Regiospecific hydroxylase and O-methyltransferase for the biosynthesis of anticancer alkaloids in Tabernaemontana elegans (toad tree).

Monoterpenoid indole alkaloids (MIAs) are a structurally diverse class natural products with significant medicinal properties. Bis-MIAs, such as chemotherapeutic vinblastine and anti-autophagic conodurine, are synthesized through enzymatic coupling of monomeric MIAs, often requiring specific modifications to activate reactive centers. In this study, we report the identification and characterization of a regiospecific enzyme pair, coronaridine 11-hydroxylase (TeC11H) and 11-hydroxycoronaridine O-methyltransferase (TeHCOMT), from Tabernaemontana elegans (toad tree).

Promiscuous and regiospecific Vinca minor hydroxylases for opioid akuammine biosynthesis and monoterpenoid indole alkaloid diversification.

The medicinal plant Vinca minor produces vincamine, a compound used for neurodegenerative diseases, along with a diverse array of monoterpenoid indole alkaloids (MIAs) primarily within the aspidosperma and akuammiline subclasses. While recent studies have elucidated the core biosynthetic pathways for these subclasses, the transformations of key intermediates into the vast diversity of naturally occurring alkaloids remain poorly understood. In this study, we identify and characterize two promiscuous cytochrome P450 monooxygenases (CYPs) in V.

Parallel evolution of methyltransferases leads to vobasine biosynthesis in and .

Monoterpenoid indole alkaloids (MIA) are one of the largest and most complex alkaloid class in nature, boasting many clinically significant drugs such as anticancer vinblastine and antiarrhythmic ajmaline. Many MIAs undergo nitrogen -methylation, altering their reactivity and affinity to the biological targets through a straightforward reaction. Remarkably, all known MIA -methyltransferases (NMT) originate from the neofunctionalization of ancestral γ-tocopherol -methyltransferases (γTMTs), a phenomenon seemingly unique to the Apocynaceae family.

Bent Bond/Antiperiplanar Hypothesis and the Chemical Reactivity of Annulenes.

The properties and stereochemical reactivity of cyclobutadiene, benzene, cyclooctatetraene, and the [10]- to [14]annulenes can be uniformly rationalized through the bent bond/antiperiplanar hypothesis (BBAH). This new orbital model considers electronic delocalization between pyramidal diradical resonance structures and associated bent bonds, as it applies to aromatic, nonaromatic, and antiaromatic molecules.

Bent Bond/Antiperiplanar Hypothesis: Modulating the Reactivity and the Selectivity in the Glycosylation of Bicyclic Pyranoside Models.

Glycosylation reactions were performed on a series of bicyclic C-substituted pyranoside models to isolate and analyze factors that control the glycosylation stereoselectivities observed in carbohydrates. The bent bond/antiperiplanar hypothesis (BBAH) orbital model rationalizes all of these results by considering hyperconjugation interactions between groups at C and the two τ bonds (bent bonds) of oxocarbenium ion intermediates formed under the glycosylation conditions. According to the BBAH, nucleophiles add to oxocarbenium intermediates by S2-like antiperiplanar displacement of the weaker of their two τ bonds.

Matrix Metalloproteinase 13 Activity is Required for Normal and Hypoxia-Induced Precocious Hatching in Zebrafish Embryos.

Hypoxia induces precocious hatching in zebrafish, but we do not have a clear understanding of the molecular mechanisms regulating the activation of the hatching enzyme or how these mechanisms trigger precocious hatching under unfavorable environmental conditions. Using immunohistochemistry, pharmacological inhibition of matrix metalloproteinase 13 (Mmp13), and in vivo zymography, we show that Mmp13a is present in the hatching gland just as embryos become hatching competent and that Mmp13a activity is required for both normal hatching and hypoxia-induced precocious hatching. We conclude that Mmp13a likely functions in activating the hatching enzyme zymogen and that Mmp13a activity is necessary but not sufficient for hatching in zebrafish.

Applying the Bent Bond/Antiperiplanar Hypothesis to the Stereoselective Glycosylation of Bicyclic Furanosides.

The glycosylation stereoselectivities for a series of bicyclic furanoside models have been carried out in the presence of weak nucleophiles. These results were analyzed through the bent bond/antiperiplanar hypothesis (BBAH) orbital model to test its validity. According to the BBAH, incoming nucleophiles displace one of the two bent bonds of bicyclic oxocarbenium ion intermediates in an antiperiplanar fashion.

Thermal rearrangement of optically active tetradeuterated 2-methoxymethyl-methylenecyclopropane and the bent bond/antiperiplanar hypothesis.

The thermolysis of an optically active tetradeuterated 2-methoxymethyl methylenecyclopropane produces a specific ratio of eight possible rearrangement stereoisomers. Despite numerous efforts, this reaction and other similar transformations have defied mechanistic interpretation until now. The direct application of the bent bond/antiperiplanar hypothesis (BBAH) to this reaction produces a mechanistic model that rationalizes all the observed reaction kinetics and products.

Bent Bonds and the Antiperiplanar Hypothesis. A Model To Account for Sigmatropic [1, n]-Hydrogen Shifts.

The bent bond/antiperiplanar hypothesis (BBAH) is used to propose a mechanism-based orbital model for the facial selectivity of sigmatropic hydrogen shifts under both thermal and photochemical conditions. The BBAH analysis of these concerted rearrangements invokes transient vibrationally excited singlet diradicals in both 4 n and 4 n+2 polyenes.

Bent Bonds (τ) and the Antiperiplanar Hypothesis-The Chemistry of Cyclooctatetraene and Other CH Isomers.

The bent bond/antiperiplanar hypothesis (BBAH) has been applied to the thermal rearrangements of cyclooctatetraene and related CH isomers. This novel orbital model shows that pyramidal singlet diradical intermediates produced from thermal vibrational states of CH isomers account for their chemical reactivity.

Bent bonds and the antiperiplanar hypothesis - a simple model to rationalize [1,3]-sigmatropic alkyl shifts.

The bent bond/antiperiplanar (BBA) hypothesis has been applied to the analysis of [1,3]-sigmatropic alkyl shifts. These thermal rearrangements, for which there is evidence that they proceed through diradical intermediates, can be interpreted by considering their transient allyl radical structures. For the thermolysis of cyclic molecules, the preferred generation of pyramidal allyl radicals in staggered conformations is postulated on the basis of the BBA hypothesis.

Crystallographic snapshot of an arrested intermediate in the biomimetic activation of CO2.

The design of molecular catalysts that mimic the behavior of enzymes is a topical field of activity in emerging technologies, and can lead to an improved understanding of biological systems. Herein, we report how the bulky arms of the cations in [(n C4 H9 )4 N](+) [HCO3 ](-) give rise to a host scaffold that emulates the substrate binding sites in carbonic anhydrase enzymes, affording a unique glimpse of an arrested intermediate in the base-mediated binding and activation of CO2 .

When do spatial abilities support student comprehension of STEM visualizations?

Spatial visualization abilities are positively related to performance on science, technology, engineering, and math tasks, but this relationship is influenced by task demands and learner strategies. In two studies, we illustrate these interactions by demonstrating situations in which greater spatial ability leads to problematic performance. In Study 1, chemistry students observed and explained sets of simultaneously presented displays depicting chemical phenomena at macroscopic and particulate levels of representation.

Bent bonds, the antiperiplanar hypothesis and the theory of resonance. A simple model to understand reactivity in organic chemistry.

By taking into consideration bent bonds (τ-bonds, tau-bonds), the antiperiplanar hypothesis, the classic theory of resonance, and the preference for staggered bonds over eclipsed bonds in tetrahedral systems, a simple qualitative model is presented to rationalize the conformation and reactivity for a wide range of compounds containing double bonds and/or carbonyl groups. Alkenes, carbonyl and carboxyl derivatives, conjugated systems as well as other functional groups are revisited. This also leads to a simple model to understand aromaticity, and electrocyclic reactions.

Reverse-docking study of the TADDOL-catalyzed asymmetric hetero-Diels-Alder reaction.

The reverse-docking of a TADDOL catalyst to rigid transition-state (TS) representations of an asymmetric hetero-Diels-Alder reaction is described. The resulting docking poses represent a simplified geometric model of the TS for the catalyzed reaction. The conformational space of the catalyst in proximity to the catalyst-free TS models is sampled stochastically and the energetically favored poses are subjected to a clustering procedure to highlight structural attributes compatible with organocatalysis.

Reverse-docking as a computational tool for the study of asymmetric organocatalysis.

A novel methodology for 'reverse-docking' a cationic peptide-based organocatalyst to a rigid anionic transition state (TS) model for the conjugate addition of azide to alpha,beta-unsaturated carbonyl substrates is described. The resulting docking poses serve as simplified TS models for enantioselective catalysis. Molecular mechanics-based scoring and ranking of the docking poses, followed by clustering and structural analysis, reveal a clear energetic preference for docking to the S-enantiomeric azidation TS model, in agreement with experiment.

Dual binding mode of methylmethanetriacetic Acid to tripodal amidopyridine receptors.

A series of tripodal amidopyridine receptors capable of selective recognition of methylmethanetriacetic acid (MMTA) in organic solvents is described. Intramolecular hydrogen-bonding groups, built into some of the receptors, were designed as preorganization devices. Binding was studied by NMR titration, variable temperature NMR experiments, 2D-NMR, isothermal titration calorimetry, and single-crystal X-ray crystallography.