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Telomeres are nucleoprotein structures that play a pivotal role in the protection and maintenance of eukaryotic chromosomes. Telomeres and the enzyme telomerase, which replenishes telomeric DNA lost during replication, are important factors necessary to ensure continued cell proliferation. Cell proliferation is also dependent on proper and efficient protein synthesis, which is carried out by ribosomes. Mutations in genes involved in either ribosome biogenesis or telomere biology result in cellular abnormalities and can cause human genetic diseases, defined as ribosomopathies and telomeropathies, respectively. Interestingly, recent discoveries indicate that many of the ribosome assembly and rRNA maturation factors have additional noncanonical functions in telomere biology. Similarly, several key proteins and enzymes involved in telomere biology, including telomerase, have unexpected roles in rRNA transcription and maturation. These observations point to an intriguing cross-talk mechanism potentially explaining the multiple pleiotropic symptoms of mutations in many causal genes identified in various telomeropathy and ribosomopathy diseases. In this review, we provide a brief summary of eukaryotic telomere and rDNA loci structures, highlight several universal features of rRNA and telomerase biogenesis, evaluate intriguing interconnections between telomere biology and ribosome assembly, and conclude with an assessment of overlapping features of human diseases of telomeropathies and ribosomopathies. Key words: rDNA, telomerase, ribonucleoprotein, ribosomal proteins, telomeropathy, ribosomopathy, Introduction Eukaryotic cells are very complex systems with numerous processes functioning simultaneously to support their normal growth and metabolism. Some of the most important cellular processes include the maintenance of [...]

Bibenzyls are a specialized metabolite class found throughout the plant kingdom. One of the most prolific producers of bibenzyls are liverworts, specifically plants of the Radula genera. These plants possess an incredible diversity of bibenzyls, prenylated bibenzyls, and a few (bis)bibenzyls, several of which have medicinal properties, including perrottetinene, an analog of tetrahydrocannabinol from cannabis. To provide insight into the bibenzyls' biosynthesis in planta, exogenous phytohormones were applied to in vitro grown Radula complanata and bibenzyl metabolite production was monitored with targeted and untargeted metabolomics. The targeted metabolomic analysis of six prenylated bibenzyls revealed that production of these metabolites was largely reduced when plants were treated with abscisic acid (AA), salicylic acid (SA), 1-naphthaleneacetic acid (NAA), or 6-benzylaminopurine (BAP). The reduction of these metabolites in the BAP and NAA treatment suggests that prenylated bibenzyl production is negatively correlated with vegetative plant growth. The reduction of bibenzyls at low AA and SA concentrations and mild increase at higher AA and SA concentrations suggest that their production is regulated by these stress hormones. In addition, six other bibenzyl metabolites were tentatively identified from the untargeted analysis. These results provide insight into the influence of phytohormones on the bioactive bibenzyl content of R. complanata. Key words: liverwort, Radula complanata, prenylated bibenzyl, specialized metabolism, phytohormones, metabolomics, Introduction Liverworts (Phylum Marchantiophyta) are a widely distributed phylum of nonvascular plants that fall under the bryophyte classification (Soderstrom et al. 2016). They are incredibly chemically diverse plants and possess [...]

Abstratct [beta]-Nicotinamide adenine dinucleotide ([beta]-NAD) is a pivotal metabolite for all living organisms and functions as a diffusible electron acceptor and carrier in the catabolic arms of metabolism.sup.1,2. Furthermore, [beta]-NAD is involved in diverse epigenetic, immunological and stress-associated processes, where it is known to be sacrificially utilized as an ADP-ribosyl donor for protein and DNA modifications, or the generation of cell-signalling molecules.sup.3,4. Here we report the function of [beta]-NAD in secondary metabolite biosynthetic pathways, in which the nicotinamide dinucleotide framework is heavily decorated and serves as a building block for the assembly of a novel class of natural products. The gatekeeping enzyme of the discovered pathway (SbzP) catalyses a pyridoxal phosphate-dependent [3+2]-annulation reaction between [beta]-NAD and S-adenosylmethionine, generating a 6-azatetrahydroindane scaffold. Members of this novel family of [beta]-NAD-tailoring enzymes are widely distributed in the bacterial kingdom and are encoded in diverse biosynthetic gene clusters. The findings of this work set the stage for the discovery and exploitation of [beta]-NAD-derived natural products. [beta]-Nicotinamide adenine dinucleotide is used as a building block in secondary metabolite biosynthetic pathways for a novel class of natural products., Author(s): Lena Barra [sup.1] , Takayoshi Awakawa [sup.1] [sup.2] , Kohei Shirai [sup.1] , Zhijuan Hu [sup.1] , Ghader Bashiri [sup.3] , Ikuro Abe [sup.1] [sup.2] Author Affiliations: (1) Graduate [...]

Hindered ethers are of high value for various applications; however, they remain an underexplored area of chemical space because they are difficult to synthesize via conventional reactions.sup.1,2. Such motifs are highly coveted in medicinal chemistry, because extensive substitution about the ether bond prevents unwanted metabolic processes that can lead to rapid degradation in vivo. Here we report a simple route towards the synthesis of hindered ethers, in which electrochemical oxidation is used to liberate high-energy carbocations from simple carboxylic acids. These reactive carbocation intermediates, which are generated with low electrochemical potentials, capture an alcohol donor under non-acidic conditions; this enables the formation of a range of ethers (more than 80 have been prepared here) that would otherwise be difficult to access. The carbocations can also be intercepted by simple nucleophiles, leading to the formation of hindered alcohols and even alkyl fluorides. This method was evaluated for its ability to circumvent the synthetic bottlenecks encountered in the preparation of 12 chemical scaffolds, leading to higher yields of the required products, in addition to substantial reductions in the number of steps and the amount of labour required to prepare them. The use of molecular probes and the results of kinetic studies support the proposed mechanism and the role of additives under the conditions examined. The reaction manifold that we report here demonstrates the power of electrochemistry to access highly reactive intermediates under mild conditions and, in turn, the substantial improvements in efficiency that can be achieved with these otherwise-inaccessible intermediates. A route to the synthesis of hindered ethers is developed, in which electrochemical oxidation is used to liberate high-energy carbocations that are then captured by an alcohol., Author(s): Jinbao Xiang [sup.1] [sup.2] , Ming Shang [sup.1] , Yu Kawamata [sup.1] , Helena Lundberg [sup.1] [sup.3] , Solomon H. Reisberg [sup.1] , Miao Chen [sup.1] , Pavel Mykhailiuk [...]

Living systems can generate an enormous range of cellular functions, from mechanical infrastructure and signalling networks to enzymatic catalysis and information storage, using a notably limited set of chemical functional groups. This observation is especially notable when compared to the breadth of functional groups used as the basis for similar functions in synthetically derived small molecules and materials. The relatively small cross-section between biological and synthetic reactivity space forms the foundation for the development of bioorthogonal chemistry, in which the absence of a pair of reactive functional groups within the cell allows for a selective in situ reaction.sup.1-4. However, biologically 'rare' functional groups, such as the fluoro.sup.5, chloro.sup.6,7, bromo.sup.7,8, phosphonate.sup.9, enediyne.sup.10,11, cyano.sup.12, diazo.sup.13, alkene.sup.14 and alkyne.sup.15-17 groups, continue to be discovered in natural products made by plants, fungi and microorganisms, which offers a potential route to genetically encode the endogenous biosynthesis of bioorthogonal reagents within living organisms. In particular, the terminal alkyne has found broad utility via the Cu(i)-catalysed azide-alkyne cycloaddition 'click' reaction.sup.18. Here we report the discovery and characterization of a unique pathway to produce a terminal alkyne-containing amino acid in the bacterium Streptomyces cattleya. We found that l-lysine undergoes an unexpected reaction sequence that includes halogenation, oxidative C-C bond cleavage and triple bond formation through a putative allene intermediate. This pathway offers the potential for de novo cellular production of halo-, alkene- and alkyne-labelled proteins and natural products from glucose for a variety of downstream applications. Microbial generation of a terminal-alkyne-containing amino acid can be encoded into E. coli and provides the potential for in vivo generation of proteins and natural products for click chemistry., Author(s): J. A. Marchand [sup.1] , M. E. Neugebauer [sup.1] , M. C. Ing [sup.2] , C.-I. Lin [sup.3] , J. G. Pelton [sup.4] , M. C. Y. Chang [sup.2] [...]

Cannabis sativa L. has been cultivated and used around the globe for its medicinal properties for millennia.sup.1. Some cannabinoids, the hallmark constituents of Cannabis, and their analogues have been investigated extensively for their potential medical applications.sup.2. Certain cannabinoid formulations have been approved as prescription drugs in several countries for the treatment of a range of human ailments.sup.3. However, the study and medicinal use of cannabinoids has been hampered by the legal scheduling of Cannabis, the low in planta abundances of nearly all of the dozens of known cannabinoids.sup.4, and their structural complexity, which limits bulk chemical synthesis. Here we report the complete biosynthesis of the major cannabinoids cannabigerolic acid, [DELTA].sup.9-tetrahydrocannabinolic acid, cannabidiolic acid, [DELTA].sup.9-tetrahydrocannabivarinic acid and cannabidivarinic acid in Saccharomyces cerevisiae, from the simple sugar galactose. To accomplish this, we engineered the native mevalonate pathway to provide a high flux of geranyl pyrophosphate and introduced a heterologous, multi-organism-derived hexanoyl-CoA biosynthetic pathway.sup.5. We also introduced the Cannabis genes that encode the enzymes involved in the biosynthesis of olivetolic acid.sup.6, as well as the gene for a previously undiscovered enzyme with geranylpyrophosphate:olivetolate geranyltransferase activity and the genes for corresponding cannabinoid synthases.sup.7,8. Furthermore, we established a biosynthetic approach that harnessed the promiscuity of several pathway genes to produce cannabinoid analogues. Feeding different fatty acids to our engineered strains yielded cannabinoid analogues with modifications in the part of the molecule that is known to alter receptor binding affinity and potency.sup.9. We also demonstrated that our biological system could be complemented by simple synthetic chemistry to further expand the accessible chemical space. Our work presents a platform for the production of natural and unnatural cannabinoids that will allow for more rigorous study of these compounds and could be used in the development of treatments for a variety of human health problems. Genetic engineering of yeast enables the production of cannabinoids and cannabinoid analogues from the simple sugar galactose, without the need to cultivate Cannabis., Author(s): Xiaozhou Luo [sup.1] , Michael A. Reiter [sup.1] [sup.2] , Leo d'Espaux [sup.3] [sup.12] , Jeff Wong [sup.3] [sup.12] , Charles M. Denby [sup.1] [sup.13] , Anna Lechner [sup.4] [...]

There is evidence to suggest that increasing the level of saturation (that is, the number of sp.sup.3-hybridized carbon atoms) of small molecules can increase their likelihood of success in the drug discovery pipeline.sup.1. Owing to their favourable physical properties, alkylamines have become ubiquitous among pharmaceutical agents, small-molecule biological probes and pre-clinical candidates.sup.2. Despite their importance, the synthesis of amines is still dominated by two methods: N-alkylation and carbonyl reductive amination.sup.3. Therefore, the increasing demand for saturated polar molecules in drug discovery has continued to drive the development of practical catalytic methods for the synthesis of complex alkylamines.sup.4-7. In particular, processes that transform accessible feedstocks into sp.sup.3-rich architectures provide a strategic advantage in the synthesis of complex alkylamines. Here we report a multicomponent, reductive photocatalytic technology that combines readily available dialkylamines, carbonyls and alkenes to build architecturally complex and functionally diverse tertiary alkylamines in a single step. This olefin-hydroaminoalkylation process involves a visible-light-mediated reduction of in-situ-generated iminium ions to selectively furnish previously inaccessible alkyl-substituted [alpha]-amino radicals, which subsequently react with alkenes to form C(sp.sup.3)-C(sp.sup.3) bonds. The operationally straightforward reaction exhibits broad functional-group tolerance, facilitates the synthesis of drug-like amines that are not readily accessible by other methods and is amenable to late-stage functionalization applications, making it of interest in areas such as pharmaceutical and agrochemical research.Complex tertiary alkylamines are prepared in one step from readily available amines, carbonyls and alkenes, via the visible-light-mediated reduction of in-situ-generated iminium ions to form alkyl-substituted [alpha]-amino radicals., Author(s): Aaron Trowbridge [sup.1] , Dominik Reich [sup.1] , Matthew J. Gaunt [sup.1] Author Affiliations:(1) Department of Chemistry, University of Cambridge, Cambridge, UKMain The physiological properties of tertiary aliphatic amines [...]

Large structures can be built from a microbial material with self-healing properties. Large structures can be built from a microbial material with self-healing properties., Author Affiliations: Bricks made of living organisms can be joined into a free-standing arch. Credit: R. M. McBee et al. / Nature Mater. An arch built out of building blocks [...]