' attention for a long time. Computer models of increasing sophistication have predicted an important role for electrostatic interactions in enzymatic reactions, yet this hypothesis has proved vexingly difficult to test experimentally. Recent experiments utilizing the vibrational Stark effect make it possible to measure the electric field a substrate molecule experiences when bound inside its enzyme's active site. Read More

    Ubiquitin Ligases: Structure, Function, and Regulation.
    Annu Rev Biochem 2017 Jun 27;86:129-157. Epub 2017 Mar 27.
    Howard Hughes Medical Institute and Department of Pharmacology, University of Washington, Seattle, Washington 98195; email: ,
    Ubiquitin E3 ligases control every aspect of eukaryotic biology by promoting protein ubiquitination and degradation. At the end of a three-enzyme cascade, ubiquitin ligases mediate the transfer of ubiquitin from an E2 ubiquitin-conjugating enzyme to specific substrate proteins. Early investigations of E3s of the RING (really interesting new gene) and HECT (homologous to the E6AP carboxyl terminus) types shed light on their enzymatic activities, general architectures, and substrate degron-binding modes. Read More

    Engineering and In Vivo Applications of Riboswitches.
    Annu Rev Biochem 2017 Jun 30;86:515-539. Epub 2017 Mar 30.
    Department of Chemistry, University of California, Berkeley, California 94720; email:
    Riboswitches are common gene regulatory units mostly found in bacteria that are capable of altering gene expression in response to a small molecule. These structured RNA elements consist of two modular subunits: an aptamer domain that binds with high specificity and affinity to a target ligand and an expression platform that transduces ligand binding to a gene expression output. Significant progress has been made in engineering novel aptamer domains for new small molecule inducers of gene expression. Read More

    How α-Helical Motifs Form Functionally Diverse Lipid-Binding Compartments.
    Annu Rev Biochem 2017 Jun 30;86:609-636. Epub 2017 Mar 30.
    The Hormel Institute, University of Minnesota, Austin, Minnesota 55912; email: ,
    Lipids are produced site-specifically in cells and then distributed nonrandomly among membranes via vesicular and nonvesicular trafficking mechanisms. The latter involves soluble amphitropic proteins extracting specific lipids from source membranes to function as molecular solubilizers that envelope their insoluble cargo before transporting it to destination sites. Lipid-binding and lipid transfer structural motifs range from multi-β-strand barrels, to β-sheet cups and baskets covered by α-helical lids, to multi-α-helical bundles and layers. Read More

    Isocitrate Dehydrogenase Mutation and (R)-2-Hydroxyglutarate: From Basic Discovery to Therapeutics Development.
    Annu Rev Biochem 2017 Jun 3;86:305-331. Epub 2017 Apr 3.
    Agios Pharmaceuticals Inc., Cambridge, Massachusetts 02139; email: ,
    The identification of heterozygous mutations in the metabolic enzyme isocitrate dehydrogenase (IDH) in subsets of cancers, including secondary glioblastoma, acute myeloid leukemia, intrahepatic cholangiocarcinoma, and chondrosarcomas, led to intense discovery efforts to delineate the mutations' involvement in carcinogenesis and to develop therapeutics, which we review here. The three IDH isoforms (nicotinamide adenine dinucleotide phosphate-dependent IDH1 and IDH2, and nicotinamide adenine dinucleotide-dependent IDH3) contribute to regulating the circuitry of central metabolism. Several biochemical and genetic observations led to the discovery of the neomorphic production of the oncometabolite (R)-2-hydroxyglutarate (2-HG) by mutant IDH1 and IDH2 (mIDH). Read More

    Endoplasmic Reticulum-Plasma Membrane Contact Sites.
    Annu Rev Biochem 2017 Jun 23;86:659-684. Epub 2017 Feb 23.
    Departments of Neuroscience and Cell Biology, Howard Hughes Medical Institute, Kavli Institute for Neuroscience, Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, Connecticut 06510; email:
    The endoplasmic reticulum (ER) has a broad localization throughout the cell and forms direct physical contacts with all other classes of membranous organelles, including the plasma membrane (PM). A number of protein tethers that mediate these contacts have been identified, and study of these protein tethers has revealed a multiplicity of roles in cell physiology, including regulation of intracellular Ca(2+) dynamics and signaling as well as control of lipid traffic and homeostasis. In this review, we discuss the cross talk between the ER and the PM mediated by direct contacts. Read More

    Eukaryotic DNA Replication Fork.
    Annu Rev Biochem 2017 Jun 1;86:417-438. Epub 2017 Mar 1.
    Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709; email:
    This review focuses on the biogenesis and composition of the eukaryotic DNA replication fork, with an emphasis on the enzymes that synthesize DNA and repair discontinuities on the lagging strand of the replication fork. Physical and genetic methodologies aimed at understanding these processes are discussed. The preponderance of evidence supports a model in which DNA polymerase ε (Pol ε) carries out the bulk of leading strand DNA synthesis at an undisturbed replication fork. Read More

    Microbial Rhodopsins: Diversity, Mechanisms, and Optogenetic Applications.
    Annu Rev Biochem 2017 Jun 9;86:845-872. Epub 2017 Mar 9.
    Center for Membrane Biology, Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas 77030; email: , , ,
    Microbial rhodopsins are a family of photoactive retinylidene proteins widespread throughout the microbial world. They are notable for their diversity of function, using variations of a shared seven-transmembrane helix design and similar photochemical reactions to carry out distinctly different light-driven energy and sensory transduction processes. Their study has contributed to our understanding of how evolution modifies protein scaffolds to create new protein chemistry, and their use as tools to control membrane potential with light is fundamental to optogenetics for research and clinical applications. Read More

    Mechanisms of Autophagy Initiation.
    Annu Rev Biochem 2017 Jun 15;86:225-244. Epub 2017 Mar 15.
    Department of Molecular and Cell Biology and California Institute of Quantitative Biosciences, University of California, Berkeley, California, and Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, California, 94720; email:
    Autophagy is the process of cellular self-eating by a double-membrane organelle, the autophagosome. A range of signaling processes converge on two protein complexes to initiate autophagy: the ULK1 (unc51-like autophagy activating kinase 1) protein kinase complex and the PI3KC3-C1 (class III phosphatidylinositol 3-kinase complex I) lipid kinase complex. Some 90% of the mass of these large protein complexes consists of noncatalytic domains and subunits, and the ULK1 complex has essential noncatalytic activities. Read More

    Mitochondrial Machineries for Protein Import and Assembly.
    Annu Rev Biochem 2017 Jun 15;86:685-714. Epub 2017 Mar 15.
    Institute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, and BIOSS Centre for Biological Signaling Studies, University of Freiburg, 79104 Freiburg, Germany; email: ,
    Mitochondria are essential organelles with numerous functions in cellular metabolism and homeostasis. Most of the >1,000 different mitochondrial proteins are synthesized as precursors in the cytosol and are imported into mitochondria by five transport pathways. The protein import machineries of the mitochondrial membranes and aqueous compartments reveal a remarkable variability of mechanisms for protein recognition, translocation, and sorting. Read More

    Systems Biology of Metabolism.
    Annu Rev Biochem 2017 Jun 8;86:245-275. Epub 2017 Mar 8.
    Department of Biology and Biological Engineering, Chalmers University of Technology, SE41128 Gothenburg, Sweden; email:
    Metabolism is highly complex and involves thousands of different connected reactions; it is therefore necessary to use mathematical models for holistic studies. The use of mathematical models in biology is referred to as systems biology. In this review, the principles of systems biology are described, and two different types of mathematical models used for studying metabolism are discussed: kinetic models and genome-scale metabolic models. Read More

    Multiple Functions and Regulation of Mammalian Peroxiredoxins.
    Annu Rev Biochem 2017 Jun 2;86:749-775. Epub 2017 Feb 2.
    Yonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul 120-752, Korea; email:
    Peroxiredoxins (Prxs) constitute a major family of peroxidases, with mammalian cells expressing six Prx isoforms (PrxI to PrxVI). Cells produce hydrogen peroxide (H2O2) at various intracellular locations where it can serve as a signaling molecule. Given that Prxs are abundant and possess a structure that renders the cysteine (Cys) residue at the active site highly sensitive to oxidation by H2O2, the signaling function of this oxidant requires extensive and highly localized regulation. Read More

    Telomerase Mechanism of Telomere Synthesis.
    Annu Rev Biochem 2017 Jun 30;86:439-460. Epub 2017 Jan 30.
    Department of Molecular and Cell Biology, University of California, Berkeley, California 94720-3202; email: , , ,
    Telomerase is the essential reverse transcriptase required for linear chromosome maintenance in most eukaryotes. Telomerase supplements the tandem array of simple-sequence repeats at chromosome ends to compensate for the DNA erosion inherent in genome replication. The template for telomerase reverse transcriptase is within the RNA subunit of the ribonucleoprotein complex, which in cells contains additional telomerase holoenzyme proteins that assemble the active ribonucleoprotein and promote its function at telomeres. Read More

    Molecular Characteristics and Biological Functions of Surface-Active and Surfactant Proteins.
    Annu Rev Biochem 2017 Jun 11;86:585-608. Epub 2017 Jan 11.
    School of Life and Environmental Sciences and Australian Institute for Nanoscale Science and Technology, University of Sydney, NSW 2006, Australia; email:
    Many critical biological processes take place at hydrophobic:hydrophilic interfaces, and a wide range of organisms produce surface-active proteins and peptides that reduce surface and interfacial tension and mediate growth and development at these boundaries. Microorganisms produce both small lipid-associated peptides and amphipathic proteins that allow growth across water:air boundaries, attachment to surfaces, predation, and improved bioavailability of hydrophobic substrates. Higher-order organisms produce surface-active proteins with a wide variety of functions, including the provision of protective foam environments for vulnerable reproductive stages, evaporative cooling, and gas exchange across airway membranes. Read More

    Structural Studies of Amyloid Proteins at the Molecular Level.
    Annu Rev Biochem 2017 Jun 3;86:69-95. Epub 2017 Jan 3.
    Howard Hughes Medical Institute and Molecular Biology Institute, University of California, Los Angeles, California 90095-1570; email: ,
    Dozens of proteins are known to convert to the aggregated amyloid state. These include fibrils associated with systemic and neurodegenerative diseases and cancer, functional amyloid fibrils in microorganisms and animals, and many denatured proteins. Amyloid fibrils can be much more stable than other protein assemblies. Read More

    At the Intersection of Chemistry, Biology, and Medicine.
    Annu Rev Biochem 2017 Jun 11;86:1-19. Epub 2017 Jan 11.
    Department of Chemistry and Institute for Chemistry, Engineering, and Medicine for Human Health, Stanford University, Stanford, California; email:
    After an undergraduate degree in biology at Harvard, I started graduate school at The Rockefeller Institute for Medical Research in New York City in July 1965. I was attracted to the chemical side of biochemistry and joined Fritz Lipmann's large, hierarchical laboratory to study enzyme mechanisms. That work led to postdoctoral research with Robert Abeles at Brandeis, then a center of what, 30 years later, would be called chemical biology. Read More

    The Biochemistry of O-GlcNAc Transferase: Which Functions Make It Essential in Mammalian Cells?
    Annu Rev Biochem 2016 Jun;85:631-57
    Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115; email: ,
    O-linked N-acetylglucosamine transferase (OGT) is found in all metazoans and plays an important role in development but at the single-cell level is only essential in dividing mammalian cells. Postmitotic mammalian cells and cells of invertebrates such as Caenorhabditis elegans and Drosophila can survive without copies of OGT. Why OGT is required in dividing mammalian cells but not in other cells remains unknown. Read More

    Nucleic Acid-Based Nanodevices in Biological Imaging.
    Annu Rev Biochem 2016 Jun;85:349-73
    Department of Chemistry, University of Chicago, Chicago, Illinois 60637; email: , ,
    The nanoscale engineering of nucleic acids has led to exciting molecular technologies for high-end biological imaging. The predictable base pairing, high programmability, and superior new chemical and biological methods used to access nucleic acids with diverse lengths and in high purity, coupled with computational tools for their design, have allowed the creation of a stunning diversity of nucleic acid-based nanodevices. Given their biological origin, such synthetic devices have a tremendous capacity to interface with the biological world, and this capacity lies at the heart of several nucleic acid-based technologies that are finding applications in biological systems. Read More

    Nucleotide Excision Repair and Transcriptional Regulation: TFIIH and Beyond.
    Annu Rev Biochem 2016 Jun;85:265-90
    Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université de Strasbourg, 67404 Illkirch Cedex, Commune Urbaine Strasbourg, France; email: ,
    Transcription factor IIH (TFIIH) is a multiprotein complex involved in both transcription and DNA repair, revealing a striking functional link between these two processes. Some of its subunits also belong to complexes involved in other cellular processes, such as chromosome segregation and cell cycle regulation, emphasizing the multitasking capabilities of this factor. This review aims to depict the structure of TFIIH and to dissect the roles of its subunits in different cellular mechanisms. Read More

    Signaling Networks Determining Life Span.
    Annu Rev Biochem 2016 Jun;85:35-64
    Department of Molecular and Cell Biology, University of California, Berkeley, California 94720; email:
    The health of an organism is orchestrated by a multitude of molecular and biochemical networks responsible for ensuring homeostasis within cells and tissues. However, upon aging, a progressive failure in the maintenance of this homeostatic balance occurs in response to a variety of endogenous and environmental stresses, allowing the accumulation of damage, the physiological decline of individual tissues, and susceptibility to diseases. What are the molecular and cellular signaling events that control the aging process and how can this knowledge help design therapeutic strategies to combat age-associated diseases? Here we provide a comprehensive overview of the evolutionarily conserved biological processes that alter the rate of aging and discuss their link to disease prevention and the extension of healthy life span. Read More

    Mechanisms of Mitotic Spindle Assembly.
    Annu Rev Biochem 2016 Jun 21;85:659-83. Epub 2016 Apr 21.
    Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544-1014; email:
    Life depends on cell proliferation and the accurate segregation of chromosomes, which are mediated by the microtubule (MT)-based mitotic spindle and ∼200 essential MT-associated proteins. Yet, a mechanistic understanding of how the mitotic spindle is assembled and achieves chromosome segregation is still missing. This is mostly due to the density of MTs in the spindle, which presumably precludes their direct observation. Read More

    Understanding the Chemistry and Biology of Glycosylation with Glycan Synthesis.
    Annu Rev Biochem 2016 Jun 25;85:599-630. Epub 2016 Apr 25.
    Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037; email:
    Glycoscience research has been significantly impeded by the complex compositions of the glycans present in biological molecules and the lack of convenient tools suitable for studying the glycosylation process and its function. Polysaccharides and glycoconjugates are not encoded directly by genes; instead, their biosynthesis relies on the differential expression of carbohydrate enzymes, resulting in heterogeneous mixtures of glycoforms, each with a distinct physiological activity. Access to well-defined structures is required for functional study, and this has been provided by chemical and enzymatic synthesis and by the engineering of glycosylation pathways. Read More

    Ice-Binding Proteins and Their Function.
    Annu Rev Biochem 2016 Jun 25;85:515-42. Epub 2016 Apr 25.
    Department of Biomedical and Molecular Science, Queen's University, Kingston, Ontario K7L 3N6, Canada; email:
    Ice-binding proteins (IBPs) are a diverse class of proteins that assist organism survival in the presence of ice in cold climates. They have different origins in many organisms, including bacteria, fungi, algae, diatoms, plants, insects, and fish. This review covers the gamut of IBP structures and functions and the common features they use to bind ice. Read More

    CRISPR/Cas9 in Genome Editing and Beyond.
    Annu Rev Biochem 2016 Jun 25;85:227-64. Epub 2016 Apr 25.
    Department of Bioengineering, Stanford University, Stanford, California 94305; email: , ,
    The Cas9 protein (CRISPR-associated protein 9), derived from type II CRISPR (clustered regularly interspaced short palindromic repeats) bacterial immune systems, is emerging as a powerful tool for engineering the genome in diverse organisms. As an RNA-guided DNA endonuclease, Cas9 can be easily programmed to target new sites by altering its guide RNA sequence, and its development as a tool has made sequence-specific gene editing several magnitudes easier. The nuclease-deactivated form of Cas9 further provides a versatile RNA-guided DNA-targeting platform for regulating and imaging the genome, as well as for rewriting the epigenetic status, all in a sequence-specific manner. Read More

    Dietary Protein, Metabolism, and Aging.
    Annu Rev Biochem 2016 Jun 29;85:5-34. Epub 2016 Apr 29.
    Max Planck Institute for Biology of Ageing, Department of Biological Mechanisms of Ageing, Cologne 50931, Germany; email: ,
    Dietary restriction (DR), a moderate reduction in food intake, improves health during aging and extends life span across multiple species. Specific nutrients, rather than overall calories, mediate the effects of DR, with protein and specific amino acids (AAs) playing a key role. Modulations of single dietary AAs affect traits including growth, reproduction, physiology, health, and longevity in animals. Read More

    Enjoy the Trip: Calcium in Mitochondria Back and Forth.
    Annu Rev Biochem 2016 Jun 4;85:161-92. Epub 2016 May 4.
    Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy; email: , ,
    In the last 5 years, most of the molecules that control mitochondrial Ca(2+) homeostasis have been finally identified. Mitochondrial Ca(2+) uptake is mediated by the Mitochondrial Calcium Uniporter (MCU) complex, a macromolecular structure that guarantees Ca(2+) accumulation inside mitochondrial matrix upon increases in cytosolic Ca(2+). Conversely, Ca(2+) release is under the control of the Na(+)/Ca(2+) exchanger, encoded by the NCLX gene, and of a H(+)/Ca(2+) antiporter, whose identity is still debated. Read More

    The p53 Pathway: Origins, Inactivation in Cancer, and Emerging Therapeutic Approaches.
    Annu Rev Biochem 2016 Jun 4;85:375-404. Epub 2016 May 4.
    Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom.
    Inactivation of the transcription factor p53, through either direct mutation or aberrations in one of its many regulatory pathways, is a hallmark of virtually every tumor. In recent years, screening for p53 activators and a better understanding of the molecular mechanisms of oncogenic perturbations of p53 function have opened up a host of novel avenues for therapeutic intervention in cancer: from the structure-guided design of chemical chaperones to restore the function of conformationally unstable p53 cancer mutants, to the development of potent antagonists of the negative regulators MDM2 and MDMX and other modulators of the p53 pathway for the treatment of cancers with wild-type p53. Some of these compounds have now moved from proof-of-concept studies into clinical trials, with prospects for further, personalized anticancer medicines. Read More

    Radical S-Adenosylmethionine Enzymes in Human Health and Disease.
    Annu Rev Biochem 2016 Jun 4;85:485-514. Epub 2016 May 4.
    Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802.
    Radical S-adenosylmethionine (SAM) enzymes catalyze an astonishing array of complex and chemically challenging reactions across all domains of life. Of approximately 114,000 of these enzymes, 8 are known to be present in humans: MOCS1, molybdenum cofactor biosynthesis; LIAS, lipoic acid biosynthesis; CDK5RAP1, 2-methylthio-N(6)-isopentenyladenosine biosynthesis; CDKAL1, methylthio-N(6)-threonylcarbamoyladenosine biosynthesis; TYW1, wybutosine biosynthesis; ELP3, 5-methoxycarbonylmethyl uridine; and RSAD1 and viperin, both of unknown function. Aberrations in the genes encoding these proteins result in a variety of diseases. Read More

    Mechanics and Single-Molecule Interrogation of DNA Recombination.
    Annu Rev Biochem 2016 Jun 18;85:193-226. Epub 2016 Apr 18.
    Department of Microbiology and Molecular Genetics, and Department of Molecular and Cellular Biology, University of California, Davis, California 95616; email:
    The repair of DNA by homologous recombination is an essential, efficient, and high-fidelity process that mends DNA lesions formed during cellular metabolism; these lesions include double-stranded DNA breaks, daughter-strand gaps, and DNA cross-links. Genetic defects in the homologous recombination pathway undermine genomic integrity and cause the accumulation of gross chromosomal abnormalities-including rearrangements, deletions, and aneuploidy-that contribute to cancer formation. Recombination proceeds through the formation of joint DNA molecules-homologously paired but metastable DNA intermediates that are processed by several alternative subpathways-making recombination a versatile and robust mechanism to repair damaged chromosomes. Read More

    The Substrate Specificity of Sirtuins.
    Annu Rev Biochem 2016 Jun 18;85:405-29. Epub 2016 Apr 18.
    Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14850.
    Sirtuins are NAD(+)-dependent enzymes universally present in all organisms, where they play central roles in regulating numerous biological processes. Although early studies showed that sirtuins deacetylated lysines in a reaction that consumes NAD(+), more recent studies have revealed that these enzymes can remove a variety of acyl-lysine modifications. The specificities for varied acyl modifications may thus underlie the distinct roles of the different sirtuins within a given organism. Read More

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