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1. Expanding the thiol–X toolbox: photoinitiation and materials application of the acid-catalyzed thiol–ene (ACT) reaction

   https://doi.org/10.1039/D0PY01593H  

   Sutherland, Bryan P.; Kabra, Mukund; Kloxin, Christopher J. (March 2021, Polymer Chemistry)

   null (Ed.)

   The acid-catalyzed thiol–ene reaction (ACT) is a unique thiol–X conjugation strategy that produces S,X-acetal conjugates. Unlike the well-known radical-mediated thiol–ene and anion-mediated thiol-Michael reactions that produce static thioether bonds, acetals provide unique function for various fields such as drug delivery and protecting group chemistries; however, this reaction is relatively underutilized for creating new and unique materials owing to the unexplored reactivity over a broad set of substrates and potential side reactions. Solution-phase studies using a range of thiol and alkene substrates were conducted to evaluate the ACT reaction as a conjugation strategy. Substrates that efficiently undergo cationic polymerizations, such as those containing vinyl functional groups, were found to be highly reactive to thiols in the presence of catalytic amounts of acid. Additionally, sequential initiation of three separate thiol–X reactions (thiol-Michael, ACT, and thiol–ene) was achieved in a one-pot scheme simply by the addition of the appropriate catalyst demonstrating substrate selectivity. Furthermore, photoinitiation of the ACT reaction was achieved for the first time under 470 nm blue light using a novel photochromic photoacid. Finally, using multifunctional monomers, solid-state polymer networks were formed using the ACT reaction producing acetal crosslinks. The presence of S,X-acetal bonds results in an increased glass transition temperature of 20 °C as compared with the same polymeric film polymerized through the radical thiol–ene mechanism. This investigation demonstrates the broad impact of the ACT reaction and expands upon the diverse thiol–X library of conjugation strategies towards the development of novel materials systems. 

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2. Catalytic synthesis of azoarenes via metal-mediated nitrene coupling

   https://doi.org/10.1039/D2DT00228K  

   Kurup, Sudheer S.; Groysman, Stanislav (March 2022, Dalton Transactions)

   Various valuable properties of azoarenes (“azo dyes”), including their vivid colors and their facile cis – trans photoisomerization, lead to their wide use in the chemical industry. As a result, ∼700 000 metric tons of azo dyes are produced each year. Most currently utilized synthetic methods towards azoarenes involve harsh reaction conditions and/or toxic reagents in stoichiometric amounts, which may affect selectivity and produce significant amounts of waste. An efficient alternative method towards this functional group includes transition metal catalyzed nitrene coupling. This method is generally more sustainable compared with most stoichiometric methods as it uses only catalytic amounts of co-reactants (metal catalysts), requires easily synthesizable organoazide precursors, and forms only dinitrogen as a by-product of catalysis. During the last decade, several catalytic systems were reported, and their reactivity was investigated. This perspective article will review these systems, focusing on various nitrene coupling mechanisms, and the substrate scope for each system. Particular attention will be devoted to the iron-alkoxide catalytic systems investigated in the PI's laboratory. The design and structural features of several generations of iron bis(alkoxide) complexes will be discussed, followed by the structure–activity studies of these catalysts in nitrene homo- and heterocoupling. 

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3. Molecularly imprinted artificial esterases with highly specific active sites and precisely installed catalytic groups

   https://doi.org/10.1039/C8OB01584H  

   Hu, Lan; Zhao, Yan (January 2018, Organic & Biomolecular Chemistry)

   A difficult challenge in synthetic enzymes is the creation of substrate-selective active sites with accurately positioned catalytic groups. Covalent molecular imprinting in cross-linked micelles afforded such active sites in protein-sized, water-soluble nanoparticle catalysts. Our method allowed a systematic tuning of the distance of the catalytic group to the bound substrate. The catalysts displayed enzyme-like kinetics and easily distinguished substrates with subtle structural differences. 

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4. De novo design of luciferases using deep learning

   https://doi.org/10.1038/s41586-023-05696-3  

   Yeh, Andy Hsien-Wei; Norn, Christoffer; Kipnis, Yakov; Tischer, Doug; Pellock, Samuel J.; Evans, Declan; Ma, Pengchen; Lee, Gyu Rie; Zhang, Jason Z.; Anishchenko, Ivan; et al (February 2023, Nature)

   Abstract De novo enzyme design has sought to introduce active sites and substrate-binding pockets that are predicted to catalyse a reaction of interest into geometrically compatible native scaffolds^1,2, but has been limited by a lack of suitable protein structures and the complexity of native protein sequence–structure relationships. Here we describe a deep-learning-based ‘family-wide hallucination’ approach that generates large numbers of idealized protein structures containing diverse pocket shapes and designed sequences that encode them. We use these scaffolds to design artificial luciferases that selectively catalyse the oxidative chemiluminescence of the synthetic luciferin substrates diphenylterazine³and 2-deoxycoelenterazine. The designed active sites position an arginine guanidinium group adjacent to an anion that develops during the reaction in a binding pocket with high shape complementarity. For both luciferin substrates, we obtain designed luciferases with high selectivity; the most active of these is a small (13.9 kDa) and thermostable (with a melting temperature higher than 95 °C) enzyme that has a catalytic efficiency on diphenylterazine (k_cat/K_m = 10⁶ M⁻¹ s⁻¹) comparable to that of native luciferases, but a much higher substrate specificity. The creation of highly active and specific biocatalysts from scratch with broad applications in biomedicine is a key milestone for computational enzyme design, and our approach should enable generation of a wide range of luciferases and other enzymes. 

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5. Structural basis for divergent and convergent evolution of catalytic machineries in plant aromatic amino acid decarboxylase proteins

   https://doi.org/10.1073/pnas.1920097117  

   Torrens-Spence, Michael P.; Chiang, Ying-Chih; Smith, Tyler; Vicent, Maria A.; Wang, Yi; Weng, Jing-Ke (May 2020, Proceedings of the National Academy of Sciences)

   Radiation of the plant pyridoxal 5′-phosphate (PLP)-dependent aromaticl-amino acid decarboxylase (AAAD) family has yielded an array of paralogous enzymes exhibiting divergent substrate preferences and catalytic mechanisms. Plant AAADs catalyze either the decarboxylation or decarboxylation-dependent oxidative deamination of aromaticl-amino acids to produce aromatic monoamines or aromatic acetaldehydes, respectively. These compounds serve as key precursors for the biosynthesis of several important classes of plant natural products, including indole alkaloids, benzylisoquinoline alkaloids, hydroxycinnamic acid amides, phenylacetaldehyde-derived floral volatiles, and tyrosol derivatives. Here, we present the crystal structures of four functionally distinct plant AAAD paralogs. Through structural and functional analyses, we identify variable structural features of the substrate-binding pocket that underlie the divergent evolution of substrate selectivity toward indole, phenyl, or hydroxyphenyl amino acids in plant AAADs. Moreover, we describe two mechanistic classes of independently arising mutations in AAAD paralogs leading to the convergent evolution of the derived aldehyde synthase activity. Applying knowledge learned from this study, we successfully engineered a shortened benzylisoquinoline alkaloid pathway to produce (S)-norcoclaurine in yeast. This work highlights the pliability of the AAAD fold that allows change of substrate selectivity and access to alternative catalytic mechanisms with only a few mutations. 

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