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Tackling Achilles' Heel in Synthetic Biology: Pairing Intracellular Synthesis of Noncanonical Amino Acids with Genetic-Code Expansion to Foster Biotechnological Applications.
Biava, HD
Chembiochem : a European journal of chemical biology. 2020;(9):1265-1273
Abstract
For the last two decades, synthetic biologists have been able to unlock and expand the genetic code, generating proteins with unique properties through the incorporation of noncanonical amino acids (ncAAs). These evolved biomaterials have shown great potential for applications in industrial biocatalysis, therapeutics, bioremediation, bioconjugation, and other areas. Our ability to continue developing such technologies depends on having relatively easy access to ncAAs. However, the synthesis of enantiomerically pure ncAAs in practical quantitates for large-scale processes remains a challenge. Biocatalytic ncAA production has emerged as an excellent alternative to traditional organic synthesis in terms of cost, enantioselectivity, and sustainability. Moreover, biocatalytic synthesis offers the opportunity of coupling the intracellular generation of ncAAs with genetic-code expansion to overcome the limitations of an external supply of amino acid. In this minireview, we examine some of the most relevant achievements of this approach and its implications for improving technological applications derived from synthetic biology.
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2.
Advances in the discovery of novel biomarkers for cancer: spotlight on protein N-glycosylation.
Zhang, W, Yang, Z, Gao, X, Wu, Q
Biomarkers in medicine. 2020;(11):1031-1045
Abstract
Progress on glycosylation and tumor markers has not been extensively reported. Glycosylation plays an important part in post-translational modification. Previous research on glycosylation-modified biomarkers has lagged behind due to insufficient understanding of glycosylation-related regulations. However, some new methods and ideas illustrated in recent research may provide new inspirations in the field. This article aims to review current advances in revealing relationship between tumors and abnormal N-glycosylation and discuss leading-edge applications of N-glycosylation in developing novel tumor biomarkers.
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Recent trends in peptide and protein-based hydrogels.
Katyal, P, Mahmoudinobar, F, Montclare, JK
Current opinion in structural biology. 2020;:97-105
Abstract
Hydrogels are classic examples of biomaterials that have found its niche in biomedical and allied fields. Here, we describe examples of peptide-based and protein-based hydrogels with a focus on smart gels that respond to various stimuli including temperature, pH, light, and ionic strength. With the recent advancements in computational modeling, it has been possible to predict as well as design peptide and protein sequences that can assemble into hydrogels with unique and improved properties. We briefly discuss coarse grained and atomistic simulations in designing peptides that can form hydrogels. In addition, we highlight the trends that will influence the future design and applications of hydrogels, with emphasis on bioadhesion, exosomes delivery, tissue and organoids engineering, and even intracellular production of gels.
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4.
Phenotypic spectrum and genetic analysis in the fatal cases of Schaaf-Yang syndrome: Two case reports and literature review.
Chen, X, Ma, X, Zou, C
Medicine. 2020;(29):e20574
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Abstract
RATIONALE Schaaf-Yang syndrome, a rare imprinted hereditary disease caused by MAGEL2 variants, manifests as developmental delay/intellectual disability, neonatal hypotonia, feeding difficulties, contractures, and autism spectrum disorder. PATIENT CONCERNS Patient 1 and 2 were infant girls presenting facial dysmorphisms, contractures of interphalangeal joints, neonatal hypotonia, feeding difficulties, congenital heart diseases, and respiratory complications. Besides, Patient 2 presented with delayed psychomotor development. DIAGNOSIS Whole-exome sequencing was performed and heterozygous mutations of the MAGEL2 gene were detected in the patients. They were diagnosed as Schaaf-Yang syndrome. INTERVENTIONS The patients received supportive treatment including mechanical ventilation, parenteral nutrition and gastric tube feeding. OUTCOMES Whole-exome sequencing revealed de novo heterozygous c.1996dupC pathogenic mutations in the MAGEL2 gene in the 2 patients. They died due to respiratory failure at the age of 20 days and 98 days, respectively. LESSONS Our results indicate that MAGEL2 variants can cause congenital heart disease and fatal respiratory complications, broadening the phenotypic spectrum and adding to the fatal cases of Schaaf-Yang syndrome. We highly suggest that the MAGEL2 gene should be added to gene-panels or gene-filters in next-generation sequencing-based diagnostics, which is of great significance for early diagnosis and early intervention of Schaaf-Yang syndrome patients.
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Genetically encoded selective cross-linkers and emerging applications.
Ren, H
Biochemical Society transactions. 2020;(4):1807-1817
Abstract
There has been a large amount of interest in the development of genetically encoded cross-linkers that target functional groups naturally present in cells. Recently, a new class of unnatural amino acids that specifically react with target residues were developed and genetically incorporated. The selective reaction shows higher cross-linking efficiency, lower background and predictable cross-linking sites. It has been applied to enhance protein/peptide stability, pinpoint protein-protein interactions, stabilize protein complexes, engineer covalent protein inhibitors, identify phosphatases in living cells, etc. These new covalent linkages provide excellent new tools for protein engineering and biological studies. Their applications in biotherapy will provide considerable opportunities for innovating and improving biomolecular medicines.
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Chemoselective Methionine Bioconjugation on a Polypeptide, Protein, and Proteome.
Zang, J, Chen, Y, Zhu, W, Lin, S
Biochemistry. 2020;(2):132-138
Abstract
Methionine is one of the most hydrophobic, redox-sensitive, and one of the only two sulfur-containing amino acids on protein. Because of these biochemical properties, the methionine residue plays a central role in a variety of biological processes, such as metal coordination, antioxidant stress, and aging. However, studies on the molecular functions of methionine are much less common than the other primary sulfur-containing amino acid, cysteine. The limited number of publications on methionine-related studies is partially due to the lack of tools for methionine modification. Methionine bioconjugation offers a new strategy to decipher the biological function of methionine and expands the toolbox for protein functionalization in the context of the application, such as synthesizing proteins with novel properties and producing new biomaterials. The purpose of this Perspective is to highlight the biochemical properties and functions of methionine, list recent progress in the development of methionine bioconjugation reagents, and briefly demonstrate the application of these reagents on polypeptides, proteins, and proteomes.
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Retention Time Prediction and Protein Identification.
Henneman, A, Palmblad, M
Methods in molecular biology (Clifton, N.J.). 2020;:115-132
Abstract
In bottom-up proteomics, proteins are typically identified by enzymatic digestion into peptides, tandem mass spectrometry and comparison of the tandem mass spectra with those predicted from a sequence database for peptides within measurement uncertainty from the experimentally obtained mass. Although now decreasingly common, isolated proteins or simple protein mixtures can also be identified by measuring only the masses of the peptides resulting from the enzymatic digest, without any further fragmentation. Separation methods such as liquid chromatography and electrophoresis are often used to fractionate complex protein or peptide mixtures prior to analysis by mass spectrometry. Although the primary reason for this is to avoid ion suppression and improve data quality, these separations are based on physical and chemical properties of the peptides or proteins and therefore also provide information about them. Depending on the separation method, this could be protein molecular weight (SDS-PAGE), isoelectric point (IEF), charge at a known pH (ion exchange chromatography), or hydrophobicity (reversed phase chromatography). These separations produce approximate measurements on properties that to some extent can be predicted from amino acid sequences. In the case of molecular weight of proteins without posttranslational modifications this is straightforward: simply add the molecular weights of the amino acid residues in the protein. For IEF, charge and hydrophobicity, the order of the amino acids, and folding state of the peptide or protein also matter, but it is nevertheless possible to predict the behavior of peptides and proteins in these separation methods to a degree which renders such predictions useful. This chapter reviews the topic of using data from separation methods for identification and validation in proteomics, with special emphasis on predicting retention times of tryptic peptides in reversed-phase chromatography under acidic conditions, as this is one of the most commonly used separation methods in bottom-up proteomics.
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8.
Divalent Cations: A Molecular Glue for Protein Materials.
López-Laguna, H, Sánchez, J, Unzueta, U, Mangues, R, Vázquez, E, Villaverde, A
Trends in biochemical sciences. 2020;(11):992-1003
Abstract
Among inorganic materials, divalent cations modulate thousands of physiological processes that support life. Their roles in protein assembly and aggregation are less known, although they are progressively being brought to light. We review the structural roles of divalent cations here, as well as the novel protein materials that are under development, in which they are used as glue-like agents. More specifically, we discuss how mechanically stable nanoparticles, fibers, matrices, and hydrogels are generated through their coordination with histidine-rich proteins. We also describe how the rational use of divalent cations combined with simple protein engineering offers unexpected and very simple biochemical approaches to biomaterial design that might address unmet clinical needs in precision medicine.
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9.
Evolution of Protein Structure and Stability in Global Warming.
Barik, S
International journal of molecular sciences. 2020;(24)
Abstract
This review focuses on the molecular signatures of protein structures in relation to evolution and survival in global warming. It is based on the premise that the power of evolutionary selection may lead to thermotolerant organisms that will repopulate the planet and continue life in general, but perhaps with different kinds of flora and fauna. Our focus is on molecular mechanisms, whereby known examples of thermoresistance and their physicochemical characteristics were noted. A comparison of interactions of diverse residues in proteins from thermophilic and mesophilic organisms, as well as reverse genetic studies, revealed a set of imprecise molecular signatures that pointed to major roles of hydrophobicity, solvent accessibility, disulfide bonds, hydrogen bonds, ionic and π-electron interactions, and an overall condensed packing of the higher-order structure, especially in the hydrophobic regions. Regardless of mutations, specialized protein chaperones may play a cardinal role. In evolutionary terms, thermoresistance to global warming will likely occur in stepwise mutational changes, conforming to the molecular signatures, such that each "intermediate" fits a temporary niche through punctuated equilibrium, while maintaining protein functionality. Finally, the population response of different species to global warming may vary substantially, and, as such, some may evolve while others will undergo catastrophic mass extinction.
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10.
Photo-Degradation of Therapeutic Proteins: Mechanistic Aspects.
Schöneich, C
Pharmaceutical research. 2020;(3):45
Abstract
Therapeutic proteins are sensitive to photo-degradation by UV A and visible light. As none of the essential amino acids exhibits significant absorption in the UV A and visible light regions, the underlying mechanisms of photo-degradation induced by UV A and visible light are not well understood. This review addresses potential mechanisms, by which protein structure, oxidative modifications or impurities can promote the photo-degradation of therapeutic proteins during the exposure to UV A and visible light.