An emergent biosynthetic pathway to essential amino acids by metabolic metathesis

International audienceAbstract An experimental approach to implanting foreign chemical reactions into living cells is to select for the catalytic production of a vital building-block such as an amino acid. Alkene metathesis is unknown in extant biochemistry, but is emerging as a new type of reaction to be catalyzed by protein enzymes. Here we show how the alkenic amino acid vinylglycine can be generated in a biocompatible reaction from 5-allyloxy-2-amino-pent-3-enoate (APE) by ring-closing metathesis catalyzed by a standard Hoveyda-Grubbs catalyst. The vinylglycine produced in situ is then used as a precursor of isoleucine and methionine, thus allowing the growth of strains of Escherichia coli requiring these essential amino acids. The robust nutritional screen we have developed paves the way for the directed evolution of genetically encoded metathesis enzymes and the chemical elaboration of metathesis coenzymes

Extension of the Bambus[<i>n</i>]uril Family: Microwave Synthesis and Reactivity of Allylbambus[<i>n</i>]urils

Microwave irradiations allow the preparation of unsaturated bambusurils in 85% yield compared to 20% yield under classical reaction conditions. Five new bambusurils were synthesized including unsaturated derivatives Allyl₈BU[4] and Allyl₁₂BU[6] bearing diallylglycoluril units. The reactivity of Allyl₈BU[4] was tested in a variety of organic reactions showing that this macrocycle acts as a classical double bond-bearing product. The first monofunctionalized bambusuril Allyl₇HepBU[4] prepared by a cross metathesis reaction is also reported

Cucurbit[5]uril derivatives as oxygen carriers

International audienceCucurbit[n]urils are rigid cage-molecules of pumpkin-like shape, made of n-glycoluril units, able to bind mainly neutral molecules and cations. In this work, we investigate the binding of three cucurbit[5]uril derivatives with dioxygen O$_2$ and show that one of them, namely per-hydroxylated cucurbit[5]uril, (OH)$_{10}$CB[5], is able to significantly bind dioxygen gas at physiological temperature, even in the presence of sodium chloride at the concentration of injectable solution in blood. As cucurbit[n]urils studied up to now reveal low toxicity, per-hydroxylated cucurbit[5]uril appears as a promising precursor to design a host able to transport O$_2$ in a haemoglobin substitute solution

Clickable Bambusurils to Access Multivalent Architectures

Publisher: American Chemical SocietyInternational audiencePropargylated bambus[4,6]urils were prepared by an efficient one-step condensation of dipropargylglycoluril with formaldehyde under microwave irradiation. Their functionalization by click chemistry (CuAAC) afforded new multivalent architectures decorated with 8 or 12 ligands. Grafting of glycosides provided water-soluble glycobambus[4,6]uril platforms with glucosyl12BU[6] showing good affinity toward iodide anion in aqueous medium

Incorporation of Amino Acids with Long-Chain Terminal Olefins into Proteins

The increasing need for site-specific protein decorations that mimic natural posttranslational modifications requires access to a variety of noncanonical amino acids with moieties enabling bioorthogonal conjugation chemistry. Here we present the incorporation of long-chain olefinic amino acids into model proteins with rational variants of pyrrolysyl-tRNA synthetase (PylRS). Nε-heptenoyl lysine was incorporated for the first time using the known promiscuous variant PylRS(Y306A/Y384F), and Nε-pentenoyl lysine was incorporated in significant yields with the novel variant PylRS(C348A/Y384F). This is the only example of rational modification at position C348 to enlarge the enzyme’s binding pocket. Furthermore, we demonstrate the feasibility of our chosen amino acids in the thiol-ene conjugation reaction with a thiolated polysaccharide

Functionalization of Bambusurils by a thiol-ene click reaction and a facile method for the preparation of anion-free Bambus[6]urils

International audienceNew sulfide‐functionalized bambus[4]urils ((RS)$_8$BU[4]) and bambus[6]urils ((RS)$_{12}$BU[6]) have been synthesized through thiol‐ene click coupling reactions (TEC) of allylbambus[n]urils. Synthesis of BU[6] derivatives always requires the use of a template anion (iodide, chloride or bromide) which is enclosed in the cavity of BU[6]. We show that this anion influences the reactivity of bambus[6]urils. An encapsulated iodide makes allyl functions of allyl$_{12}$BU[6] less reactive towards TEC and hydrogenation reactions in comparison to the corresponding chloride or bromide inclusion complexes. This is critical for the chemical reactivity of BU[6] and even more to determine their anion‐binding properties. We report a new, facile and fast method using AgSbF$_6$ to prepare anion‐free BU[6]. NMR methods were used to estimate association constants of these new empty BU[6] with different anions. Quantum chemistry calculations were employed to rationalize the observed results. These new functionalized bambusuril scaffolds in alternate conformation could find applications as multivalent binders

Incorporation of Amino Acids with Long-Chain Terminal Olefins into Proteins

The increasing need for site-specific protein decorations that mimic natural posttranslational modifications requires access to a variety of noncanonical amino acids with moieties enabling bioorthogonal conjugation chemistry. Here we present the incorporation of long-chain olefinic amino acids into model proteins with rational variants of pyrrolysyl-tRNA synthetase (PylRS). Nε-heptenoyl lysine was incorporated for the first time using the known promiscuous variant PylRS(Y306A/Y384F), and Nε-pentenoyl lysine was incorporated in significant yields with the novel variant PylRS(C348A/Y384F). This is the only example of rational modification at position C348 to enlarge the enzyme's binding pocket. Furthermore, we demonstrate the feasibility of our chosen amino acids in the thiol-ene conjugation reaction with a thiolated polysaccharide.status: publishe

Influence of polygenic risk scores for schizophrenia and resilience on the cognition of individuals at-risk for psychosis

International audienceCognitive impairment is a core feature of schizophrenia which precedes the onset of full psychotic symptoms, even in the ultrahigh-risk stage (UHR). Polygenic risk scores (PRS) can be computed for many psychiatric disorders and phenotyping traits, including scores for resilience. We explored the correlations between several PRS and neurocognition in UHR individuals. We included 107 UHR individuals; 29.9% of them converted to psychosis (UHR-C) while 57.0% did not (UHR-NC) during the 1-year follow-up. Cognitive performances were assessed with the Wechsler Adult Intelligence Scale estimating the Intelligence Quotient (IQ), the Trail Making Test, the verbal fluency, the Stroop test, and the Wisconsin card sorting test. Linear regression models were used to test their association with the PRS for schizophrenia, bipolar disorder, major depression, ADHD, cross-disorders, cognitive performance, intelligence, education attainment, and resilience to schizophrenia. UHR-C had a lower IQ than UHR-NC. The PRS for schizophrenia negatively correlated with IQ, while the PRS for cognitive performance and for resilience positively correlated with IQ. PRS for schizophrenia showed a significant correlation with working memory and processing speed indices. PRS for schizophrenia showed a higher effect on IQ in UHR-NC, and UHR-NC with high PRS for schizophrenia had a similar IQ as UHR-C. Conversely, UHR-C with a high PRS for resilience performed as well as UHR-NC. Our findings suggest that cognitive deficits may predate the onset of psychosis. The genetic architecture of schizophrenia seems to impacts the cognition in UHR-NC. Cognition is also mediated by PRS for resilience

Synthesis and Enzymatic Conversion of Amino Acids Equipped with the Silanetriol Functionality: A Prelude to Silicon Biodiversification

Abstract Synthetic routes are reported for the three analogues of the simplest L‐2‐amino‐dicarboxylic acids, aspartate, glutamate, and aminoadipate, in which the silanetriol group (Si(OH)3) replaces the distal carboxyl group (CO2H). Direct access to the silanetriol amino acids relied either on catalytic hydrosilylation of a terminal alkene using triethoxysilane, or on alkylation of a glycine equivalent anion by triallyl(iodomethyl)silane. In both cases, acid hydrolysis afforded the silanetriol amino acids. These were shown to self‐assemble into siloxane Si‐O clusters as their concentration in water increased in the pH range of 1–12. Such reversible cross‐linking did not prevent silanetriol amino acids from serving as substrates of an aminotransferase enzyme, boding well for their utilization as microbial nutrients to encompass silicon in future stages of metabolism and polypeptide edifices