Natural Building Blocks Research Articles

Syn-Propanethial S-Oxide as an Available Natural Building Block for the Preparation of Nitro-Functionalized, Sulfur-Containing Five-Membered Heterocycles: An MEDT Study.

The regio- and stereoselectivity and the molecular mechanisms of the [3 + 2] cycloaddition reactions between Syn-propanethial S-oxide and selected conjugated nitroalkenes were explored theoretically in the framework of the Molecular Electron Density Theory. It was found that cycloadditions with the participation of nitroethene as well as its methyl- and chloro-substituted analogs can be realized via a single-step mechanism. On the other hand, [3 + 2] cycloaddition reactions between Syn-propanethial S-oxide and 1,1-dinitroethene can proceed according to a stepwise mechanism with a zwitterionic intermediate. Finally, we evaluated the affinity of model reaction products for several target proteins: cytochrome P450 14α-sterol demethylase CYP51 (RSCB Database PDB ID: 1EA1), metalloproteinase gelatinase B (MMP-9; PDB ID: 4XCT), and the inhibitors of cyclooxygenase COX-1 (PDB:3KK6) and COX-2 (PDB:5KIR).

Noncanonical Amino Acids: Bringing New-to-Nature Functionalities to Biocatalysis.

Biocatalysis has become an important component of modern organic chemistry, presenting an efficient and environmentally friendly approach to synthetic transformations. Advances in molecular biology, computational modeling, and protein engineering have unlocked the full potential of enzymes in various industrial applications. However, the inherent limitations of the natural building blocks have sparked a revolutionary shift. In vivo genetic incorporation of noncanonical amino acids exceeds the conventional 20 amino acids, opening new avenues for innovation. This review provides a comprehensive overview of applications of noncanonical amino acids in biocatalysis. We aim to examine the field from multiple perspectives, ranging from their impact on enzymatic reactions to the creation of novel active sites, and subsequent catalysis of new-to-nature reactions. Finally, we discuss the challenges, limitations, and promising opportunities within this dynamic research domain.

Fine Structural Analysis of Degummed Fibroin Fibers Reveals Its Superior Mechanical Capabilities.

Bombyx mori silk fibroin fibers constitute a class of protein building blocks capable of functionalization and reprocessing into various material formats. The properties of these fibers are typically affected by the intense thermal treatments needed to remove the sericin gum coating layer. Additionally, their mechanical characteristics are often misinterpreted by assuming the asymmetrical cross-sectional area (CSA) as a perfect circle. The thermal treatments impact not only the mechanics of the degummed fibroin fibers, but also the structural configuration of the resolubilized protein, thereby limiting the performance of the resulting silk-based materials. To mitigate these limitations, we explored varying alkali conditions at low temperatures for surface treatment, effectively removing the sericin gum layer while preserving the molecular structure of the fibroin protein, thus, maintaining the hierarchical integrity of the exposed fibroin microfiber core. The precise determination of the initial CSA of the asymmetrical silk fibers led to a comprehensive analysis of their mechanical properties. Our findings indicate that the alkali surface treatment raised the Young's modulus and tensile strength, by increasing the extent of the fibers' crystallinity, by approximately 40 % and 50 %, respectively, without compromising their strain. Furthermore, we have shown that this treatment facilitated further production of high-purity soluble silk protein with rheological and self-assembly characteristics comparable to those of native silk feedstock, initially stored in the animal's silk gland. The developed approaches benefits both the development of silk-based materials with tailored properties and the proper mechanical characterization of asymmetrical fibrous biological materials made of natural building blocks.

Mind the Particle Rigidity: Blooms the Bioavailability via Rapidly Crossing the Mucus Layer and Alters the Intracellular Fate of Curcumin.

Overcoming intestinal epithelial barriers to enhance bioavailability is a major challenge for oral delivery systems. Desirable nanocarriers should simultaneously exhibit rapid mucus penetration and efficient epithelial uptake; however, they two generally require contradictory structural properties. Herein, we proposed a strategy to construct multiperformance nanoparticles by modifying the rigidity of amphiphilic nanostructures originating from soy polypeptides (SPNPs), where its ability to overcome multibarriers was examined from both in vitro and in vivo, using curcumin (CUR) as a model cargo. Low-rigidity SPNPs showed higher affinity to mucin and were prone to getting stuck in the mucus layer. When they reached epithelial cells, they tended to be endocytosed through the clathrin and macropinocytosis pathways and further transferred to lysosomes, showing severe degradation and lower transport of CUR. Increased particle rigidity generally improved the absorption of CUR, with medium-rigidity SPNPs bloomed maximum plasma concentration of CUR by 80.62-fold and showed the highest oral bioavailability. Results from monocultured and cocultured cell models demonstrated that medium-rigidity SPNPs were least influenced by the mucus layer and changes in rigidity significantly influenced the endocytosis and intracellular fate of SPNPs. Those with higher rigidity preferred to be endocytosed via a caveolae-mediated pathway and trafficked to the ER and Golgi, facilitating their whole transcytosis, and avoiding intracellular metabolism. Moreover, rigidity modulation efficiently induces the reversible opening of intercellular tight junctions, which synergistically improves the transport of CUR into blood circulation. This study suggested that rigidity regulation on food originated amphiphilic peptides could overcome multiple physiological barriers, showing great potential as natural building block toward oral delivery.

Conformational control over proton-coupled electron transfer in metalloenzymes.

From the reduction of dinitrogen to the oxidation of water, thechemical transformations catalysed by metalloenzymes underlie global geochemical and biochemical cycles. These reactions represent some of the most kinetically and thermodynamically challenging processes knownand require the complex choreography of the fundamental building blocks of nature, electrons and protons, to be carried out with utmost precision and accuracy. The rate-determining step of catalysis in many metalloenzymes consists of aprotein structural rearrangement, suggestingthat nature has evolved to leverage macroscopic changes in protein molecularstructure to control subatomicchanges in metallocofactor electronicstructure. The proton-coupled electron transfermechanisms operative in nitrogenase, photosystem II and ribonucleotide reductase exemplify this interplay between molecular and electronic structural control. We present the culmination of decades of study on each of these systems and clarify what is known regarding the interplay between structural changesand functional outcomes in these metalloenzyme linchpins.

Engineering advanced cellulosics for enhanced triboelectric performance using biomanufactured proteins

Biological polymers, such as polysaccharides and polypeptides, offer renewable and biodegradable solutions for a more sustainable future. These polymers comprise natural building blocks, such as amino acids and glycans, which ensure their true environmental benefits at the end of their lifecycle. For example, cellulose is a highly sustainable material with many excellent properties, including renewability, biodegradability, and versatility in its functionality. It can be used in various forms, such as textiles, packaging materials, and building insulation. Here, we studied advanced cellulosic materials produced by blending or creating bi-composites with biomanufactured proteins inspired by squid ring teeth (SRT). Biomanufactured proteins can be synthesized in larger quantities, have a controlled production process, be modified to create desirable variants, and their production can be scaled up or down. Specifically, we engineered recombinant SRT proteins to have high electrostatic charge, induce crystallinity, and provide polar hydroxyl groups, which enhances cellulosic materials’ triboelectric response. The triboelectric voltage of blend triacetate and cellulose fibers increased by 72–108% and 49–57%, respectively, with a protein content of 10% wt. Furthermore, coating proteins on cellulosic fibers to create bi-composite fibers is a highly effective method for doubling (200%) the triboelectric performance. This finding has important implications for developing sustainable triboelectric materials and producing advanced materials using biomanufacturing.

Biocatalytic stereocontrolled head-to-tail cyclizations of unbiased terpenes as a tool in chemoenzymatic synthesis

Terpene synthesis stands at the forefront of modern synthetic chemistry and represents the state-of-the-art in the chemist’s toolbox. Notwithstanding, these endeavors are inherently tied to the current availability of natural cyclic building blocks. Addressing this limitation, the stereocontrolled cyclization of abundant unbiased linear terpenes emerges as a valuable tool, which is still difficult to achieve with chemical catalysts. In this study, we showcase the remarkable capabilities of squalene-hopene cyclases (SHCs) in the chemoenzymatic synthesis of head-to-tail-fused terpenes. By combining engineered SHCs and a practical reaction setup, we generate ten chiral scaffolds with >99% ee and de, at up to decagram scale. Our mechanistic insights suggest how cyclodextrin encapsulation of terpenes may influence the performance of the membrane-bound enzyme. Moreover, we transform the chiral templates to valuable (mero)-terpenes using interdisciplinary synthetic methods, including a catalytic ring-contraction of enol-ethers facilitated by cooperative iodine/lipase catalysis.

Self-Evolving Hierarchical Hydrogel Fibers with Circadian Rhythms and Memory Functions.

The fusion of hierarchical tissues at interfaces, incorporating ultrafast selective transport channels, enables efficient matter exchange and energy transfer across multiscale structures in living organisms. However, achieving these characteristics simultaneously in an artificial multimaterial system is challenging. Here, this work presents a multimaterial hydrogel fiber with a hierarchical structure of interface fusion, which forms spontaneously through in situ hierarchy evolution induced by ionic cross-linking and molecular shear flow. Water transport occurs in the angstrom-scale confined slits created by aligned cellulose nanocrystals (CNCs) by direct Coulomb knock-on, resembling Newton's cradle motion. The fusion of interfaces enables high-efficiency water transport across multiscale layers, combined with Newton's cradle-like collective water motion, creating a highly sensitive negative feedback loop within the fiber. These fibers exhibit integrated behaviors of time-space perception, short-term memory and adaptive changes in shape. Additionally, they demonstrate rhythm characteristics, changing periodically in a 24-h day-night cycle. Composed of natural building blocks, these hierarchical hydrogel fibers exhibit a memristor effect similar to that of an elementary neuron, making them promising for applications in seamless on-skin and implantable bioelectronics.

The ambient space formalism

We present a new formalism to solve the kinematical constraints due to Weyl invariance for CFTs in curved backgrounds and/or non-trivial states, and we apply it to thermal CFTs and to CFTs on squashed spheres. The ambient space formalism is based on constructing a class of geometric objects that are Weyl covariant and identifying them as natural building blocks of correlation functions. We construct (scalar) n-point functions and we illustrate the formalism with a detailed computation of 2-point functions. We compare our results for thermal 2-point functions with results that follow from thermal OPEs and holographic computations, finding exact agreement. In our holographic computation we also obtain the OPE coefficient of the leading double-twist contribution, and we discuss how the double-twist coefficients may be computed from the multi-energy-momentum contributions, given knowledge of the analytic structure of the correlator. The 2-point function for the CFT on squashed spheres is a new result. We also discuss the relation of our work to flat holography.

Sonochemical Synthesis of Natural Polyphenolic Nanoparticles for Modulating Oxidative Stress.

Natural polyphenolic compounds play a vital role in nature and are widely utilized as building blocks in the fabrication of emerging functional nanomaterials. Although diverse fabrication methodologies are developed in recent years, the challenges of purification, uncontrollable reaction processes and additional additives persist. Herein, a modular and facile methodology is reported toward the fabrication of natural polyphenolic nanoparticles. By utilizing low frequency ultrasound (40kHz), the assembly of various natural polyphenolic building blocks is successfully induced, allowing for precise control over the particle formation process. The resulting natural polyphenolic nanoparticles possessed excellent in vitro antioxidative abilities and in vivo therapeutic effects in typical oxidative stress models including wound healing and acute kidney injury. This study opens new avenues for the fabrication of functional materials from naturally occurring building blocks, offering promising prospects for future advancements in this field.

Thiolation-Based Protein-Protein Hydrogels for Improved Wound Healing.

The limitations of protein-based hydrogels, including their insufficient mechanical properties and restricted biological functions, arise from the highly specific functions of proteins as natural building blocks. A potential solution to overcome these shortcomings is the development of protein-protein hydrogels, which integrate structural and functional proteins. In this study, a protein-protein hydrogel formed by crosslinking bovine serum albumin (BSA) and a genetically engineered intrinsically disordered collagen-like protein (CLP) through Ag─S bonding is introduced. The approach involves thiolating lysine residues of BSA and crosslinking CLP with Ag+ ions, utilizing thiolation of BSA and the free-cysteines of CLP. The resulting protein-protein hydrogels exhibit exceptional properties, including notable plasticity, inherent self-healing capabilities, and gel-sol transition in response to redox conditions. In comparison to standalone BSA hydrogels, these protein-protein hydrogels demonstrate enhanced cellular viability, and improved cellular migration. In vivo experiments provide conclusive evidence of accelerated wound healing, observed not only in murine models with streptozotocin (Step)-induced diabetes but also in zebrafish models subjected to UV-burn injuries. Detailed mechanistic insights, combined with assessments of proinflammatory cytokines and the expression of epidermal differentiation-related proteins, robustly validate the protein-protein hydrogel's effectiveness in promoting wound repair.

α-D-2'-Deoxyadenosine, an irradiation product of canonical DNA and a component of anomeric nucleic acids: crystal structure, packing and Hirshfeld surface analysis.

α-D-2'-Deoxyribonucleosides are products of the γ-irradiation of DNA under oxygen-free conditions and are constituents of anomeric DNA. They are not found as natural building blocks of canonical DNA. Reports on their conformational properties are limited. Herein, the single-crystal X-ray structure of α-D-2'-deoxyadenosine (α-dA), C10H13N5O3, and its conformational parameters were determined. In the crystalline state, α-dA forms two conformers in the asymmetric unit which are connected by hydrogen bonds. The sugar moiety of each conformer is arranged in a `clamp'-like fashion with respect to the other conformer, forming hydrogen bonds to its nucleobase and sugar residue. For both conformers, a syn conformation of the nucleobase with respect to the sugar moiety was found. This is contrary to the anti conformation usually preferred by α-nucleosides. The sugar conformation of both conformers is C2'-endo, and the 5'-hydroxyl groups are in a +sc orientation, probably due to the hydrogen bonds formed by the conformers. The formation of the supramolecular assembly of α-dA is controlled by hydrogen bonding and stacking interactions, which was verified by a Hirshfeld and curvedness surface analysis. Chains of hydrogen-bonded nucleobases extend parallel to the b direction and are linked to equivalent chains by hydrogen bonds involving the sugar moieties to form a sheet. A comparison of the solid-state structures of the anomeric 2'-deoxyadenosines revealed significant differences of their conformational parameters.

Hydrogen-bonded supramolecular biohybrid frameworks for protein biomineralization constructed from natural phenolic building blocks.

Hydrogen bond-mediated supramolecular crystalline materials, such as hydrogen-bonded organic frameworks, offer a promising strategy for protein biomineralization, yet the intricate design and multi-step synthesis of specific orthogonal units in molecular building blocks pose a significant synthetic challenge. Identifying new classes of natural building blocks capable of facilitating supramolecular framework construction while enabling stable protein binding has remained an elusive goal. Here, we introduce a versatile assembly strategy enabling the organization of diverse proteins and phenolic building blocks into highly crystalline hydrogen-bonded supramolecular phenolic frameworks (ProteinX@SPF). The natural ellagic acid (EA) exhibits a centrosymmetric structure with catechol groups on each molecular side, facilitating hydrogen bonding with protein amino acid residues for primary nucleation. Subsequently, EA self-assembles into ProteinX@SPF through hydrogen bonding and π-π interactions. The multiple hydrogen-bonding interactions impart structural rigidity and directional integrity, conferring ProteinX@SPF biohybrids with remarkable resistance to harsh conditions while preserving protein bioactivity. Additionally, the supramolecular stacking induced by π-π interactions endows ProteinX@SPF with long-range ordered nanochannels, which can serve as the gating to sieve the catalytic substrate and thus enhance the biocatalytic specificity. This work sheds light on biomineralization with natural building blocks for functional biohybrids, showing enormous potential in biocatalysis, sensing, and nanomedicine.

Molecular vessels from preorganised natural building blocks.

Supramolecular vessels emerged as tools to mimic and better understand compartmentalisation, a central aspect of living matter. However, many more applications that go beyond those initial goals have been documented in recent years, including new sensory systems, artificial transmembrane transporters, catalysis, and targeted drug or gene delivery. Peptides, carbohydrates, nucleobases, and steroids bear great potential as building blocks for the construction of supramolecular vessels, possessing complexity that is still difficult to attain with synthetic methods - they are rich in functional groups and well-defined stereogenic centers, ready for noncovalent interactions and further functions. One of the options to tame the functional and dynamic complexity of natural building blocks is to place them at spatially designed positions using synthetic scaffolds. In this review, we summarise the historical and recent advances in the construction of molecular-sized vessels by the strategy that couples synthetic predictability and durability of various scaffolds (cyclodextrins, porphyrins, crown ethers, calix[n]arenes, resorcin[n]arenes, pillar[n]arenes, cyclotriveratrylenes, coordination frameworks and multivalent high-symmetry molecules) with functionality originating from natural building blocks to obtain nanocontainers, cages, capsules, cavitands, carcerands or coordination cages by covalent chemistry, self-assembly, or dynamic covalent chemistry with the ultimate goal to apply them in sensing, transport, or catalysis.

Nanostructured single-atom catalysts derived from natural building blocks

The emerging single-atom catalysts derived from biomass sources to date have been comprehensively summarized and discussed, including synthesis strategies, various biomass precursors, catalytic applications, existing challenges, and perspectives.

A Chemo-Enzymatic Cascade Strategy for the Synthesis of Phosphatidylcholine Incorporated with Structurally Diverse FAHFAs.

Fatty acid esters of hydroxy fatty acids (FAHFAs), a newly discovered class of human endogenous complex lipids showing great promise for treating diabetes and inflammatory diseases, exist naturally in extremely low concentrations. This work reports a chemo-enzymatic approach for the comprehensive synthesis of phospholipids containing FAHFAs via sequential steps: hydratase-catalyzed hydration of unsaturated fatty acids to generate structurally diverse hydroxy fatty acids (HFAs), followed by the selective esterification of these HFAs with fatty acids mediated by secondary alcohol-specific Candida antarctica lipase A (CALA), resulting in the formation of a series of diverse FAHFA analogs. The final synthesis is completed through carbodiimide-based coupling of FAHFAs with glycerophosphatidylcholine. Optimal reaction conditions are identified for each step, and the substrate affinity of CALA, responsible for the catalytic mechanisms during FAHFA production, is evaluated through molecular docking. Compared to multistep lab-tedious chemical synthesis, this route, relying on natural building blocks and natural biocatalysts, is significantly facile, scalable, and highly selective, affording high yields (74-98 mol %) in each step for the construction of higher FAHFA-PC series (10/12/13-FAHFAs). The developed strategy aims to increase the availability of naturally occurring FAHFA species and provide the tools for the construction of versatile and novel analogs of FAHFA conjugates.

Valorisation of Chitosan Natural Building Block as a Primary Strategy for the Development of Sustainable Fully Bio-Based Epoxy Resins.

The non-toxic and biodegradable nature of chitosan makes it a valuable resource offering promising opportunities in the development of bio-based materials with enhanced mechanical and thermal properties. In this work, the combination of epoxidized linseed oil, oxalic or citric acids, and chitosan (CHI) as a curing accelerator presents an attractive strategy to create bio-based and sustainable thermosetting materials. This article aims to provide a comprehensive exploration of the systems reactivities, characteristics, and performance evaluation of the designed bio-thermosets. Both the nature of the two carboxylic acids and the presence of chitosan are shown to have a big impact on the thermomechanical properties of the developed networks. While oxalic acid favours the formation of elastic networks, with low Tg values (increasing with CHI content between 0.7 and 8.5 °C) and relatively low Young's modulus (~2.5 MPa), citric acid promotes the formation of very dense networks with lower mass of the segments between the crosslinks, having 20 times higher Tg values (from 36 to 45 °C) and ~161 times higher Young's modulus (from 94 MPa up to 404 MPa in these systems). The CHI has a strong impact on the curing reaction and on the overall properties, by increasing the materials' performance.

Enhancing biocatalytical N[sbnd]N bond formation with the actinobacterial piperazate synthase KtzT

Natural compounds with nitrogen-nitrogen bonds are diverse and have applications in medicine and agriculture. l-Piperazic acid (Piz), an α-hydrazino acid, is one of few naturally occurring compounds of its kind. Yet, Piz and its derivatives are valuable building blocks for bioactive compounds. Few NNzymes, enzymes capable of forming NN bonds, have been identified thus far. The hemoenzyme KtzT from Kutzneria sp. 744 catalyzes the intramolecular NN bond formation of N5‑hydroxy-l-ornithine (OH-Orn) to form Piz, a natural building block of kutznerides. The latter has antifungal and antibiotic properties. In our study, we established an improved expression method, with significantly improved yields (ca. 35-fold) of heme-loaded enzyme, making the enzyme much more accessible for laboratory studies. In vitro biochemical characterization under conditions for NN bond formation indicated a considerable thermo- and pH-flexibility, with optimal reaction conditions at 30 °C and 10 mM Tris buffer at pH 9 together with low salinity, paving the way for more complex applications involving KtzT. We have also identified two homologous enzymes from extremophilic organisms to exhibit piperazate-forming activity. In silico structural studies, combined with phylogenetic analysis, resulted in a heme- and substrate-binding model, suggesting target enzyme residues that we propose are critical for the structural integrity and catalytic activity of KtzT. Following this approach, we investigated the potential role of a cysteine residue in a dimer-stabilizing disulfide bridge. The interplay of in vitro and in silico data therefore provides crucial functional information on this enzyme class.

Enhancing pDNA Delivery with Hydroquinine Polymers by Modulating Structure and Composition.

Quinine is a promising natural product building block for polymer-based nucleic acid delivery vehicles as its structure enables DNA binding through both intercalation and electrostatic interactions. However, studies exploring the potential of quinine-based polymers for nucleic acid delivery applications (transfection) are limited. In this work, we used a hydroquinine-functionalized monomer, HQ, with 2-hydroxyethyl acrylate to create a family of seven polymers (HQ-X, X = mole percentage of HQ), with mole percentages of HQ ranging from 12 to 100%. We developed a flow cytometer-based assay for studying the polymer-pDNA complexes (polyplex particles) directly and demonstrate that polymer composition and monomer structure influence polyplex characteristics such as the pDNA loading and the extent of adsorption of serum proteins on polyplex particles. Biological delivery experiments revealed that maximum transgene expression, outperforming commercial controls, was achieved with HQ-25 and HQ-35 as these two variants sustained gene expression over 96 h. HQ-44, HQ-60, and HQ-100 were not successful in inducing transgene expression, despite being able to deliver pDNA into the cells, highlighting that the release of pDNA is likely the bottleneck in transfection for polymers with higher HQ content. Using confocal imaging, we quantified the extent of colocalization between pDNA and lysosomes, proving the remarkable endosomal escape capabilities of the HQ-X polymers. Overall, this study demonstrates the advantages of HQ-X polymers as well as provides guiding principles for improving the monomer structure and polymer composition, supporting the development of the next generation of polymer-based nucleic acid delivery vehicles harnessing the power of natural products.

Designing and testing the applicability of a natural green ventilation building block in an Egyptian Climatic zone using waste materials

Natural ventilation is one of the ways used to enhance building spaces' indoor air quality, especially after the COVID-19 pandemic. It also saves energy by utilizing natural wind forces to provide internal building spaces with fresh air instead of energy-consuming mechanical systems. For a multiple-floor building, adding external wall ventilation blocks can improve natural cross ventilation by catching and directing fresh air from the external prevailing wind into its internal spaces. This research aimed to enhance the building's natural ventilation by using environmentally friendly blocks. This was done by designing a green block using marble and granite waste materials as a partial substitute for conventional materials in the block. Styrofoam beads were added to the block’s mixture to reduce its weight. The block’s shape was designed to direct fresh air through building side walls by the use of natural wind pressure. The block was developed from the initial shape of the standard hollow block to a block with a wind catcher. Ventilation block shape simulations were done using (ANSYS fluent) computational fluid dynamics (CFD) software to determine the best inlet angle, catcher angle, and catcher length. The study revealed that by increasing the block inlet angle more than 45°, the block outlet air velocity starts to decrease due to the flow separation in the front part of the block inlet. The catcher angle ranged from 65° to 85°, and the catcher’s ability to redirect the airflow is decreased at a catcher angle greater than 85°. The best nondimensional catcher length-to-block length ratio (height /length) h/L was 0.625. Substitution of 5% of cement by granite in the presence of 0.15 Kg of Styrofoam (C5G) produced a lightweight green ventilation block of weight 19.3 kg. Whereas, the substitution of 15% of sand for marble in the presence of 1 Kg of Styrofoam (S15M) produced a lightweight green ventilation block of weight 15.9 kg. The produced block was tested in a building located in New Cairo City (a region currently having a tremendous increase in the building construction sector) as a study sample representing one of the Egyptian Climatic zones. The research concluded that it is preferred to allocate the building corners towards the prevailing wind direction to prevent airflow separation and to magnify the quantities of air along the building sides.