2,112 results match your criteria Annual Review Of Biochemistry[Journal]

From Bioorganic Models to Cells.

Annu Rev Biochem 2021 Jun;90:57-76

Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, USA; email:

I endeavor to share how various choices-some deliberate, some unconscious-and the unmistakable influence of many others shaped my scientific pursuits. I am fascinated by how two long-term, major streams of my research, DNA replication and purine biosynthesis, have merged with unexpected interconnections. If I have imparted to many of the talented individuals who have passed through my lab a degree of my passion for uncloaking the mysteries hidden in scientific research and an understanding of the honesty and rigor it demands and its impact on the world community, then my mentorship has been successful. Read More

View Article and Full-Text PDF

Short- and Long-Term Adaptation to Altered Levels of Glucose: Fifty Years of Scientific Adventure.

Kosaku Uyeda

Annu Rev Biochem 2021 Jun;90:31-55

Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; email:

My graduate and postdoctoral training in metabolism and enzymology eventually led me to study the short- and long-term regulation of glucose and lipid metabolism. In the early phase of my career, my trainees and I identified, purified, and characterized a variety of phosphofructokinase enzymes from mammalian tissues. These studies led us to discover fructose 2,6-P, the most potent activator of phosphofructokinase and glycolysis. Read More

View Article and Full-Text PDF

Introduction to the Theme on Membrane Channels.

Annu Rev Biochem 2021 Jun;90:503-505

Department of Biochemistry and Biophysics, Stockholm University, 106 91 Stockholm, Sweden; email:

This volume of the contains three reviews on membrane channel proteins: the first by Szczot et al., titled The Form and Function of PIEZO2; the second by Ruprecht & Kunji, titled Structural Mechanism of Transport of Mitochondrial Carriers; and the third by McIlwain et al., titled Membrane Exporters of Fluoride Ion. Read More

View Article and Full-Text PDF

An Overview of Microcrystal Electron Diffraction (MicroED).

Annu Rev Biochem 2021 Jun;90:431-450

Howard Hughes Medical Institute, Department of Biological Chemistry, University of California, Los Angeles, California 90095, USA; email:

The bedrock of drug discovery and a key tool for understanding cellular function and drug mechanisms of action is the structure determination of chemical compounds, peptides, and proteins. The development of new structure characterization tools, particularly those that fill critical gaps in existing methods, presents important steps forward for structural biology and drug discovery. The emergence of microcrystal electron diffraction (MicroED) expands the application of cryo-electron microscopy to include samples ranging from small molecules and membrane proteins to even large protein complexes using crystals that are one-billionth the size of those required for X-ray crystallography. Read More

View Article and Full-Text PDF

Posttranslational Regulation of HMG CoA Reductase, the Rate-Limiting Enzyme in Synthesis of Cholesterol.

Annu Rev Biochem 2021 Jun;90:659-679

Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA; email:

The polytopic, endoplasmic reticulum (ER) membrane protein 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase produces mevalonate, the key intermediate in the synthesis of cholesterol and many nonsterol isoprenoids including geranylgeranyl pyrophosphate (GGpp). Transcriptional, translational, and posttranslational feedback mechanisms converge on this reductase to ensure cells maintain a sufficient supply of essential nonsterol isoprenoids but avoid overaccumulation of cholesterol and other sterols. The focus of this review is mechanisms for the posttranslational regulation of HMG CoA reductase, which include sterol-accelerated ubiquitination and ER-associated degradation (ERAD) that is augmented by GGpp. Read More

View Article and Full-Text PDF

Molecular Epigenetics: Chemical Biology Tools Come of Age.

Annu Rev Biochem 2021 Jun;90:287-320

Frick Chemistry Laboratory, Department of Chemistry, Princeton University, Princeton, New Jersey 08544, USA; email:

The field of epigenetics has exploded over the last two decades, revealing an astonishing level of complexity in the way genetic information is stored and accessed in eukaryotes. This expansion of knowledge, which is very much ongoing, has been made possible by the availability of evermore sensitive and precise molecular tools. This review focuses on the increasingly important role that chemistry plays in this burgeoning field. Read More

View Article and Full-Text PDF

The Form and Function of PIEZO2.

Annu Rev Biochem 2021 Jun;90:507-534

National Center for Complementary and Integrative Health, National Institutes of Health, Bethesda, Maryland 20892, USA; email:

Mechanosensation is the ability to detect dynamic mechanical stimuli (e.g., pressure, stretch, and shear stress) and is essential for a wide variety of processes, including our sense of touch on the skin. Read More

View Article and Full-Text PDF

The Long Road to Understanding RNAPII Transcription Initiation and Related Syndromes.

Annu Rev Biochem 2021 Jun;90:193-219

Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, Université de Strasbourg, 67404 Illkirch CEDEX, Commune Urbaine de Strasbourg, France; email:

In eukaryotes, transcription of protein-coding genes requires the assembly at core promoters of a large preinitiation machinery containing RNA polymerase II (RNAPII) and general transcription factors (GTFs). Transcription is potentiated by regulatory elements called enhancers, which are recognized by specific DNA-binding transcription factors that recruit cofactors and convey, following chromatin remodeling, the activating cues to the preinitiation complex. This review summarizes nearly five decades of work on transcription initiation by describing the sequential recruitment of diverse molecular players including the GTFs, the Mediator complex, and DNA repair factors that support RNAPII to enable RNA synthesis. Read More

View Article and Full-Text PDF

Mechanisms of Vertebrate DNA Interstrand Cross-Link Repair.

Annu Rev Biochem 2021 Jun 21;90:107-135. Epub 2021 Apr 21.

Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, USA; email:

DNA interstrand cross-links (ICLs) covalently connect the two strands of the double helix and are extremely cytotoxic. Defective ICL repair causes the bone marrow failure and cancer predisposition syndrome, Fanconi anemia, and upregulation of repair causes chemotherapy resistance in cancer. The central event in ICL repair involves resolving the cross-link (unhooking). Read More

View Article and Full-Text PDF

A Natural Product Chemist's Guide to Unlocking Silent Biosynthetic Gene Clusters.

Annu Rev Biochem 2021 Jun 13;90:763-788. Epub 2021 Apr 13.

Department of Chemistry, Princeton University, Princeton, New Jersey 08544, USA; email:

Microbial natural products have provided an important source of therapeutic leads and motivated research and innovation in diverse scientific disciplines. In recent years, it has become evident that bacteria harbor a large, hidden reservoir of potential natural products in the form of silent or cryptic biosynthetic gene clusters (BGCs). These can be readily identified in microbial genome sequences but do not give rise to detectable levels of a natural product. Read More

View Article and Full-Text PDF

Understanding the Function of Mammalian Sirtuins and Protein Lysine Acylation.

Annu Rev Biochem 2021 Jun 13;90:245-285. Epub 2021 Apr 13.

Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA; email:

Protein lysine acetylation is an important posttranslational modification that regulates numerous biological processes. Targeting lysine acetylation regulatory factors, such as acetyltransferases, deacetylases, and acetyl-lysine recognition domains, has been shown to have potential for treating human diseases, including cancer and neurological diseases. Over the past decade, many other acyl-lysine modifications, such as succinylation, crotonylation, and long-chain fatty acylation, have also been investigated and shown to have interesting biological functions. Read More

View Article and Full-Text PDF

Glycyl Radical Enzymes and Sulfonate Metabolism in the Microbiome.

Annu Rev Biochem 2021 Jun 6;90:817-846. Epub 2021 Apr 6.

Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, Collaborative Innovation Center of Chemical Science and Engineering, School of Pharmaceutical Science and Technology; and Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin University, Tianjin 300072, China; email:

Sulfonates include diverse natural products and anthropogenic chemicals and are widespread in the environment. Many bacteria can degrade sulfonates and obtain sulfur, carbon, and energy for growth, playing important roles in the biogeochemical sulfur cycle. Cleavage of the inert sulfonate C-S bond involves a variety of enzymes, cofactors, and oxygen-dependent and oxygen-independent catalytic mechanisms. Read More

View Article and Full-Text PDF

Quality Control of Procollagen in Cells.

Annu Rev Biochem 2021 Jun 6;90:631-658. Epub 2021 Apr 6.

Faculty of Life Sciences, Kyoto Sangyo University, Kyoto 603-8555, Japan; email:

Collagen is the most abundant protein in mammals. A unique feature of collagen is its triple-helical structure formed by the Gly-Xaa-Yaa repeats. Three single chains of procollagen make a trimer, and the triple-helical structure is then folded in the endoplasmic reticulum (ER). Read More

View Article and Full-Text PDF

Chaperoning SNARE Folding and Assembly.

Annu Rev Biochem 2021 Jun 6;90:581-603. Epub 2021 Apr 6.

Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA; email:

SNARE proteins and Sec1/Munc18 (SM) proteins constitute the core molecular engine that drives nearly all intracellular membrane fusion and exocytosis. While SNAREs are known to couple their folding and assembly to membrane fusion, the physiological pathways of SNARE assembly and the mechanistic roles of SM proteins have long been enigmatic. Here, we review recent advances in understanding the SNARE-SM fusion machinery with an emphasis on biochemical and biophysical studies of proteins that mediate synaptic vesicle fusion. Read More

View Article and Full-Text PDF

Cullin-RING Ubiquitin Ligase Regulatory Circuits: A Quarter Century Beyond the F-Box Hypothesis.

Annu Rev Biochem 2021 Jun 6;90:403-429. Epub 2021 Apr 6.

Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried 82152, Germany; email:

Cullin-RING ubiquitin ligases (CRLs) are dynamic modular platforms that regulate myriad biological processes through target-specific ubiquitylation. Our knowledge of this system emerged from the F-box hypothesis, posited a quarter century ago: Numerous interchangeable F-box proteins confer specific substrate recognition for a core CUL1-based RING E3 ubiquitin ligase. This paradigm has been expanded through the evolution of a superfamily of analogous modular CRLs, with five major families and over 200 different substrate-binding receptors in humans. Read More

View Article and Full-Text PDF

Repair of DNA Breaks by Break-Induced Replication.

Annu Rev Biochem 2021 Jun 1;90:165-191. Epub 2021 Apr 1.

Department of Biology, University of Iowa, Iowa City, Iowa 52242, USA; email:

Double-strand DNA breaks (DSBs) are the most lethal type of DNA damage, making DSB repair critical for cell survival. However, some DSB repair pathways are mutagenic and promote genome rearrangements, leading to genome destabilization. One such pathway is break-induced replication (BIR), which repairs primarily one-ended DSBs, similar to those formed by collapsed replication forks or telomere erosion. Read More

View Article and Full-Text PDF

Structural Mechanisms for Replicating DNA in Eukaryotes.

Annu Rev Biochem 2021 Jun 30;90:77-106. Epub 2021 Mar 30.

Department of Biophysics and Biophysical Chemistry, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA; email:

The faithful and timely copying of DNA by molecular machines known as replisomes depends on a disparate suite of enzymes and scaffolding factors working together in a highly orchestrated manner. Large, dynamic protein-nucleic acid assemblies that selectively morph between distinct conformations and compositional states underpin this critical cellular process. In this article, we discuss recent progress outlining the physical basis of replisome construction and progression in eukaryotes. Read More

View Article and Full-Text PDF

Designing Biological Circuits: Synthetic Biology Within the Operon Model and Beyond.

Annu Rev Biochem 2021 Jun 30;90:221-244. Epub 2021 Mar 30.

Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA; email:

In 1961, Jacob and Monod proposed the operon model of gene regulation. At the model's core was the modular assembly of regulators, operators, and structural genes. To illustrate the composability of these elements, Jacob and Monod linked phenotypic diversity to the architectures of regulatory circuits. Read More

View Article and Full-Text PDF

Optobiochemistry: Genetically Encoded Control of Protein Activity by Light.

Annu Rev Biochem 2021 Jun 29;90:475-501. Epub 2021 Mar 29.

Department of Neurobiology, Stanford University, Stanford, California 94305, USA; email:

Optobiochemical control of protein activities allows the investigation of protein functions in living cells with high spatiotemporal resolution. Over the last two decades, numerous natural photosensory domains have been characterized and synthetic domains engineered and assembled into photoregulatory systems to control protein function with light. Here, we review the field of optobiochemistry, categorizing photosensory domains by chromophore, describing photoregulatory systems by mechanism of action, and discussing protein classes frequently investigated using optical methods. Read More

View Article and Full-Text PDF

The Roots of Genetic Coding in Aminoacyl-tRNA Synthetase Duality.

Annu Rev Biochem 2021 Jun 29;90:349-373. Epub 2021 Mar 29.

Department of Physics, University of Auckland, Auckland 1142, New Zealand.

Codon-dependent translation underlies genetics and phylogenetic inferences, but its origins pose two challenges. Prevailing narratives cannot account for the fact that aminoacyl-tRNA synthetases (aaRSs), which translate the genetic code, must collectively enforce the rules used to assemble themselves. Nor can they explain how specific assignments arose from rudimentary differentiation between ancestral aaRSs and corresponding transfer RNAs (tRNAs). Read More

View Article and Full-Text PDF

Molecules from the Microbiome.

Annu Rev Biochem 2021 Jun 26;90:789-815. Epub 2021 Mar 26.

Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut 06536, USA; email:

The human microbiome encodes a second genome that dwarfs the genetic capacity of the host. Microbiota-derived small molecules can directly target human cells and their receptors or indirectly modulate host responses through functional interactions with other microbes in their ecological niche. Their biochemical complexity has profound implications for nutrition, immune system development, disease progression, and drug metabolism, as well as the variation in these processes that exists between individuals. Read More

View Article and Full-Text PDF

Influenza Virus RNA-Dependent RNA Polymerase and the Host Transcriptional Apparatus.

Annu Rev Biochem 2021 Jun 26;90:321-348. Epub 2021 Mar 26.

European Molecular Biology Laboratory, 38042 Grenoble CEDEX 9, France; email:

Influenza virus RNA-dependent RNA polymerase (FluPol) transcribes the viral RNA genome in the infected cell nucleus. In the 1970s, researchers showed that viral transcription depends on host RNA polymerase II (RNAP II) activity and subsequently that FluPol snatches capped oligomers from nascent RNAP II transcripts to prime its own transcription. Exactly how this occurs remains elusive. Read More

View Article and Full-Text PDF

Structural Insights Accelerate the Discovery of Opioid Alternatives.

Annu Rev Biochem 2021 Jun 23;90:739-761. Epub 2021 Mar 23.

Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA; email:

Opioids such as morphine and oxycodone are analgesics frequently prescribed for the treatment of moderate or severe pain. Unfortunately, these medications are associated with exceptionally high abuse potentials and often cause fatal side effects, mainly through the μ-opioid receptor (MOR). Efforts to discover novel, safer, and more efficacious analgesics targeting MOR have encountered challenges. Read More

View Article and Full-Text PDF

Mechanisms for Regulating and Organizing Receptor Signaling by Endocytosis.

Annu Rev Biochem 2021 Jun 19;90:709-737. Epub 2021 Feb 19.

Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA; email:

Intricate relationships between endocytosis and cellular signaling, first recognized nearly 40 years ago through the study of tyrosine kinase growth factor receptors, are now known to exist for multiple receptor classes and to affect myriad physiological and developmental processes. This review summarizes our present understanding of how endocytosis orchestrates cellular signaling networks, with an emphasis on mechanistic underpinnings and focusing on two receptor classes-tyrosine kinase and G protein-coupled receptors-that have been investigated in particular detail. Together, these examples provide a useful survey of the current consensus, uncertainties, and controversies in this rapidly advancing area of cell biology. Read More

View Article and Full-Text PDF

Repair of DNA Double-Strand Breaks by the Nonhomologous End Joining Pathway.

Annu Rev Biochem 2021 Jun 8;90:137-164. Epub 2021 Feb 8.

Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, USA; email:

DNA double-strand breaks pose a serious threat to genome stability. In vertebrates, these breaks are predominantly repaired by nonhomologous end joining (NHEJ), which pairs DNA ends in a multiprotein synaptic complex to promote their direct ligation. NHEJ is a highly versatile pathway that uses an array of processing enzymes to modify damaged DNA ends and enable their ligation. Read More

View Article and Full-Text PDF

Structural Mechanism of Transport of Mitochondrial Carriers.

Annu Rev Biochem 2021 Jun 8;90:535-558. Epub 2021 Feb 8.

Medical Research Council Mitochondrial Biology Unit, Keith Peters Building, University of Cambridge, Cambridge CB2 0XY, United Kingdom; email:

Members of the mitochondrial carrier family [solute carrier family 25 (SLC25)] transport nucleotides, amino acids, carboxylic acids, fatty acids, inorganic ions, and vitamins across the mitochondrial inner membrane. They are important for many cellular processes, such as oxidative phosphorylation of lipids and sugars, amino acid metabolism, macromolecular synthesis, ion homeostasis, cellular regulation, and differentiation. Here, we describe the functional elements of the transport mechanism of mitochondrial carriers, consisting of one central substrate-binding site and two gates with salt-bridge networks on either side of the carrier. Read More

View Article and Full-Text PDF

Preparing Better Samples for Cryo-Electron Microscopy: Biochemical Challenges Do Not End with Isolation and Purification.

Robert M Glaeser

Annu Rev Biochem 2021 Jun 8;90:451-474. Epub 2021 Feb 8.

Department of Molecular and Cell Biology and Lawrence Berkeley National Laboratory, University of California, Berkeley, California 94720, USA; email:

The preparation of extremely thin samples, which are required for high-resolution electron microscopy, poses extreme risk of damaging biological macromolecules due to interactions with the air-water interface. Although the rapid increase in the number of published structures initially gave little indication that this was a problem, the search for methods that substantially mitigate this hazard is now intensifying. The two main approaches under investigation are () immobilizing particles onto structure-friendly support films and () reducing the length of time during which such interactions may occur. Read More

View Article and Full-Text PDF

Tunnels for Protein Export from the Endoplasmic Reticulum.

I Raote V Malhotra

Annu Rev Biochem 2021 Jun 27;90:605-630. Epub 2021 Jan 27.

Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona 08003, Spain; email:

The functions of coat protein complex II (COPII) coats in cargo packaging and the creation of vesicles at the endoplasmic reticulum are conserved in eukaryotic protein secretion. Standard COPII vesicles, however, cannot handle the secretion of metazoan-specific cargoes such as procollagens, apolipoproteins, and mucins. Metazoans have thus evolved modules centered on proteins like TANGO1 (transport and Golgi organization 1) to engage COPII coats and early secretory pathway membranes to engineer a novel mode of cargo export at the endoplasmic reticulum. Read More

View Article and Full-Text PDF

Membrane Exporters of Fluoride Ion.

Annu Rev Biochem 2021 Jun 25;90:559-579. Epub 2021 Jan 25.

Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA; email:

Microorganisms contend with numerous and unusual chemical threats and have evolved a catalog of resistance mechanisms in response. One particularly ancient, pernicious threat is posed by fluoride ion (F), a common xenobiotic in natural environments that causes broad-spectrum harm to metabolic pathways. This review focuses on advances in the last ten years toward understanding the microbial response to cytoplasmic accumulation of F, with a special emphasis on the structure and mechanisms of the proteins that microbes use to export fluoride: the CLC family of F/H antiporters and the Fluc/FEX family of F channels. Read More

View Article and Full-Text PDF

It's Better To Be Lucky Than Smart.

H R Kaback

Annu Rev Biochem 2021 Jun 20;90:1-29. Epub 2021 Jan 20.

Department of Physiology and Department of Microbiology, Immunology and Molecular Genetics, Molecular Biology Institute, University of California, Los Angeles, California, 90095, USA.

Bacterial cytoplasmic membrane vesicles provide a unique experimental system for studying active transport. Vesicles are prepared by lysis of osmotically sensitized cells (i.e. Read More

View Article and Full-Text PDF