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Current Opinion in Chemical Biology

Sumedh Joshi, Dmytro Fedoseyenko, Nilkamal Mahanta, Hannah Manion, Saad Naseem, Tohru Dairi, Tadhg P Begley
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...
November 14, 2018: Current Opinion in Chemical Biology
Ruijie K Zhang, Xiongyi Huang, Frances H Arnold
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...
October 18, 2018: Current Opinion in Chemical Biology
Katelyn C Cook, Ileana M Cristea
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 virus replication...
October 16, 2018: Current Opinion in Chemical Biology
Ioannis Zachos, Claudia Nowak, Volker Sieber
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 used to run biocatalytic reactions...
October 15, 2018: Current Opinion in Chemical Biology
Ana S Luis, Eric C Martens
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 detail...
October 13, 2018: Current Opinion in Chemical Biology
David Leys
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 isomerization...
October 13, 2018: Current Opinion in Chemical Biology
Spiros S Skourtis, David N Beratan
No abstract text is available yet for this article.
October 11, 2018: Current Opinion in Chemical Biology
Matthew Pasek
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...
October 10, 2018: Current Opinion in Chemical Biology
Damaris Bausch-Fluck, Emanuela Sara Milani, Bernd Wollscheid
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 extracellular cues into intracellular responses and vice versa...
October 8, 2018: Current Opinion in Chemical Biology
Sandra Pankow, Salvador Martínez-Bartolomé, Casimir Bamberger, John R Yates
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.
October 8, 2018: Current Opinion in Chemical Biology
Stijn H Peeters, Laura van Niftrik
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...
October 8, 2018: Current Opinion in Chemical Biology
Nunzia Picone, Huub Jm Op den Camp
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...
October 8, 2018: Current Opinion in Chemical Biology
Arnold J Bloom
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 balance under rising atmospheric CO2 concentrations...
October 5, 2018: Current Opinion in Chemical Biology
Nico Kreß, Julia M Halder, Lea R Rapp, Bernhard Hauer
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...
October 4, 2018: Current Opinion in Chemical Biology
Valérie de Crécy-Lagard, Drago Haas, Andrew D Hanson
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...
September 28, 2018: Current Opinion in Chemical Biology
Michael P Ledbetter, Floyd E Romesberg
No abstract text is available yet for this article.
September 27, 2018: Current Opinion in Chemical Biology
Fuzhuo Li, Xiao Zhang, Hans Renata
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...
September 27, 2018: Current Opinion in Chemical Biology
Yuji Nakano, Kyle F Biegasiewicz, Todd K Hyster
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 reactions...
September 27, 2018: Current Opinion in Chemical Biology
Bastian Vögeli, Tobias J Erb
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 at the active site of an enzyme...
September 27, 2018: Current Opinion in Chemical Biology
Benjamin J Levin, Emily P Balskus
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 radical-dependent enzymes that influence host health and disease...
September 27, 2018: Current Opinion in Chemical Biology
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