Epigenetic regulation by endogenous metabolite pharmacology.
Abstract Altered metabolite levels can drive epigenetic changes critical to development and disease. However, in many cases the specific protein-metabolite interactions that underlie this process remain enigmatic. In this review, we make the case that this fundamental missing information may be discovered by applying the tools of modern drug target validation to study endogenous metabolite pharmacology. We detail examples in which chemical proteomics has been applied to gain new insights into reversible and covalent metabolite signaling mechanisms, using acetyl-CoA and fumarate as case studies. Finally, we provide...
Source: Current Opinion in Chemical Biology - March 15, 2019 Category: Biochemistry Authors: Kulkarni RA, Montgomery DC, Meier JL Tags: Curr Opin Chem Biol Source Type: research

Updates on the epigenetic roles of sirtuins.
Abstract Sirtuins are a class of enzyme with NAD+-dependent protein lysine deacylase activities. They were initially discovered to regulate transcription and life span via histone deacetylase activities. Later studies expanded their activities to other proteins and acyl lysine modifications. Through deacylating various substrate proteins, they regulate many biological processes, including transcription, DNA repair and genome stability, metabolism, and signal transduction. Here, we review recent understandings of the epigenetic functions (broadly defined to include transcriptional, post-transcriptional regulation, ...
Source: Current Opinion in Chemical Biology - March 12, 2019 Category: Biochemistry Authors: Kosciuk T, Wang M, Hong JY, Lin H Tags: Curr Opin Chem Biol Source Type: research

The antimalarial screening landscape-looking beyond the asexual blood stage.
Abstract In recent years, the research agenda to tackle global morbidity and mortality from malaria disease has shifted towards innovation, in the hope that efforts at the frontiers of scientific research may re-invigorate gains made towards eradication. Discovery of new antimalarial drugs with novel chemotypes or modes of action lie at the heart of these efforts. There is a particular interest in drug candidates that target stages of the malaria parasite lifecycle beyond the symptomatic asexual blood stages. This is especially important given the spectre of emerging drug resistance to all current frontline antima...
Source: Current Opinion in Chemical Biology - March 12, 2019 Category: Biochemistry Authors: Yahiya S, Rueda-Zubiaurre A, Delves MJ, Fuchter MJ, Baum J Tags: Curr Opin Chem Biol Source Type: research

Construction of ligand assay systems by protein-based semisynthetic biosensors.
Abstract Proteins as causative agents of diseases such as cancers, diabetes and neurological disorders are attractive drug targets. For developing chemicals selectively acting on key disease-causing proteins, one useful concept is the direct conversion of such target proteins into biosensors. This approach provides ligand-binding assay systems based on protein-based biosensors, which can quantitatively evaluate interactions between the protein and a specific ligand in many environments. Site-specific chemical modifications are used widely for the creation of protein-based semisynthetic biosensors in vitro. Notably...
Source: Current Opinion in Chemical Biology - March 12, 2019 Category: Biochemistry Authors: Sakamoto S, Kiyonaka S, Hamachi I Tags: Curr Opin Chem Biol Source Type: research

Chemical and biophysical methods to explore dynamic mechanisms of chromatin silencing.
Abstract Chromatin, the nucleoprotein complex organizing the genome, is central in regulating gene expression and genome organization. Chromatin conformational dynamics, controlled by histone post-translational modifications (PTM) and effector proteins, play a key role in this regulatory function. Recent developments in chemical biology, cell biology, and biophysics sparked important new studies, which probe direct causal connections between histone PTMs, chromatin effector proteins that write or read these modifications, and the involved functional chromatin states. In particular, the mechanisms of heterochromati...
Source: Current Opinion in Chemical Biology - February 27, 2019 Category: Biochemistry Authors: Boichenko I, Fierz B Tags: Curr Opin Chem Biol Source Type: research

The roles of microRNAs in epigenetic regulation.
Abstract MicroRNAs (miRNAs) are small noncoding RNAs, approximately 18-25 nucleotides in length, now recognized as one of the major regulatory gene families in eukaryotes. Recent advances have been made in understanding the complicated roles of miRNAs in epigenetic regulation. miRNAs, as epigenetic modulators, affect the protein levels of the target mRNAs without modifying the gene sequences. Moreover, miRNAs can also be regulated by epigenetic modifications, including DNA methylation, RNA modification, and histone modifications. The reciprocal actions of miRNAs and epigenetic pathway appear to form a miRNA-epigen...
Source: Current Opinion in Chemical Biology - February 27, 2019 Category: Biochemistry Authors: Yao Q, Chen Y, Zhou X Tags: Curr Opin Chem Biol Source Type: research

Sulfur-dependent microbial lifestyles: deceptively flexible roles for biochemically versatile enzymes.
Abstract A wide group of microbes are able to "make a living" on Earth by basing their energetic metabolism on inorganic sulfur compounds. Because of their range of stable redox states, sulfur and inorganic sulfur compounds can be utilized as either oxidants or reductants in a diverse array of energy-conserving reactions. In this review the major enzymes and basic chemistry of sulfur-based respiration and chemolithotrophy are outlined. The reversibility and versatility of these enzymes, however, means that they can often be used in multiple ways, and several cases are discussed in which enzymes which are...
Source: Current Opinion in Chemical Biology - February 7, 2019 Category: Biochemistry Authors: Crane EJ Tags: Curr Opin Chem Biol Source Type: research

Proteomic-based approaches to cardiac development and disease.
Abstract Congenital malformations, or structural birth defects, are now the leading cause of infant mortality in the United States and Europe (Dolk et al., 2010; Heron et al., 2009). Of the congenital malformations, congenital heart disease (CHD) is the most common (Dolk et al., 2010; Heron et al., 2009). Thus, a molecular understanding of heart development is an essential goal for improving clinical approaches to CHD. However, CHDs are commonly a result of genetic defects that manifest themselves in a spatial and temporal manner during the early stages of embryogenesis, leaving them mostly intractable to mass spe...
Source: Current Opinion in Chemical Biology - January 31, 2019 Category: Biochemistry Authors: Dorr KM, Conlon FL Tags: Curr Opin Chem Biol Source Type: research

Natural product derived privileged scaffolds in drug discovery.
Abstract The biological activity and structural diversity of natural products are unsurpassed by any available synthetic screening libraries. As such, these privileged scaffolds serve as important, biologically prevalidated platforms for the design of compound libraries in the search for new drug candidates. Recent progress has focussed on improving the potency, selectivity and pharmacokinetics of bioactive natural products through structural modification, leading to the emergence of a number of drug-like lead compounds. Here, we review recent advances in the exploitation of terpenoid, polyketide, phenylpropanoid ...
Source: Current Opinion in Chemical Biology - January 22, 2019 Category: Biochemistry Authors: Davison EK, Brimble MA Tags: Curr Opin Chem Biol Source Type: research

The emergence of nitric oxide in the biosynthesis of bacterial natural products.
Abstract Nitric oxide (NO) has a broad range of biological utilities including as a biosynthon for bacterial natural products (NPs). The biosyntheses of thaxtomin A and rufomycin require an NO-dependent nitration step where a bacterial NO synthase provides the necessary NO and nitration is catalyzed by a cytochrome P450 homolog. Undiscovered NO-dependent biosynthesis pathways are likely to have similar requirements: a pathway dedicated NO source and a metalloenzyme to catalyze the NO-dependent chemistry. This review discusses the current literature on NO-dependent nitration biosynthesis and relevant enzyme mechani...
Source: Current Opinion in Chemical Biology - January 10, 2019 Category: Biochemistry Authors: Caranto JD Tags: Curr Opin Chem Biol Source Type: research

Shedding light on biocatalysis: photoelectrochemical platforms for solar-driven biotransformation.
Abstract Redox biocatalysis has come to the forefront because of its excellent catalytic efficiency, stereoselectivity, and environmental benignity. The green and sustainable biotransformation can be driven by photoelectrochemical (PEC) platforms where redox biocatalysis is coupled with photoelectrocatalysis. The main challenge is how to transfer photoexcited electrons to (or from) the enzyme redox centers for effective biotransformation using solar energy. This review commences with a conceptual discussion of biocatalytic PEC platforms and highlights recent advances in PEC-based biotransformation through cofactor...
Source: Current Opinion in Chemical Biology - January 3, 2019 Category: Biochemistry Authors: Kim J, Park CB Tags: Curr Opin Chem Biol Source Type: research

Fungal PQQ-dependent dehydrogenases and their potential in biocatalysis.
ura N Abstract In 2014, the first fungal pyrroloquinoline-quinone (PQQ)-dependent enzyme was discovered as a pyranose dehydrogenase from the basidiomycete Coprinopsis cinerea (CcPDH). This discovery laid the foundation for a new Auxiliary Activities (AA) family, AA12, in the Carbohydrate-Active enZymes (CAZy) database and revealed a novel enzymatic activity potentially involved in biomass conversion. This review summarizes recent progress made in research on this fungal oxidoreductase and related enzymes. CcPDH consists of the catalytic PQQ-binding AA12 domain, an N-terminal cytochrome b AA8 domain, and a C-termin...
Source: Current Opinion in Chemical Biology - December 20, 2018 Category: Biochemistry Authors: Takeda K, Umezawa K, Várnai A, Eijsink VG, Igarashi K, Yoshida M, Nakamura N Tags: Curr Opin Chem Biol Source Type: research

Recent preparative applications of redox enzymes.
Abstract Redox enzymes offer many powerful transformations for the efficient industrial-scale synthesis of diverse chemicals desired by society. Here we survey recent preparative applications of redox enzymes, highlighting both mature enzyme platforms and promising technologies for future applications. While in some cases commercial enzymes can be employed directly on industrial scales, in other cases protein engineering is necessary to evolve an enzyme fit for non-biological substrates and conditions. Both approaches require the input of process engineering to properly balance the needs of the enzymatic chemistry...
Source: Current Opinion in Chemical Biology - December 12, 2018 Category: Biochemistry Authors: Prier CK, Kosjek B Tags: Curr Opin Chem Biol Source Type: research

Signal enhanced proteomics: a biological perspective on dissecting the functional organisation of cell proteomes.
We describe how MS-based proteome analyses can be combined with a general physico-chemical cell fractionation procedure that can be applied to many cultured cell lines. PMID: 30551035 [PubMed - as supplied by publisher] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - December 11, 2018 Category: Biochemistry Authors: Bensaddek D, Nicolas A, Lamond AI Tags: Curr Opin Chem Biol Source Type: research

Advances and opportunities for the design of self-sufficient and spatially organized cell-free biocatalytic systems.
ego F Abstract During the past decades, biocatalysis has made important contributions to chemical manufacturing by using both whole-cell and cell-free biotransformation reactions. More recently, multi-enzyme systems that can run step-wise reactions in one-pot with high selectivity are increasingly being developed. The use of multiple isolated enzymes to perform a series of reactions offers operational and process advantages over the use of living or resting cells, but such cell free processes need to be optimized to meet industrial productivity and titer requirements. Major advances have been made in enzyme discov...
Source: Current Opinion in Chemical Biology - December 11, 2018 Category: Biochemistry Authors: Schmid-Dannert C, López-Gallego F Tags: Curr Opin Chem Biol Source Type: research

How to make the reducing power of H2 available for in vivo biosyntheses and biotransformations.
Abstract Solar-driven electrolysis enables sustainable production of molecular hydrogen (H2), which represents a cheap and carbon-free reductant. Knallgas bacteria like Ralstonia eutropha are able to split H2 to supply energy in form of ATP and NADH, which can be subsequently used to power reactions of interest. R. eutropha employs the Calvin-Benson-Bassham cycle for the fixation of CO2, which is considered as an abundant and non-competing raw material. In this article, we summarize state-of-the-art approaches for H2-driven biosyntheses using engineered R. eutropha. Furthermore, we describe strategies for syntheti...
Source: Current Opinion in Chemical Biology - December 10, 2018 Category: Biochemistry Authors: Lauterbach L, Lenz O Tags: Curr Opin Chem Biol Source Type: research

A bright future: optogenetics to dissect the spatiotemporal control of cell behavior.
Abstract Cells sense, process, and respond to extracellular information using signaling networks: collections of proteins that act as precise biochemical sensors. These protein networks are characterized by both complex temporal organization, such as pulses of signaling activity, and by complex spatial organization, where proteins assemble structures at particular locations and times within the cell. Yet despite their ubiquity, studying these spatial and temporal properties has remained challenging because they emerge from the entire protein network rather than a single node, and cannot be easily tuned by drugs or...
Source: Current Opinion in Chemical Biology - December 4, 2018 Category: Biochemistry Authors: Goglia AG, Toettcher JE Tags: Curr Opin Chem Biol Source Type: research

Dynamics of protein complex components.
Abstract Identifying protein-protein interactions (PPIs) is necessary to understand the molecular mechanisms behind cellular processes. This task is complicated by the facts that many proteins can interact simultaneously (i.e. a protein complex) and may participate in more than one distinct complex. Because of this, a large number of combinatorial arrangements are possible, both of PPIs and complexes, making it a difficult task to identify all truly interacting proteins. Protein interactions also range from stable to highly transient assemblies, with lifetimes on the order of seconds [1]. Therefore, studies identi...
Source: Current Opinion in Chemical Biology - December 4, 2018 Category: Biochemistry Authors: Rattray DG, Foster LJ Tags: Curr Opin Chem Biol Source Type: research

Cysteine reactivity across the subcellular universe.
Abstract Cysteine residues are concentrated at key functional sites within proteins, performing diverse roles in metal binding, catalysis, and redox chemistry. Chemoproteomic platforms to interrogate the reactive cysteinome have developed significantly over the past 10 years, resulting in a greater understanding of cysteine functionality, modification, and druggability. Recently, chemoproteomic methods to examine reactive cysteine residues from specific subcellular organelles have provided significantly improved proteome coverage and highlights the unique functionalities of cysteine residues mediated by cellular l...
Source: Current Opinion in Chemical Biology - November 30, 2018 Category: Biochemistry Authors: Bak DW, Bechtel TJ, Falco JA, Weerapana E Tags: Curr Opin Chem Biol Source Type: research

The subcellular organisation of Saccharomyces cerevisiae.
Abstract Subcellular protein localisation is essential for the mechanisms that govern cellular homeostasis. The ability to understand processes leading to this phenomenon will therefore enhance our understanding of cellular function. Here we review recent developments in this field with regard to mass spectrometry, fluorescence microscopy and computational prediction methods. We highlight relative strengths and limitations of current methodologies focussing particularly on studies in the yeast Saccharomyces cerevisiae. We further present the first cell-wide spatial proteome map of S. cerevisiae, generated using hy...
Source: Current Opinion in Chemical Biology - November 29, 2018 Category: Biochemistry Authors: Nightingale DJ, Geladaki A, Breckels LM, Oliver SG, Lilley KS Tags: Curr Opin Chem Biol Source Type: research

Editorial overview: Novel enzymes, coenzymes, and metabolic pathways.
PMID: 30497880 [PubMed - as supplied by publisher] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - November 26, 2018 Category: Biochemistry Authors: Gerlt JA, Erb TJ Tags: Curr Opin Chem Biol Source Type: research

Regulation of phagosome functions by post-translational modifications: a new paradigm.
t M Abstract Phagosomes are highly dynamic organelles formed by the uptake of particles through phagocytic innate immune cells such as macrophages. Their key roles in microbe elimination and antigen presentation make them essential for innate and adaptive immunity. However, phagosomes are also important for tissue homeostasis as even in healthy individuals billions of dead cells are phagocytosed each day. In this short review, we highlight how the use of latex beads as inert baits for phagocytosis and subsequent analysis by proteomics has changed our understanding of the phagosome. We further discuss recent data o...
Source: Current Opinion in Chemical Biology - November 24, 2018 Category: Biochemistry Authors: Dean P, Heunis T, Härtlova A, Trost M Tags: Curr Opin Chem Biol Source Type: research

Protein identification strategies in MALDI imaging mass spectrometry: a brief review.
Abstract Matrix assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) is a powerful technology used to investigate the spatial distributions of thousands of molecules throughout a tissue section from a single experiment. As proteins represent an important group of functional molecules in tissue and cells, the imaging of proteins has been an important point of focus in the development of IMS technologies and methods. Protein identification is crucial for the biological contextualization of molecular imaging data. However, gas-phase fragmentation efficiency of MALDI generated proteins presents...
Source: Current Opinion in Chemical Biology - November 23, 2018 Category: Biochemistry Authors: Ryan DJ, Spraggins JM, Caprioli RM Tags: Curr Opin Chem Biol Source Type: research

Proteomics of nucleocytoplasmic partitioning.
r M Abstract The partitioning of the proteome between nucleus and cytoplasm affects nearly every aspect of eukaryotic biology. Despite this central role, we still have a poor understanding of which proteins localize in the nucleus and how this varies in different cell types and conditions. Recent advances in quantitative proteomics and high-throughput imaging are starting to close this knowledge gap. Studies on protein interaction are beginning to reveal the spectrum of cargos of nuclear import and export receptors. We anticipate that it will soon be possible to predict each protein's nucleocytoplasmic localizatio...
Source: Current Opinion in Chemical Biology - November 22, 2018 Category: Biochemistry Authors: Nguyen T, Pappireddi N, Wühr M Tags: Curr Opin Chem Biol Source Type: research

Getting to know the neighborhood: using proximity-dependent biotinylation to characterize protein complexes and map organelles.
Abstract The use of proximity-dependent biotinylation approaches combined with mass spectrometry (e.g. BioID and APEX) has revolutionized the study of protein-protein interactions and organellar proteomics. These powerful techniques are based on the fusion of an enzyme (e.g. a biotin ligase or peroxidase) to a 'bait' protein of interest, which is then expressed in a relevant biological setting. Addition of enzyme substrate enables covalent biotin labeling of proteins in the vicinity of the bait in vivo. These approaches thus allow for the capture and identification of 'neighborhood' proteins in the context of a li...
Source: Current Opinion in Chemical Biology - November 17, 2018 Category: Biochemistry Authors: Gingras AC, Abe KT, Raught B Tags: Curr Opin Chem Biol Source Type: research

Whole-cell based synthetic enzyme cascades-light and shadow of a promising technology.
Abstract Mimicking Nature by biocatalytic cascade reactions in a whole-cell environment is a revolutionary development in multistep synthesis for the production of bulk and fine chemicals. In the past decade, several proof of concept success stories demonstrated the power of those synthetic cascades and paved the road for future industrial applications. Although enzymes and their promiscuity are best suited to construct such artificial pathways, the complexity and the lack of understanding of the cellular machinery slowed down this progress significantly. In this review, recent achievements in the field of whole-c...
Source: Current Opinion in Chemical Biology - November 17, 2018 Category: Biochemistry Authors: Rudroff F Tags: Curr Opin Chem Biol Source Type: research

Identification and development of amino acid oxidases.
Abstract Amino acid oxidases are an important class of enzymes that mostly participate in the oxidation of amino acids using FAD as a cofactor. Many of them function in the catabolism of amino acids with wider substrate specificities. On the other hand, based on the recent, successful use of the enzymes for diagnoses with new cofactor and mechanism, highly selective enzymes have been screened from Nature, and many new enzymes have been discovered and further characterized by X-ray crystallography. As a result of the screening for amino acid oxidases with biosynthetic or antibiotic functions, l-Trp oxidase, l-Lys o...
Source: Current Opinion in Chemical Biology - November 15, 2018 Category: Biochemistry Authors: Asano Y, Yasukawa K Tags: Curr Opin Chem Biol Source Type: research

Novel enzymology in futalosine-dependent menaquinone biosynthesis.
Abstract The recently discovered futalosine-dependent menaquinone biosynthesis pathway employs radical chemistry for the naphthoquinol core assembly. Mechanistic studies on this pathway have resulted in the discovery of novel reaction motifs. MqnA is the first example of a chorismate dehydratase. MqnE is the first example of a radical SAM enzyme that catalyzes the addition of the 5'-deoxyadenosyl radical to the substrate double bond rather than hydrogen atom abstraction. Both MqnE and MqnC reaction sequences involve radical additions to a benzene ring followed by formation of an aryl radical anion intermediate. Th...
Source: Current Opinion in Chemical Biology - November 14, 2018 Category: Biochemistry Authors: Joshi S, Fedoseyenko D, Mahanta N, Manion H, Naseem S, Dairi T, Begley TP Tags: Curr Opin Chem Biol Source Type: research

Selective CH bond functionalization with engineered heme proteins: new tools to generate complexity.
Abstract CH functionalization is an attractive strategy to construct and diversify molecules. Heme proteins, predominantly cytochromes P450, are responsible for an array of CH oxidations in biology. Recent work has coupled concepts from synthetic chemistry, computation, and natural product biosynthesis to engineer heme protein systems to deliver products with tailored oxidation patterns. Heme protein catalysis has been shown to go well beyond these native reactions and now accesses new-to-nature CH transformations, including CN and CC bond forming processes. Emerging work with these systems moves us along the ambi...
Source: Current Opinion in Chemical Biology - October 18, 2018 Category: Biochemistry Authors: Zhang RK, Huang X, Arnold FH Tags: Curr Opin Chem Biol Source Type: research

Location is everything: protein translocations as a viral infection strategy.
Abstract Protein movement between different subcellular compartments is an essential aspect of biological processes, including transcriptional and metabolic regulation, and immune and stress responses. As obligate intracellular parasites, viruses are master manipulators of cellular composition and organization. Accumulating evidences have highlighted the importance of infection-induced protein translocations between organelles. Both directional and temporal, these translocation events facilitate localization-dependent protein interactions and changes in protein functions that contribute to either host defense or v...
Source: Current Opinion in Chemical Biology - October 16, 2018 Category: Biochemistry Authors: Cook KC, Cristea IM Tags: Curr Opin Chem Biol Source Type: research

Biomimetic cofactors and methods for their recycling.
Abstract Nicotinamide cofactor biomimetics (NCBs) belong to a class of compounds that, as the name suggests, mimic the structures and functions of natural nicotinamide cofactors, namely nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate and their corresponding reduced forms. The first set of NCBs was discovered in the 1930s; these were initially used to study the chemical properties of this class of cofactors as well as understand nicotinamide binding of oxidoreductases. Since then, various NCBs, enzymes, and recycling systems have evolved and lately, new NCBs have been developed and...
Source: Current Opinion in Chemical Biology - October 15, 2018 Category: Biochemistry Authors: Zachos I, Nowak C, Sieber V Tags: Curr Opin Chem Biol Source Type: research

Flavin metamorphosis: cofactor transformation through prenylation.
Abstract Prenylated flavin (prFMN) is a recently discovered cofactor that underpins catalysis in the ubiquitous microbial UbiDX system. UbiX acts as a flavin prenyltransferase while UbiD is a prFMN-dependent reversible (de)carboxylase. The extensive modification of flavin by prenylation, and the consecutive oxidation to the prFMNiminium azomethine ylide, leads to cofactor metamorphosis. While prFMN is no longer able to perform N5-based classical flavin chemistry, it is capable of forming cycloadducts with dipolarophiles, long-lived C4a-based radical species as well as undergoing extensive light driven isomerizatio...
Source: Current Opinion in Chemical Biology - October 13, 2018 Category: Biochemistry Authors: Leys D Tags: Curr Opin Chem Biol Source Type: research

Interrogating gut bacterial genomes for discovery of novel carbohydrate degrading enzymes.
Abstract Individual human gut bacteria often encode hundreds of enzymes for degrading different polysaccharides. Identification of co-localized and co-regulated genes in these bacteria has been a successful approach to identify enzymes that participate in full or partial saccharification of complex carbohydrates, often unmasking novel catalytic activities. Here, we review recent studies that have led to the discovery of new activities from gut bacteria and summarize a general scheme for identifying gut bacteria with novel catalytic abilities, locating the enzymes involved and investigating their activities in deta...
Source: Current Opinion in Chemical Biology - October 13, 2018 Category: Biochemistry Authors: Luis AS, Martens EC Tags: Curr Opin Chem Biol Source Type: research

Editorial overview: Biological pathways for electrons, protons and photo-excitations.
PMID: 30318402 [PubMed - as supplied by publisher] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - October 11, 2018 Category: Biochemistry Authors: Skourtis SS, Beratan DN Tags: Curr Opin Chem Biol Source Type: research

A role for phosphorus redox in emerging and modern biochemistry.
Abstract Phosphorus is a major biogeochemical element controlling growth in many ecosystems. It has presumably been an important element since the onset of life. In most chemical and biochemical considerations, phosphorus is synonymous with phosphates, a pentavalent oxidation state that includes the phosphate backbone of DNA and RNA, as well as major metabolites such as ATP. However, redox processing of phosphates to phosphites and phosphonates, and to even lower oxidation states provides a work-around to many of the problems of prebiotic chemistry, including phosphorus's low solubility and poor reactivity. In add...
Source: Current Opinion in Chemical Biology - October 10, 2018 Category: Biochemistry Authors: Pasek M Tags: Curr Opin Chem Biol Source Type: research

Role of rare earth elements in methanol oxidation.
Abstract For decades rare earth elements (or lanthanides) were considered not to be involved in biological processes, until their discovery in the active site of the XoxF-type methanol dehydrogenase of the methanotrophic bacterium Methylacidiphilum fumariolicum SolV. Follow-up studies revealed the presence of lanthanides in other pyrroloquinoline quinone-containing enzymes involved in alcohol metabolism. This review discusses the biochemistry of the lanthanide-dependent enzymes and the ability of these metals of influencing the gene expression and the type of methanol dehydrogenase used by microorganisms. Furtherm...
Source: Current Opinion in Chemical Biology - October 8, 2018 Category: Biochemistry Authors: Picone N, Op den Camp HJ Tags: Curr Opin Chem Biol Source Type: research

Trending topics and open questions in anaerobic ammonium oxidation.
Abstract Anaerobic ammonium-oxidizing (anammox) bacteria are major players in the biological nitrogen cycle and can be applied in wastewater treatment for the removal of nitrogen compounds. Anammox bacteria anaerobically convert the substrates ammonium and nitrite into dinitrogen gas in a specialized intracellular compartment called the anammoxosome. The anammox cell biology, physiology and biochemistry is of exceptional interest but also difficult to study because of the lack of a pure culture, standard cultivation techniques and genetic tools. Here we review the most important recent developments regarding the c...
Source: Current Opinion in Chemical Biology - October 8, 2018 Category: Biochemistry Authors: Peeters SH, van Niftrik L Tags: Curr Opin Chem Biol Source Type: research

Understanding molecular mechanisms of disease through spatial proteomics.
C, Yates JR Abstract Mammalian cells are organized into different compartments that separate and facilitate physiological processes by providing specialized local environments and allowing different, otherwise incompatible biological processes to be carried out simultaneously. Proteins are targeted to these subcellular locations where they fulfill specialized, compartment-specific functions. Spatial proteomics aims to localize and quantify proteins within subcellular structures. PMID: 30308467 [PubMed - as supplied by publisher] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - October 8, 2018 Category: Biochemistry Authors: Pankow S, Martínez-Bartolomé S, Bamberger C, Yates JR Tags: Curr Opin Chem Biol Source Type: research

Surfaceome nanoscale organization and extracellular interaction networks.
Abstract The reductionist view of 'one target-one drug' has fueled the development of therapeutic agents to treat human disease. However, many compounds that have efficacy in vitro are inactive in complex in vivo systems. It has become clear that a molecular understanding of signaling networks is needed to address disease phenotypes in the human body. Protein signaling networks function at the molecular level through information transfer via protein-protein interactions. Cell surface exposed proteins, termed the surfaceome, are the gatekeepers between the intra- and extracellular signaling networks, translating ex...
Source: Current Opinion in Chemical Biology - October 8, 2018 Category: Biochemistry Authors: Bausch-Fluck D, Milani ES, Wollscheid B Tags: Curr Opin Chem Biol Source Type: research

Metal regulation of metabolism.
Abstract A broad range of biochemicals, from proteins to nucleic acids, function properly only when associated with a metal, usually a divalent cation. Not any divalent metal will do: these metals differ in their ionic radius, dissociation in water, ionization potential, and number of unpaired electrons in their outer shells, and so substituting one metal for another often changes substrate positioning, redox reactivities, and physiological performance, and thus may serve as a regulatory mechanism. For instance, exchanging manganese for magnesium in several chloroplast enzymes maintains plant carbon-nitrogen balan...
Source: Current Opinion in Chemical Biology - October 5, 2018 Category: Biochemistry Authors: Bloom AJ Tags: Curr Opin Chem Biol Source Type: research

Unlocked potential of dynamic elements in protein structures: channels and loops.
er B Abstract Enzymes are nature's powerful catalytic proteins to perform reactions with often outstanding activity, selectivity and specificity. Moreover, the access to non-natural functions of biocatalysts can be facilitated by enzyme engineering. While rational approaches are often focused on an enzyme's active site, from random directed evolution we know that further functional hotspots must exist beyond the active site. Addressing flexible structural elements of these biocatalysts like loops and channels in enzyme engineering has the potential to fill this knowledge gap. The structural dynamics of enzyme cata...
Source: Current Opinion in Chemical Biology - October 4, 2018 Category: Biochemistry Authors: Kreß N, Halder JM, Rapp LR, Hauer B Tags: Curr Opin Chem Biol Source Type: research

Editorial overview: Expanding the genetic alphabet and code.
PMID: 30270151 [PubMed - as supplied by publisher] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - September 27, 2018 Category: Biochemistry Authors: Ledbetter MP, Romesberg FE Tags: Curr Opin Chem Biol Source Type: research

Newly-discovered enzymes that function in metabolite damage-control.
on AD Abstract Enzymes of unknown function are estimated to make up around 25% of the sequenced proteome. In the past decade, over 20 conserved families have been shown to function in the metabolism of 'damaged' or abnormal metabolites that are wasteful and often toxic. These newly discovered damage-control enzymes either repair or inactivate the offending metabolites, or pre-empt their formation in the first place. Comparative genomics has been of prime importance in predicting the functions of damage-control enzymes and in guiding the biochemical and genetic tests required to validate these functions. PMID:...
Source: Current Opinion in Chemical Biology - September 27, 2018 Category: Biochemistry Authors: de Crécy-Lagard V, Haas D, Hanson AD Tags: Curr Opin Chem Biol Source Type: research

'Democratized' genomic enzymology web tools for functional assignment.
Abstract The protein databases contain an exponentially growing number of sequences as a result of the recent increase in ease and decrease in cost of genome sequencing. The rate of data accumulation far exceeds the rate of functional studies, producing an increase in genomic 'dark matter', sequences for which no precise and validated function is defined. Publicly accessible, that is 'democratized,' genomic enzymology web tools are essential to leverage the protein and genome databases for discovery of the in vitro activities and in vivo functions of novel enzymes and proteins belonging to the dark matter. In this...
Source: Current Opinion in Chemical Biology - September 27, 2018 Category: Biochemistry Authors: Zallot R, Oberg NO, Gerlt JA Tags: Curr Opin Chem Biol Source Type: research

Discovering radical-dependent enzymes in the human gut microbiota.
Abstract Human gut microbes have a tremendous impact on human health, in part due to their unique chemical capabilities. In the anoxic environment of the healthy human gut, many important microbial metabolic transformations are performed by radical-dependent enzymes. Although identifying and characterizing these enzymes has been challenging, recent advances in genome and metagenome sequencing have enabled studies of their chemistry and biology. Focusing on the glycyl radical enzyme family, one of the most enriched protein families in the human gut microbiota, we highlight different approaches for discovering radic...
Source: Current Opinion in Chemical Biology - September 27, 2018 Category: Biochemistry Authors: Levin BJ, Balskus EP Tags: Curr Opin Chem Biol Source Type: research

'Negative' and 'positive catalysis': complementary principles that shape the catalytic landscape of enzymes.
TJ Abstract Our understanding of enzyme catalysis is dominated by transition state theory. According to this concept, an enzymatic reaction is guided along a desired reaction coordinate through the stabilization of favorable transition state. But how much is the outcome of an enzyme reaction controlled by the destabilization of unwanted transition states? Here, we revive and critically review the hypothesis that the active site of enzymes also features elements of 'negative catalysis'. We provide examples that show that enzyme catalysis can be achieved by the combined action of positive and negative constraints a...
Source: Current Opinion in Chemical Biology - September 27, 2018 Category: Biochemistry Authors: Vögeli B, Erb TJ Tags: Curr Opin Chem Biol Source Type: research

Biocatalytic hydrogen atom transfer: an invigorating approach to free-radical reactions.
Abstract Initiating and terminating free-radical reactionis via hydrogen atom transfer (HAT) is an attractive means of avoiding substrate prefunctionalization. Small molecule catalysts and reagents, however, struggle to execute this fundamental step with useful levels of diastereoselectivity and enantioselectivity. In contrast, nature often carries out HAT with exquisite levels of selectivity for even electronically unactivated carbon-hydrogen bonds. By understanding how enzymes exploit and control this fundamental step, new strategies can be developed to address several long-standing challenges in free-radical re...
Source: Current Opinion in Chemical Biology - September 27, 2018 Category: Biochemistry Authors: Nakano Y, Biegasiewicz KF, Hyster TK Tags: Curr Opin Chem Biol Source Type: research

Enzymatic CH functionalizations for natural product synthesis.
Abstract Direct functionalization of CH bond is rapidly becoming an indispensible tool in chemical synthesis. However, due to the ubiquity of CH bonds, achieving site-selective functionalization remains an arduous task, especially on advanced synthetic intermediates or natural products. In contrast, Nature has evolved a multitude of enzymes capable of performing this task with extraordinary selectivity, and the use of these enzymes in organic synthesis may provide a viable solution to contemporary challenges in site-selective functionalization of complex molecules. This review covers recent applications of enzymat...
Source: Current Opinion in Chemical Biology - September 27, 2018 Category: Biochemistry Authors: Li F, Zhang X, Renata H Tags: Curr Opin Chem Biol Source Type: research

Strategies for designing non-natural enzymes and binders.
r B Abstract The design of tailor-made enzymes is a major goal in biochemical research that can result in wide-range applications and will lead to a better understanding of how proteins fold and function. In this review we highlight recent advances in enzyme and small molecule binder design. A focus is placed on novel strategies for the design of scaffolds, developments in computational methods, and recent applications of these techniques on receptors, sensors, and enzymes. Further, the integration of computational and experimental methodologies is discussed. The outlined examples of designed enzymes and binders f...
Source: Current Opinion in Chemical Biology - September 21, 2018 Category: Biochemistry Authors: Lechner H, Ferruz N, Höcker B Tags: Curr Opin Chem Biol Source Type: research

Reactive sulfur species (RSS): persulfides, polysulfides, potential, and problems.
Abstract Sulfur is a crucial element in biology due to its unique properties and wide range of accessible oxidation states. This reactivity gives rise to the generation of reactive sulfur species (RSS), which have emerged as a diverse class of small molecules and functional groups with important roles in chemical biology and bioinorganic chemistry. In this review, we focus on basic properties of simple RSS, highlight recent insights into the interconnectivity of RSS with reactive nitrogen species, and discuss recent advances in methods for RSS detection and measurement. Finally, we highlight key reactivity conside...
Source: Current Opinion in Chemical Biology - September 19, 2018 Category: Biochemistry Authors: Lau N, Pluth MD Tags: Curr Opin Chem Biol Source Type: research