Expanding the Structural Diversity of Protein Building Blocks with Noncanonical Amino Acids Biosynthesized from Aromatic Thiols

2021 ◽  
Vol 60 (18) ◽  
pp. 10040-10048
Author(s):  
Yong Wang ◽  
Xiaoxu Chen ◽  
Wenkang Cai ◽  
Linzhi Tan ◽  
Yutong Yu ◽  
...  
Keyword(s):  
Amino Acids ◽  
Structural Diversity ◽  
Building Blocks ◽  
Noncanonical Amino Acids ◽  
Aromatic Thiols

Expanding the Structural Diversity of Protein Building Blocks with Noncanonical Amino Acids Biosynthesized from Aromatic Thiols

2021 ◽  
Vol 133 (18) ◽  
pp. 10128-10136
Author(s):  
Yong Wang ◽  
Xiaoxu Chen ◽  
Wenkang Cai ◽  
Linzhi Tan ◽  
Yutong Yu ◽  
...  
Keyword(s):  
Amino Acids ◽  
Structural Diversity ◽  
Building Blocks ◽  
Noncanonical Amino Acids ◽  
Aromatic Thiols

scholarly journals Enhancing protein stability with extended disulfide bonds

2016 ◽  
Vol 113 (21) ◽  
pp. 5910-5915 ◽  
Author(s):  
Tao Liu ◽  
Yan Wang ◽  
Xiaozhou Luo ◽  
Jack Li ◽  
Sean A. Reed ◽  
...  
Keyword(s):  
Amino Acids ◽  
Disulfide Bond ◽  
Disulfide Bonds ◽  
Building Blocks ◽  
Side Chain ◽  
Cross Linking ◽  
Noncanonical Amino Acids ◽  
Genetic Encoding ◽  
Selection Experiments ◽  
Significant Distance

Disulfide bonds play an important role in protein folding and stability. However, the cross-linking of sites within proteins by cysteine disulfides has significant distance and dihedral angle constraints. Here we report the genetic encoding of noncanonical amino acids containing long side-chain thiols that are readily incorporated into both bacterial and mammalian proteins in good yields and with excellent fidelity. These amino acids can pair with cysteines to afford extended disulfide bonds and allow cross-linking of more distant sites and distinct domains of proteins. To demonstrate this notion, we preformed growth-based selection experiments at nonpermissive temperatures using a library of random β-lactamase mutants containing these noncanonical amino acids. A mutant enzyme that is cross-linked by one such extended disulfide bond and is stabilized by ∼9 °C was identified. This result indicates that an expanded set of building blocks beyond the canonical 20 amino acids can lead to proteins with improved properties by unique mechanisms, distinct from those possible through conventional mutagenesis schemes.

scholarly journals Recombinant thiopeptides containing noncanonical amino acids

2016 ◽  
Vol 113 (13) ◽  
pp. 3615-3620 ◽  
Author(s):  
Xiaozhou Luo ◽  
Claudio Zambaldo ◽  
Tao Liu ◽  
Yuhan Zhang ◽  
Weimin Xuan ◽  
...  
Keyword(s):  
Amino Acids ◽  
Chemical Reactivity ◽  
Biological Activities ◽  
Structural Diversity ◽  
Trna Synthetase ◽  
Aminoacyl Trna Synthetase ◽  
Noncanonical Amino Acids ◽  
Amber Suppressor ◽  
Modified Peptides ◽  
Biophysical Probes

Thiopeptides are a subclass of ribosomally synthesized and posttranslationally modified peptides (RiPPs) with complex molecular architectures and an array of biological activities, including potent antimicrobial activity. Here we report the generation of thiopeptides containing noncanonical amino acids (ncAAs) by introducing orthogonal amber suppressor aminoacyl-tRNA synthetase/tRNA pairs into a thiocillin producer strain ofBacillus cereus. We demonstrate that thiopeptide variants containing ncAAs with bioorthogonal chemical reactivity can be further postbiosynthetically modified with biophysical probes, including fluorophores and photo-cross-linkers. This work allows the site-specific incorporation of ncAAs into thiopeptides to increase their structural diversity and probe their biological activity; similar approaches can likely be applied to other classes of RiPPs.

In the Pursuit of (Ald)Imine Surrogates for the Direct Asymmetric Synthesis of Non-Proteinogenic α-Amino Acids

Synthesis ◽  
2021 ◽  
Author(s):  
Stéphane P. Roche
Keyword(s):  
Amino Acids ◽  
Asymmetric Synthesis ◽  
Nucleophilic Substitution ◽  
Posttranslational Modifications ◽  
Kinetic Studies ◽  
Structural Diversity ◽  
Building Blocks ◽  
Bioactive Molecules ◽  
Biological Functions ◽  
Imino Esters

Nature remarkably employs posttranslational modifications of the 20 canonical α-amino acids to devise a far larger structural, conformational, and functional diversity found in non-proteinogenic amino acids (NPAAs) which ultimately translates into a plethora of complex biological functions. Synthetic chemists are continuously trying to reproduce and even extrapolate the repertoire of NPAA building blocks to build structural diversity into bioactive molecules and materials. The direct asymmetric functionalization of α-imino esters represents one of the most robust and attractive routes to NPAAs. This review summarizes the most prominent examples of bench-stable (ald)imine surrogates exploited for the synthesis of NPAAs including our most recent results in the nucleophilic substitution of α-haloglycines and other α-haloaminals. A synopsis of kinetic studies, reaction optimizations, and enantioselective catalytic methods is also presented.

Bio-organometallic Peptide Conjugates: Recent Advances in Their Synthesis and Prospects for Biomedical Application

2020 ◽  
Vol 24 (21) ◽  
pp. 2508-2523
Author(s):  
Johana Gómez ◽  
Diego Sierra ◽  
Constanza Cárdenas ◽  
Fanny Guzmán
Keyword(s):  
Amino Acids ◽  
Biomedical Application ◽  
Structural Diversity ◽  
Biological Properties ◽  
Therapeutic Agents ◽  
Organometallic Complexes ◽  
Chemical Behavior ◽  
Metal Compounds ◽  
Bioorganometallic Chemistry ◽  
Pharmacological Control

One area of organometallic chemistry that has attracted great interest in recent years is the syntheses, characterization and study of organometallic complexes conjugated to biomolecules with different steric and electronic properties as potential therapeutic agents against cancer and malaria, as antibiotics and as radiopharmaceuticals. This minireview focuses on the unique structural diversity that has recently been discovered in α- amino acids and the reactions of metallocene complexes with peptides having different chemical behavior and potential medical applications. Replacing α-amino acids with metallocene fragments is an effective way of selectively influencing the physicochemical, structural, electrochemical and biological properties of the peptides. Consequently, research in the field of bioorganometallic chemistry offers the opportunity to develop bioactive metal compounds as an innovative and promising approach in the search for pharmacological control of different diseases.

scholarly journals Meroterpenoids: A Comprehensive Update Insight on Structural Diversity and Biology

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 957
Author(s):  
Mamona Nazir ◽  
Muhammad Saleem ◽  
Muhammad Imran Tousif ◽  
Muhammad Aijaz Anwar ◽  
Frank Surup ◽  
...  
Keyword(s):  
Amino Acids ◽  
Secondary Metabolites ◽  
Biological Effects ◽  
Structural Diversity ◽  
Chemical Diversity ◽  
Biosynthetic Pathways ◽  
Natural Sources ◽  
Hybrid Compounds ◽  
Anti Inflammatory

Meroterpenoids are secondary metabolites formed due to mixed biosynthetic pathways which are produced in part from a terpenoid co-substrate. These mixed biosynthetically hybrid compounds are widely produced by bacteria, algae, plants, and animals. Notably amazing chemical diversity is generated among meroterpenoids via a combination of terpenoid scaffolds with polyketides, alkaloids, phenols, and amino acids. This review deals with the isolation, chemical diversity, and biological effects of 452 new meroterpenoids reported from natural sources from January 2016 to December 2020. Most of the meroterpenoids possess antimicrobial, cytotoxic, antioxidant, anti-inflammatory, antiviral, enzyme inhibitory, and immunosupressive effects.

Noncanonical Amino Acids for Hypoxia-Responsive Peptide Self-Assembly and Fluorescence

2021 ◽  
Author(s):  
Binbin Hu ◽  
Na Song ◽  
Yawei Cao ◽  
Mingming Li ◽  
Xin Liu ◽  
...  
Keyword(s):  
Amino Acids ◽  
Self Assembly ◽  
Noncanonical Amino Acids

scholarly journals Chiroptical activity of hydroxycarboxylic acids with implications for the origin of biological homochirality

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Jana Bocková ◽  
Nykola C. Jones ◽  
Uwe J. Meierhenrich ◽  
Søren V. Hoffmann ◽  
Cornelia Meinert
Keyword(s):  
Amino Acids ◽  
Lactic Acid ◽  
Organic Molecules ◽  
Building Blocks ◽  
Aliphatic Chain ◽  
Monocarboxylic Acids ◽  
Hydroxycarboxylic Acids ◽  
Polarised Light ◽  
Suitable Target ◽  
Anisotropy Spectra

AbstractCircularly polarised light (CPL) interacting with interstellar organic molecules might have imparted chiral bias and hence preluded prebiotic evolution of biomolecular homochirality. The l-enrichment of extra-terrestrial amino acids in meteorites, as opposed to no detectable excess in monocarboxylic acids and amines, has previously been attributed to their intrinsic interaction with stellar CPL revealed by substantial differences in their chiroptical signals. Recent analyses of meteoritic hydroxycarboxylic acids (HCAs) – potential co-building blocks of ancestral proto-peptides – indicated a chiral bias toward the l-enantiomer of lactic acid. Here we report on novel anisotropy spectra of several HCAs using a synchrotron radiation electronic circular dichroism spectrophotometer to support the re-evaluation of chiral biomarkers of extra-terrestrial origin in the context of absolute photochirogenesis. We found that irradiation by CPL which would yield l-excess in amino acids would also yield l-excess in aliphatic chain HCAs, including lactic acid and mandelic acid, in the examined conditions. Only tartaric acid would show “unnatural” d-enrichment, which makes it a suitable target compound for further assessing the relevance of the CPL scenario.

scholarly journals Synthesis, Characterization and Evaluation of Peptide Nanostructures for Biomedical Applications

Molecules ◽  
2021 ◽  
Vol 26 (15) ◽  
pp. 4587
Author(s):  
Fanny d’Orlyé ◽  
Laura Trapiella-Alfonso ◽  
Camille Lescot ◽  
Marie Pinvidic ◽  
Bich-Thuy Doan ◽  
...  
Keyword(s):  
Amino Acids ◽  
Biomedical Applications ◽  
Chemical Reactivity ◽  
Physical Stability ◽  
Chemical Properties ◽  
Building Blocks ◽  
Imaging Probes ◽  
Therapeutic Molecules

There is a challenging need for the development of new alternative nanostructures that can allow the coupling and/or encapsulation of therapeutic/diagnostic molecules while reducing their toxicity and improving their circulation and in-vivo targeting. Among the new materials using natural building blocks, peptides have attracted significant interest because of their simple structure, relative chemical and physical stability, diversity of sequences and forms, their easy functionalization with (bio)molecules and the possibility of synthesizing them in large quantities. A number of them have the ability to self-assemble into nanotubes, -spheres, -vesicles or -rods under mild conditions, which opens up new applications in biology and nanomedicine due to their intrinsic biocompatibility and biodegradability as well as their surface chemical reactivity via amino- and carboxyl groups. In order to obtain nanostructures suitable for biomedical applications, the structure, size, shape and surface chemistry of these nanoplatforms must be optimized. These properties depend directly on the nature and sequence of the amino acids that constitute them. It is therefore essential to control the order in which the amino acids are introduced during the synthesis of short peptide chains and to evaluate their in-vitro and in-vivo physico-chemical properties before testing them for biomedical applications. This review therefore focuses on the synthesis, functionalization and characterization of peptide sequences that can self-assemble to form nanostructures. The synthesis in batch or with new continuous flow and microflow techniques will be described and compared in terms of amino acids sequence, purification processes, functionalization or encapsulation of targeting ligands, imaging probes as well as therapeutic molecules. Their chemical and biological characterization will be presented to evaluate their purity, toxicity, biocompatibility and biodistribution, and some therapeutic properties in vitro and in vivo. Finally, their main applications in the biomedical field will be presented so as to highlight their importance and advantages over classical nanostructures.

Sign in / Sign up

Export Citation Format

Share Document