Unravelling the complex mechanisms of transgenerational epigenetic inheritance.
Abstract There are numerous benefits to elucidating how our environment affects our health: from a greater understanding of adaptation to disease prevention. Evidence shows that stressors we are exposed to during our lifetime might cause disease in our descendants. Transgenerational epigenetic inheritance involves the transmission of 'information' over multiple generations via the gametes independent of the DNA base sequence. Despite extensive research, the epigenetic mechanisms remain unclear. Analysis of model organisms exposed to environmental insults (e.g., diet manipulation, stress, toxin exposure) or carryin...
Source: Current Opinion in Chemical Biology - June 18, 2016 Category: Biochemistry Authors: Blake GE, Watson ED Tags: Curr Opin Chem Biol Source Type: research

Nutrient regulation of gene expression by O-GlcNAcylation of chromatin.
rt GW Abstract O-GlcNAcylation is a dynamic post-translational modification that is responsive to nutrient availably via the hexosamine biosynthetic pathway and its endproduct UDP-GlcNAc. O-GlcNAcylation serves as a nutrient sensor to regulate the activities of many proteins involved in nearly all biological processes. Within the last decade, OGT, OGA and O-GlcNAcylation have been shown to be at the nexus of epigenetic marks controlling gene expression during embryonic development, cell differentiation, in the maintenance of epigenetic states and in the etiology of epigenetic related diseases. OGT O-GlcNAcylates h...
Source: Current Opinion in Chemical Biology - June 17, 2016 Category: Biochemistry Authors: Hardivillé S, Hart GW Tags: Curr Opin Chem Biol Source Type: research

Current progress in genetically encoded voltage indicators for neural activity recording.
Abstract Genetically Encoded Voltage Indicators (GEVIs) are powerful tools used to investigate neural activity in the brain. The spatiotemporal resolution of GEVIs is on a subcellular and millisecond scale, and is superior to that of the functional magnetic resonance imaging (fMRI) and electroencephalogram (EEG). Further, while patch-clamp techniques record membrane voltage for tens of neurons simultaneously, GEVIs can do so for hundreds of neurons. It is important for neuroscientists to understand the pros and cons of GEVIs and to choose appropriate ones for their specific requirements. Here, we summarize the cha...
Source: Current Opinion in Chemical Biology - June 17, 2016 Category: Biochemistry Authors: Inagaki S, Nagai T Tags: Curr Opin Chem Biol Source Type: research

Small molecule fluorescent voltage indicators for studying membrane potential.
Abstract Voltage imaging has the potential to unravel the contributions that rapid changes in membrane voltage make to cellular physiology, especially in the context of neuroscience. In particular, small molecule fluorophores are especially attractive because they can, in theory, provide fast and sensitive measurements of membrane potential dynamics. A number of classes of small molecule voltage indicators will be discussed, including dyes with improved two-photon voltage sensing, near infrared optical profiles for use in in vivo applications, and newly developed electron-transfer based indicators, or VoltageFluor...
Source: Current Opinion in Chemical Biology - June 16, 2016 Category: Biochemistry Authors: Miller EW Tags: Curr Opin Chem Biol Source Type: research

Methyltransferase inhibitors for modulation of the epigenome and beyond.
Abstract Over the past two years tremendous progress has been made in the discovery of new inhibitors of protein lysine and arginine methyltransferases, establishing this class of epigenetic enzymes, along with DNA methyltransferases, as druggable protein families. New inhibitors of protein methyltransferases have been described with a variety of mechanisms of action including cofactor competitive, substrate competitive, allosteric inhibitors and disruptors of protein-protein interactions. Inhibitors have been used extensively in oncology studies, and inhibitors of EZH2, and DOT1L are currently in clinical trials....
Source: Current Opinion in Chemical Biology - June 16, 2016 Category: Biochemistry Authors: Schapira M, Arrowsmith CH Tags: Curr Opin Chem Biol Source Type: research

The expanding scope and impact of epigenetic cytosine modifications.
Abstract Chemical modifications to genomic DNA can expand and shape its coding potential. Cytosine methylation in particular has well-established roles in regulating gene expression and defining cellular identity. The discovery of TET family enzymes opened a major frontier beyond DNA methylation, revealing three oxidized forms of cytosine that could mediate DNA demethylation or encode independent epigenetic functions. Chemical biology has been instrumental in uncovering TET's intricate reaction mechanisms and scope of reactivity on a surprising variety of substrates. Moreover, innovative chemoenzymatic strategies ...
Source: Current Opinion in Chemical Biology - June 14, 2016 Category: Biochemistry Authors: Liu MY, DeNizio JE, Schutsky EK, Kohli RM Tags: Curr Opin Chem Biol Source Type: research

Towards synthesis of monoterpenes and derivatives using synthetic biology.
Abstract Synthetic biology is opening up new opportunities for the sustainable and efficient production of valuable chemicals in engineered microbial factories. Here we review the application of synthetic biology approaches to the engineering of monoterpene/monoterpenoid production, highlighting the discovery of novel catalytic building blocks, their accelerated assembly into functional pathways, general strategies for product diversification, and new methods for the optimization of productivity to economically viable levels. Together, these emerging tools allow the rapid creation of microbial production systems f...
Source: Current Opinion in Chemical Biology - June 14, 2016 Category: Biochemistry Authors: Zebec Z, Wilkes J, Jervis AJ, Scrutton NS, Takano E, Breitling R Tags: Curr Opin Chem Biol Source Type: research

Clinical progress and pharmacology of small molecule bromodomain inhibitors.
Abstract Bromodomains have emerged as an exciting target class for drug discovery over the past decade. Research has primarily focused on the bromodomain and extra terminal (BET) family of bromodomains, which has led to the development of multiple small molecule inhibitors and an increasing number of clinical assets. The excitement centred on the clinical potential of BET inhibition has stimulated intense interest in the broader family and the growing number of non-BET bromodomain chemical probes has facilitated phenotypic investigations, implicating these targets in a variety of disease pathways including cancer,...
Source: Current Opinion in Chemical Biology - June 10, 2016 Category: Biochemistry Authors: Theodoulou NH, Tomkinson NC, Prinjha RK, Humphreys PG Tags: Curr Opin Chem Biol Source Type: research

Deciphering single cell metabolism by coherent Raman scattering microscopy.
Abstract Metabolism is highly dynamic and intrinsically heterogeneous at the cellular level. Although fluorescence microscopy has been commonly used for single cell analysis, bulky fluorescent probes often perturb the biological activities of small biomolecules such as metabolites. Such challenge can be overcome by a vibrational imaging technique known as coherent Raman scattering microscopy, which is capable of chemically selective, highly sensitive, and high-speed imaging of biomolecules with submicron resolution. Such capability has enabled quantitative assessments of metabolic activities of biomolecules (e.g. ...
Source: Current Opinion in Chemical Biology - June 8, 2016 Category: Biochemistry Authors: Yue S, Cheng JX Tags: Curr Opin Chem Biol Source Type: research

Applications of CRISPR-Cas in its natural habitat.
Abstract Key components of CRISPR-Cas systems have been adapted into a powerful genome-editing tool that has caught the headlines and the attention of the public. Canonically, a customized RNA serves to guide an endonuclease (e.g. Cas9) to its DNA target, resulting in precise genomic lesions that can be repaired in a personalized fashion by cellular machinery. Here, we turn to the microbes that are the source of this system to explore many of its other notable applications. These include mining the CRISPR 'memory' arrays for functional genomic data, generation of customized virus-resistant or plasmid-refractory ba...
Source: Current Opinion in Chemical Biology - June 6, 2016 Category: Biochemistry Authors: Hynes AP, Lemay ML, Moineau S Tags: Curr Opin Chem Biol Source Type: research

Monoclonal antibody-based optical molecular imaging probes; considerations and caveats in chemistry, biology and pharmacology.
Abstract The monoclonal antibody (mAb) has proven to be a good platform for designing specific molecular imaging probes due to its superior binding specificity. Several optical imaging probes have been developed for surgical navigation in patients and are in early phase clinical trials. However, an inherent limitation of using the mAb is its pharmacokinetics which result in a prolonged circulating half-life and slow clearance from the body. This results in undesirable target to background ratios during imaging. In this review, we first describe the mAb as a platform material for optical probe design and then discu...
Source: Current Opinion in Chemical Biology - June 6, 2016 Category: Biochemistry Authors: Kobayashi H, Choyke PL, Ogawa M Tags: Curr Opin Chem Biol Source Type: research

Intracellular and in vivo oxygen sensing using phosphorescent iridium(III) complexes.
Abstract Molecular oxygen plays an indispensable role as a terminal electron acceptor in the electron transport chain in mitochondria. Acute or chronic oxygen deprivation (hypoxia) in organisms results in various diseases, and the elucidation of the pathogenic mechanism of hypoxia-related diseases and various cellular responses to hypoxia is an urgent issue. Optical oxygen imaging methods using phosphorescent probes have opened up techniques for noninvasive imaging of the intracellular and tissue oxygen status, and oxygen-sensitive probes play a key role in the development of this approach. We expect that phosphor...
Source: Current Opinion in Chemical Biology - June 6, 2016 Category: Biochemistry Authors: Tobita S, Yoshihara T Tags: Curr Opin Chem Biol Source Type: research

From Natural Product to the First Oral Treatment for Multiple Sclerosis: The Discovery of FTY720 (Gilenya™)?
From Natural Product to the First Oral Treatment for Multiple Sclerosis: The Discovery of FTY720 (Gilenya™)? Curr Opin Chem Biol. 2016 May 31;32:60-66 Authors: Zécri FJ Abstract Multiple sclerosis is a devastating chronic autoimmune disease affecting women and men of all ages. Inflammation of the central nervous system causes demyelination and ultimately neuropsychological dysfunction. Myriocin, a natural product with strong immunosuppressant activity was interrogated leading to a new class of immunomodulator with a unique mode of action. In this review, we will summarize these findings, ...
Source: Current Opinion in Chemical Biology - May 31, 2016 Category: Biochemistry Authors: Zécri FJ Tags: Curr Opin Chem Biol Source Type: research

From dirt to industrial applications: Pseudomonas putida as a Synthetic Biology chassis for hosting harsh biochemical reactions.
nzo V Abstract The soil bacterium Pseudomonas putida is endowed with a central carbon metabolic network capable of fulfilling high demands of reducing power. This situation arises from a unique metabolic architecture that encompasses the partial recycling of triose phosphates to hexose phosphates-the so-called EDEMP cycle. In this article, the value of P. putida as a bacterial chassis of choice for contemporary, industrially-oriented metabolic engineering is addressed. The biochemical properties that make this bacterium adequate for hosting biotransformations involving redox reactions as well as toxic compounds an...
Source: Current Opinion in Chemical Biology - May 27, 2016 Category: Biochemistry Authors: Nikel PI, Chavarría M, Danchin A, de Lorenzo V Tags: Curr Opin Chem Biol Source Type: research

The best of both worlds: reaping the benefits from mammalian and bacterial therapeutic circuits.
Abstract Synthetic biology has revolutionized the field of biology in the last two decades. By taking apart natural systems and recombining engineered parts in novel constellations, it has not only unlocked a staggering variety of biological control mechanisms but it has also created a panoply of biomedical achievements, such as innovative diagnostics and therapies. The most common mode of action in the field of synthetic biology is mediated by synthetic gene circuits assembled in a systematic and rational manner. This review covers the most recent therapeutic gene circuits implemented in mammalian and bacterial c...
Source: Current Opinion in Chemical Biology - May 26, 2016 Category: Biochemistry Authors: Bojar D, Fussenegger M Tags: Curr Opin Chem Biol Source Type: research

Encapsulins: microbial nanocompartments with applications in biomedicine, nanobiotechnology and materials science.
Abstract Compartmentalization is one of the defining features of life. Cells use protein compartments to exert spatial control over their metabolism, store nutrients and create unique microenvironments needed for essential physiological processes. Encapsulins are a recently discovered class of protein nanocompartments found in bacteria and archaea that naturally encapsulate cargo proteins. A short C-terminal targeting sequence directs the highly specific encapsulation process in vivo. Here, I will initially discuss the properties, diversity and putative function of encapsulins. The unique characteristics and poten...
Source: Current Opinion in Chemical Biology - May 24, 2016 Category: Biochemistry Authors: Giessen TW Tags: Curr Opin Chem Biol Source Type: research

Editorial overview: Next-generation therapeutics: Breaking new ground and making a difference for patients.
PMID: 27206139 [PubMed - as supplied by publisher] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - May 17, 2016 Category: Biochemistry Authors: Khosla C, Baryza J Tags: Curr Opin Chem Biol Source Type: research

Editorial overview: Bioinorganic chemistry: Key roles for biological metal centers.
PMID: 27155932 [PubMed - as supplied by publisher] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - May 4, 2016 Category: Biochemistry Authors: David Britt R, Raven E Tags: Curr Opin Chem Biol Source Type: research

Emerging concepts in functional and molecular photoacoustic imaging.
Abstract Providing the specific imaging contrast of optical absorption and excellent spatial scalability across the optical and ultrasonic dimensions, photoacoustic imaging has been rapidly emerging and expanding in the past two decades. In this review, I focus on a few latest advances in this enabling technology that hold the potential to transform in vivo functional and molecular imaging at multiple length scales. Specifically, multi-parametric photoacoustic microscopy enables simultaneous high-resolution mapping of hemoglobin concentration, oxygen saturation and blood flow-opening up the possibility of quantify...
Source: Current Opinion in Chemical Biology - April 22, 2016 Category: Biochemistry Authors: Hu S Tags: Curr Opin Chem Biol Source Type: research

High-speed Raman imaging of cellular processes.
Abstract Raman scattering microscopy provides information about the distribution and chemical state of molecules in live cells without any labeling or modification. In recent years, the imaging speed of Raman microscopy has improved greatly owing to the development of instruments that can perform parallel acquisition of Raman spectra from multiple points. In this article, we review recent advances in high-speed hyperspectral Raman imaging and its application to observe various biological processes such as cell mitosis, apoptosis and cell differentiation. Furthermore, we discuss the recent progress in Raman tags fo...
Source: Current Opinion in Chemical Biology - April 20, 2016 Category: Biochemistry Authors: Ando J, Palonpon AF, Sodeoka M, Fujita K Tags: Curr Opin Chem Biol Source Type: research

Raman activated cell sorting.
Abstract Single cell Raman spectra (SCRS) are intrinsic biochemical profiles and 'chemical images' of single cells which can be used to characterise phenotypic changes, physiological states and functions of cells. On the base of SCRS, Raman activated cell sorting (RACS) provides a label-free cell sorting approach, which can link single cells to their chemical or phenotypic profiles. Overcoming naturally weak Raman signals, establishing Raman biomarker as sorting criteria to RACS and improving specific sorting technology are three challenges of developing RACS. Advances on Raman spectroscopy such as stimulated Rama...
Source: Current Opinion in Chemical Biology - April 18, 2016 Category: Biochemistry Authors: Song Y, Yin H, Huang WE Tags: Curr Opin Chem Biol Source Type: research

Rapid and sensitive fluorescent imaging of tiny tumors in vivo and in clinical specimens.
Abstract Fluorescence-guided diagnostics is one of the most powerful techniques for real-time in situ tumor detection. Here, we introduce two categories of fluorescence probes used for tumor imaging (always-on probes and activatable probes) and briefly summarize recent advances in tumor-targeted fluorescence imaging probes and their clinical/preclinical applications, including our recent work on rational design of activatable fluorescence probes for tumors expressing aminopeptidases and glycosidases. These probes enable rapid and sensitive detection of tiny tumors as small as
Source: Current Opinion in Chemical Biology - April 18, 2016 Category: Biochemistry Authors: Kamiya M, Urano Y Tags: Curr Opin Chem Biol Source Type: research

On the catalytic mechanisms of lytic polysaccharide monooxygenases.
Abstract Lytic polysaccharide monooxygenases (LPMOs) are recently discovered copper-containing oxygenases. LPMOs oxidise recalcitrant polysaccharides such as chitin and cellulose, thereby making these substrates more tractable to canonical chitinase or cellulase action. As such, LPMOs are attracting much attention not only for their capacity to greatly increase the efficiency of production of cellulosic-based biofuels, but also for the new questions they pose about the mechanisms of biological oxidation of recalcitrant substrates. This review draws together the current thinking on the catalytic mechanisms of LPMOs...
Source: Current Opinion in Chemical Biology - April 16, 2016 Category: Biochemistry Authors: Walton PH, Davies GJ Tags: Curr Opin Chem Biol Source Type: research

Molybdenum cofactor and human disease.
Abstract Four molybdenum-dependent enzymes are known in humans, each harboring a pterin-based molybdenum cofactor (Moco) in the active site. They catalyze redox reactions using water as oxygen acceptor or donator. Moco is synthesized by a conserved biosynthetic pathway. Moco deficiency results in a severe inborn error of metabolism causing often early childhood death. Disease-causing symptoms mainly go back to the lack of sulfite oxidase (SO) activity, an enzyme in cysteine catabolism. Besides their name-giving functions, Mo-enzymes have been recognized to catalyze novel reactions, including the reduction of nitri...
Source: Current Opinion in Chemical Biology - April 4, 2016 Category: Biochemistry Authors: Schwarz G Tags: Curr Opin Chem Biol Source Type: research

How did life survive Earth's great oxygenation?
Abstract Life on Earth originated and evolved in anoxic environments. Around 2.4 billion-years-ago, ancestors of Cyanobacteria invented oxygenic photosynthesis, producing substantial amounts of O2 as a byproduct of phototrophic water oxidation. The sudden appearance of O2 would have led to significant oxidative stress due to incompatibilities with core cellular biochemical processes. Here we examine this problem through the lens of Cyanobacteria-the first taxa to observe significant fluxes of intracellular dioxygen. These early oxygenic organisms likely adapted to the oxidative stress by co-opting preexisting syst...
Source: Current Opinion in Chemical Biology - April 1, 2016 Category: Biochemistry Authors: Fischer WW, Hemp J, Valentine JS Tags: Curr Opin Chem Biol Source Type: research

Development of a platform for the discovery and practical synthesis of new tetracycline antibiotics.
Abstract Tetracyclines have proven to be safe and effective antibiotics over decades but to date all approved members of the class have been discovered and manufactured by chemical modification of fermentation products, which greatly limits the number of new structures that can be explored as future medicines. This review summarizes research leading to the development of a platform synthetic technology that enabled the discovery of the clinical candidate eravacycline, as well as other promising new tetracycline antibiotics, and provides the basis for a practical route for their manufacture. The approach argues for...
Source: Current Opinion in Chemical Biology - April 1, 2016 Category: Biochemistry Authors: Liu F, Myers AG Tags: Curr Opin Chem Biol Source Type: research

Beyond Mg(2+): functional interactions between RNA and transition metals.
Abstract It is well-known that RNA structure and function depend heavily on cations, and the ability of Mg(2+) to stabilize RNA structures has been emphasized. Recent studies, however, highlight the importance of transition metals in RNA function. Riboswitches that selectively bind Ni(2+), Co(2+), and Mn(2+) have been discovered with specific RNA-metal sites that influence metal-related gene expression. Exogenous metals such as Pt(II) from therapeutics also bind and may inhibit cellular RNA. Novel reports that RNA can host Fe(II) in catalytic sites are relevant to early life in pre-oxygenic atmospheres. These new ...
Source: Current Opinion in Chemical Biology - March 28, 2016 Category: Biochemistry Authors: Saunders AM, DeRose VJ Tags: Curr Opin Chem Biol Source Type: research

Recent advances in designed coiled coils and helical bundles with inorganic prosthetic groups-from structural to functional applications.
Abstract Recent contributions to the de novo design of metalloproteins based on coiled coils and helical bundles are described herein, with examples covering mononuclear, multinuclear, and metallo-porphyrin sites, as well as membrane soluble designs. Important progress is being made in the field with a diverse range of functionalities, sometimes beyond those found in biology, being successfully engineered into these simplified scaffolds and represents an exciting prospect for the future. PMID: 27031927 [PubMed - as supplied by publisher] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - March 28, 2016 Category: Biochemistry Authors: Peacock AF Tags: Curr Opin Chem Biol Source Type: research

Electron bifurcation.
Abstract Electron bifurcation is the recently recognized third mechanism of biological energy conservation. It simultaneously couples exergonic and endergonic oxidation-reduction reactions to circumvent thermodynamic barriers and minimize free energy loss. Little is known about the details of how electron bifurcating enzymes function, but specifics are beginning to emerge for several bifurcating enzymes. To date, those characterized contain a collection of redox cofactors including flavins and iron-sulfur clusters. Here we discuss the current understanding of bifurcating enzymes and the mechanistic features requir...
Source: Current Opinion in Chemical Biology - March 23, 2016 Category: Biochemistry Authors: Peters JW, Miller AF, Jones AK, King PW, Adams MW Tags: Curr Opin Chem Biol Source Type: research

Catalytic strategies of the non-heme iron dependent oxygenases and their roles in plant biology.
Abstract Non-heme iron-dependent oxygenases catalyse the incorporation of O2 into a wide range of biological molecules and use diverse strategies to activate their substrates. Recent kinetic studies, including in crystallo, have provided experimental support for some of the intermediates used by different subclasses of this enzyme family. Plant non-heme iron-dependent oxygenases have diverse and important biological roles, including in growth signalling, stress responses and secondary metabolism. Recently identified roles include in strigolactone biosynthesis, O-demethylation in morphine biosynthesis and regulatin...
Source: Current Opinion in Chemical Biology - March 22, 2016 Category: Biochemistry Authors: White MD, Flashman E Tags: Curr Opin Chem Biol Source Type: research

Applications of microbial cytochrome P450 enzymes in biotechnology and synthetic biology.
This article reviews recent research on the application of wild-type and engineered P450s in the production of important chemicals, including pharmaceuticals and drug metabolites, steroids and antibiotics. In addition, the properties of unusual members of the P450 superfamily that do not follow the canonical P450 catalytic pathway are described. PMID: 27015292 [PubMed - as supplied by publisher] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - March 22, 2016 Category: Biochemistry Authors: Girvan HM, Munro AW Tags: Curr Opin Chem Biol Source Type: research

Zn(2+) at a cellular crossroads.
Abstract Zinc is an essential micronutrient for cellular homeostasis. Initially proposed to only contribute to cellular viability through structural roles and non-redox catalysis, advances in quantifying changes in nM and pM quantities of Zn(2+) have elucidated increasing functions as an important signaling molecule. This includes Zn(2+)-mediated regulation of transcription factors and subsequent protein expression, storage and release of intracellular compartments of zinc quanta into the extracellular space which modulates plasma membrane protein function, as well as intracellular signaling pathways which contrib...
Source: Current Opinion in Chemical Biology - March 21, 2016 Category: Biochemistry Authors: Liang X, Dempski RE, Burdette SC Tags: Curr Opin Chem Biol Source Type: research

Prevention of cervical cancer: journey to develop the first human papillomavirus virus-like particle vaccine and the next generation vaccine.
Abstract In 2006, the first human papillomavirus (HPV) virus-like particle (VLP) vaccine was licensed. Gardasil(®), the quadrivalent HPV 6, 11, 16 and 18 recombinant VLP vaccine (4vHPV), developed by Merck demonstrated remarkable efficacy in prevention of important clinical pre-cursors to cervical cancer and genital warts. The vaccine was designed to protect against HPV 16 and 18 that cause ∼70% of cervical cancers and HPV 6 and 11 that cause ∼90% of genital warts. Initially, Gardasil(®) was indicated in the United States for women 9-26 years of age for the prevention of HPV 16 and 18-related cervi...
Source: Current Opinion in Chemical Biology - March 17, 2016 Category: Biochemistry Authors: Bryan JT, Buckland B, Hammond J, Jansen KU Tags: Curr Opin Chem Biol Source Type: research

Recent developments in biological water oxidation.
Cox N Abstract Rapid progress has been made in the last five years towards resolution of the structure of nature's water splitting catalyst - a Mn4O5Ca cofactor embedded in Photosystem II - especially in the field of X-ray crystallography. In addition, recent magnetic resonance data have allowed the structure of the cofactor to be accessed in its last metastable intermediate state, prior to O-O bond formation. This activated form of the catalyst is geometrically similar to that seen by X-ray crystallography, which represents the resting state of the cofactor, but requires the coordination of an additional water mo...
Source: Current Opinion in Chemical Biology - March 17, 2016 Category: Biochemistry Authors: Pérez-Navarro M, Neese F, Lubitz W, Pantazis DA, Cox N Tags: Curr Opin Chem Biol Source Type: research

Janus kinase inhibitors for rheumatoid arthritis.
Abstract Treatment of autoimmune diseases, such as rheumatoid arthritis (RA), has advanced substantially over the past decade with the development of biologics targeting inflammatory cytokines. Recent progress in treating RA has been achieved with janus kinase (JAK) inhibitors (Jakinibs), an orally available disease-modifying anti-rheumatic drug targeting the intracellular kinase JAK and with similar efficacy to biologics. The first Jakinib approved for RA was tofacitinib, which exerted superiority to methotrexate and non-inferiority to tumor necrosis factor (TNF) inhibitors. In recent years, the Jakinib baricitin...
Source: Current Opinion in Chemical Biology - March 16, 2016 Category: Biochemistry Authors: Yamaoka K Tags: Curr Opin Chem Biol Source Type: research

Editorial overview: Biocatalysis and Biotransformation: Esoteric, Niche Enzymology.
PMID: 26972779 [PubMed - as supplied by publisher] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - March 10, 2016 Category: Biochemistry Authors: Tawfik DS, van der Donk WA Tags: Curr Opin Chem Biol Source Type: research

Peptide-based synthetic pulmonary surfactant for the treatment of respiratory distress disorders.
Abstract KL4 (sinapultide) represents the first peptide-based replacement for surfactant protein B in pulmonary surfactant (PS) therapies approved for clinical use. Surfaxin, its formulation with PS lipids, shows the promise of synthetic PS for replacing animal-derived PS in the treatment of respiratory distress syndromes and for treating acute lung injury. Efforts to characterize the molecular basis for KL4 function have revealed the peptide exhibits a helical structure which differentially partitions in response to both lipid saturation levels and pH. The penta-residue repeat of KL4 leads to adaptive peptide hel...
Source: Current Opinion in Chemical Biology - March 10, 2016 Category: Biochemistry Authors: Braide-Moncoeur O, Tran NT, Long JR Tags: Curr Opin Chem Biol Source Type: research

Maturation of nitrogenase cofactor-the role of a class E radical SAM methyltransferase NifB.
Abstract Nitrogenase catalyzes the important reactions of N2-reduction, CO-reduction and CO2-reduction at its active cofactor site. Designated the M-cluster, this complex metallocofactor is assembled through the generation of a characteristic 8Fe-core before the insertion of Mo and homocitrate that completes the stoichiometry of the M-cluster. NifB catalyzes the crucial step of radical SAM-dependent carbide insertion that occurs concomitant with the insertion a '9th' sulfur and the rearrangement/coupling of two 4Fe-clusters into a complete 8Fe-core of the M-cluster. Further categorization of a family of NifB prote...
Source: Current Opinion in Chemical Biology - March 8, 2016 Category: Biochemistry Authors: Hu Y, Ribbe MW Tags: Curr Opin Chem Biol Source Type: research

Fresh insight to functioning of selected enzymes of the nitrogen cycle.
Abstract The global nitrogen cycle is the process in which different forms of environmental N are interconverted by microorganisms either for assimilation into biomass or in respiratory energy-generating pathways. This short review highlights developments over the last 5 years in our understanding of functionality of nitrogenase, Cu-nitrite reductase, NO reductase and N2O reductase, complex metalloenzymes that catalyze electron/proton-coupled substrate reduction reactions. PMID: 26963700 [PubMed - as supplied by publisher] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - March 7, 2016 Category: Biochemistry Authors: Eady RR, Antonyuk SV, Hasnain SS Tags: Curr Opin Chem Biol Source Type: research

Recent advances in understanding the enzymatic reactions of [4+2] cycloaddition and spiroketalization.
Abstract Diels-Alder-like [4+2] cycloaddition and ketalization of dihydroxy ketones are cyclization reactions with different mechanisms that produce characteristic cyclohexene and spiroketal units, respectively. Here, we review newly identified, naturally occurring '[4+2] cycloadditionases' and 'spiroketalases' and reveal several similarities between the two types of enzymes. During catalysis, these enzymes control product stereochemistry or/and enhance the transformation rate. They exhibit convergent evolution of [4+2] cycloaddition or spiroketalization activity, which is likely dependent on interactions of varia...
Source: Current Opinion in Chemical Biology - February 9, 2016 Category: Biochemistry Authors: Zheng Q, Tian Z, Liu W Tags: Curr Opin Chem Biol Source Type: research

On-line enzymatic tailoring of polyketides and peptides in thiotemplate systems.
Abstract Non-ribosomal peptide synthetases (NRPS) and type I polyketide synthases (PKS) are versatile thiotemplate systems for the programmed assembly of biosynthetic building blocks. Typically, the post-PKS/NRPS enzymes tailor the resulting chains to yield the bioactive natural product scaffolds. However, more and more examples have surfaced showing that important structural modifications take place while the intermediates are still bound to the assembly line. A growing number of enzymatic domains and trans-acting enzymes as well as their recruiting areas in the modules have been identified and characterized. In ...
Source: Current Opinion in Chemical Biology - February 6, 2016 Category: Biochemistry Authors: Sundaram S, Hertweck C Tags: Curr Opin Chem Biol Source Type: research

A current pharmacologic agent versus the promise of next generation therapeutics to ameliorate protein misfolding and/or aggregation diseases.
Abstract The list of protein aggregation-associated degenerative diseases is long and growing, while the portfolio of disease-modifying strategies is very small. In this review and perspective, we assess what has worked to slow the progression of an aggregation-associated degenerative disease, covering the underlying mechanism of pharmacologic action and what we have learned about the etiology of the transthyretin amyloid diseases and likely amyloidoses in general. Next, we introduce emerging therapies that should apply more generally to protein misfolding and/or aggregation diseases, approaches that rely on adapt...
Source: Current Opinion in Chemical Biology - February 6, 2016 Category: Biochemistry Authors: Baranczak A, Kelly JW Tags: Curr Opin Chem Biol Source Type: research

Catalytic repertoire of bacterial bisindole formation.
Abstract Bacterial bisindole alkaloids that derive from the oxidative dimerization of l-tryptophan possess diversified biological activities and unique molecular structures. In recent years, the number of bisindoles and their gene clusters has greatly expanded, revealing a large genetic toolbox for the generation of unique structural modifications. In this review, we will discuss the enzymatic pathways leading to diverse bisindoles structures. We will focus on the discovery of molecules through metagenomic mining, the elucidation of new enzymatic mechanisms, and the identification of new biosynthetic protecting gr...
Source: Current Opinion in Chemical Biology - February 5, 2016 Category: Biochemistry Authors: Du YL, Ryan KS Tags: Curr Opin Chem Biol Source Type: research

Enzymatic breakage of dimethylsulfoniopropionate-a signature molecule for life at sea.
Abstract Largely using gene-based evidence, the last few years have seen real insights on the diverse ways in which different microbes break down dimethylsulfoniopropionate, an abundant anti-stress molecule that is made by marine algae, some corals and a few angiosperms. Here, we review more recent advances in which in vitro biochemical tools-including structural determinations-have shed new light on how the corresponding enzymes act on DMSP. These have revealed how enzymes in very different polypeptide families can act on this substrate, often by novel ways, and with broader implications that extend from enzymati...
Source: Current Opinion in Chemical Biology - February 3, 2016 Category: Biochemistry Authors: Johnston AW, Green RT, Todd JD Tags: Curr Opin Chem Biol Source Type: research

Harvesting the biosynthetic machineries that cultivate a variety of indispensable plant natural products.
Abstract Plants are a sustainable resource for valuable natural chemicals best illustrated by large-scale farming centered on specific products. Here, we review recent discoveries of plant metabolic pathways producing natural products with unconventional biomolecular structures. Prenylation of polyketides by aromatic prenyltransferases (aPTases) ties together two of the major groups of plant specialized chemicals, terpenoids and polyketides, providing a core modification leading to new bioactivities and downstream metabolic processing. Moreover, PTases that biosynthesize Z-terpenoid precursors for small molecules ...
Source: Current Opinion in Chemical Biology - February 3, 2016 Category: Biochemistry Authors: Vickery CR, La Clair JJ, Burkart MD, Noel JP Tags: Curr Opin Chem Biol Source Type: research

Microbial transformations in phosphonate biosynthesis and catabolism, and their importance in nutrient cycling.
Abstract Phosphorus cycling in the biosphere has traditionally been thought to involve almost exclusively transformations of the element in its pentavalent oxidation state. Recent evidence, however, suggests that a significant fraction of environmental phosphorus may exist in a more reduced form. Most abundant of these reduced phosphorus compounds are the phosphonates, with their direct carbon-phosphorus bonds, and striking progress has recently been made in elucidating the biochemistry of microbial phosphonate transformations. These advances are now presented in the context of their contribution to our understand...
Source: Current Opinion in Chemical Biology - January 30, 2016 Category: Biochemistry Authors: Chin JP, McGrath JW, Quinn JP Tags: Curr Opin Chem Biol Source Type: research

Biocatalytic portfolio of Basidiomycota.
Abstract Basidiomycota fungi have received little attention for applications in biocatalysis and biotechnology and remain greatly understudied despite their importance for carbon recycling, ecosystem functioning and medicinal properties. The steady influx of genome data has facilitated detailed studies aimed at understanding the evolution and function of fungal lignocellulose degradation. These studies and recent explorations into the secondary metabolomes have uncovered large portfolios of enzymes useful for biocatalysis and biosynthesis. This review will provide an overview of the biocatalytic repertoires of Bas...
Source: Current Opinion in Chemical Biology - January 23, 2016 Category: Biochemistry Authors: Schmidt-Dannert C Tags: Curr Opin Chem Biol Source Type: research

Unusual flavoenzyme catalysis in marine bacteria.
Abstract Ever since the discovery of the flavin cofactor more than 80 years ago, flavin-dependent enzymes have emerged as ubiquitous and versatile redox catalysts in primary metabolism. Yet, the recent advances in the discovery and characterization of secondary metabolic pathways exposed new roles for flavin-mediated catalysis in the generation of structurally complex natural products. Here, we review a selection of key biosynthetic flavoenzymes from marine bacterial secondary metabolism and illustrate how their functional and mechanistic investigation expanded our view of the cofactor's chemical repertoire and le...
Source: Current Opinion in Chemical Biology - January 20, 2016 Category: Biochemistry Authors: Teufel R, Agarwal V, Moore BS Tags: Curr Opin Chem Biol Source Type: research

Biocatalysts from alkaloid producing plants.
Abstract Metabolic pathways leading to benzylisoquinoline and monoterpene indole alkaloids in plants are revealing remarkable new reactions. Understanding of the enzymes involved in alkaloid biosynthesis provides access to a variety of applications in biocatalysis and bioengineering. In chemo-enzymatic settings, plant biocatalysts can transform medically important scaffolds. Additionally, synthetic biologists are taking alkaloid pathways as templates to assemble pathways in microorganisms that are tailored to the needs of medicinal chemistry. In light of these many recent discoveries, it is expected that plants wi...
Source: Current Opinion in Chemical Biology - January 13, 2016 Category: Biochemistry Authors: Kries H, O'Connor SE Tags: Curr Opin Chem Biol Source Type: research

Editorial overview: Omics: The maturation of chemical biology.
PMID: 26739665 [PubMed - as supplied by publisher] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - December 28, 2015 Category: Biochemistry Authors: Saghatelian A, Nomura DK, Weerapena E Tags: Curr Opin Chem Biol Source Type: research