Article
Chemistry, Multidisciplinary
Renzhong Yu, Rui Wang, Zhaoyin Wang, Bo Liu, Xue He, Zhihui Dai
Summary: The study introduces an enzyme cascade sensor based on AND logic that can differentiate between target and intermediate product, showing resistance to the inherently existing intermediate product H2O2, providing a new potential for enzyme cascade sensing.
CHEMICAL COMMUNICATIONS
(2021)
Article
Chemistry, Organic
Ranuka T. Hewage, Rou-Jie Huang, Shu-Jung Lai, Ya-Chu Lien, Shao-Hsing Weng, Dehai Li, Yu-Ju Chen, Shih-Hsiung Wu, Rong-Jie Chein, Hsiao-Ching Lin
Summary: Meleagrin B is a terpene-alkaloid hybrid natural product with the conidiogenone and meleagrin scaffold. Derivatives of Meleagrin B show diverse biological activities, with compound 6 demonstrating stronger antibacterial effects against Staphylococcus aureus strains compared to compound 1.
Article
Chemistry, Physical
Jia-Liang Chen, Xiao Wang, Feng Yang, Bin Li, Gottfried Otting, Xun-Cheng Su
Summary: We report the solution structure of an authentic sortaseA thioester intermediate with the bound substrate. Through advanced techniques, we determined the 3D structure of this short-lived enzymatic reaction intermediate at atomic resolution. The formation and stability of the intermediate are influenced by calcium binding and its interaction with the substrate, highlighting the importance of calcium in the function of sortase A.
Article
Cell Biology
Ao Hu, Jing-Zan Zhang, Jie Wang, Chen-Chen Li, Meng Yuan, Gang Deng, Zi-Cun Lin, Zhi-Ping Qiu, Hu-Yue Liu, Xian-Wei Wang, Peng-Cheng Wei, Xiao He, Xiaolu Zhao, Wen-Wei Qiu, Bao-Liang Song
Summary: In this study, the researchers uncover the autocatalytic mechanism of SMO cholesterylation and its dependence on calcium ions. They show that SMO-CRD undergoes auto-cholesterylation, which is enhanced by calcium and involves an intramolecular ester intermediate. Hh stimulation increases the local calcium concentration in SMO-localized endosomes through store-operated calcium entry. The researchers also identify a signaling-incompetent SMO mutant and demonstrate that cholesterylation of the CRD is required for full-length SMO activation. This study reveals new insights into the cholesterylation process and the role of calcium in Hh signaling.
Article
Biotechnology & Applied Microbiology
Lili Sun, Yuan Liu, Hanxin Song, Jian Hao, Liang Lin
Summary: A simple biological reduction method using ene-reductase was developed to synthesize the key chiral intermediate R-4-propyldihydrofuran-2(3H)-one (R-PDFO) for the antiepileptic drug Brivaracetam, with a 25.7% yield and 97% ee (R) achieved.
APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
(2023)
Article
Materials Science, Multidisciplinary
Christopher J. South, Lindsay E. Roy
Summary: The thermal decomposition of plutonium oxalate to oxide and the intermediates involved have been studied using solid state density functional theory calculations. The results suggest that anhydrous analogues of the hydrated Pu(IV) and Pu(III) oxalates are preferred crystal structures formed through an overall exothermic reaction process, with a possibility of more complex structures with higher energy formation as well.
JOURNAL OF NUCLEAR MATERIALS
(2021)
Article
Environmental Sciences
Junhee Park, Muthuraman Govindan, Daekeun Kim
Summary: The study developed a modified zeolite with Mg2+ ions for the removal of acetaldehyde, achieving high breakthrough capacity and production of intermediate products, indicating the importance of acid-base reaction sites in the process.
Article
Biochemistry & Molecular Biology
Itai Sharon, Marcel Grogg, Donald Hilvert, T. Martin Schmeing
Summary: This study investigates the mechanism of how cyanophycinase specifically binds and degrades cyanophycin, a resistant polymer. The findings provide important insights into the metabolism of cyanophycin.
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
(2022)
Article
Chemistry, Physical
Ronaldo Junio de Oliveira
Summary: This study investigated the grafting of the HIV-1 broadly neutralizing antibody epitope 2F5 into the Top7 protein scaffold. It was found that the grafted protein precipitates during storage, unlike its biotinylated version which remains soluble. Molecular dynamics revealed that biotinylation eliminates the intermediate state and induces a cooperative folding. The findings contribute to the prediction of stable and soluble scaffold-epitopes for the development of novel therapeutic and diagnostic platforms.
JOURNAL OF PHYSICAL CHEMISTRY B
(2022)
Article
Chemistry, Medicinal
Nicole Balasco, Josephine Alba, Marco D'Abramo, Luigi Vitagliano
Summary: This study used molecular dynamics simulations to investigate the intermediate states of the functional transition of HbA, revealing similarities in deoxygenation pathways between HbA and Antarctic fish Hbs despite a significant evolutionary distance.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)
Article
Agriculture, Multidisciplinary
Joanna Afokai Quaye, Daniel Ouedraogo, Giovanni Gadda
Summary: The commercial food and l-amino acid industries use bioengineered d-amino acid oxidizing enzymes to detect and remove d-amino acid contaminants. This study successfully engineered a faster biocatalyst through mutation and kinetic methods, which has potential applications in industrial settings.
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Ashleigh J. Burke, William R. Birmingham, Ying Zhuo, Thomas W. Thorpe, Bruna Zucoloto da Costa, Rebecca Crawshaw, Ian Rowles, James D. Finnigan, Carl Young, Gregory M. Holgate, Mark P. Muldowney, Simon J. Charnock, Sarah L. Lovelock, Nicholas J. Turner, Anthony P. Green
Summary: The Covid-19 pandemic has emphasized the need for efficient and cost-effective production of antiviral drugs on a large scale. This study presents a concise biocatalytic process for synthesizing Molnupiravir, a nucleoside analogue used for oral treatment of SARS-CoV-2. The novel biocatalyst developed through evolutionary adaptation of the enzyme cytidine deaminase exhibits remarkable efficiency, achieving over 85,000 turnovers within 3 hours and operating at high substrate loading. Additionally, in situ crystallization of the N-hydroxy-cytidine product increases its yield and facilitates its conversion to Molnupiravir.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Astronomy & Astrophysics
Jack T. Warfield, Joel C. Zinn, Marc H. Pinsonneault, Jennifer A. Johnson, Dennis Stello, Yvonne Elsworth, Rafael A. Garcia, Thomas Kallinger, Savita Mathur, Benoit Mosser, Rachael L. Beaton, D. A. Garcia-Hernandez
Summary: This study explores the relationships between the chemistry, ages, and locations of stars in the Galaxy using asteroseismic and spectroscopic data, finding that stars with high [alpha/Fe] tend to be older. The research provides age estimates for red giant branch stars in the Kepler field and suggests that including the effect of alpha-enrichment on opacity can lead to up to 10% older ages for low-mass stars. Age distributions for low- and high-[alpha/Fe] stars converge as distance from the Galactic plane increases, indicating potential unevenness in star formation or radial migration in the Galaxy.
ASTRONOMICAL JOURNAL
(2021)
Article
Chemistry, Multidisciplinary
Alexander F. Kiefer, Yu-Chang Liu, Rebecca Gummerer, Christina Jager, Jan Deska
Summary: This study successfully incorporated non-natural biocatalytic modules into an artificial metabolism, combining the benefits of traditional retrosynthesis with the elegance and efficacy of biosynthetic networks. In a highly streamlined process, the total synthesis of tricyclic angiopterlactone B was achieved in two steps operating entirely in an aqueous environment while relying mainly on enzymes as key reaction mediators.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Applied
Shixia Xi, Xiaofeng Ban, Haocun Kong, Caiming Li, Zhengbiao Gu, Zhaofeng Li
Summary: This study investigated the amino acids involved in the recognition and catalysis of alpha-1,6 glycosidic bonds, and identified E343 and W521 as crucial residues for alpha-1,6-glucanases. By studying engineered mutants, it was found that these amino acids significantly affected the product structure. The catalytic mechanism revealed that bulky aromatic side chains controlled the ratio of branch glucans, and E148 acted as a proton donor to regulate the generation of branched structures.
Article
Biochemistry & Molecular Biology
Michele Vendruscolo, Monika Fuxreiter
Summary: This study investigates the sequence determinants of protein aggregation via the condensation pathway and identifies three relevant features: droplet-promoting propensity, aggregation-promoting propensity, and multimodal interactions quantified by the binding mode entropy. By using this approach, aggregation-promoting mutations in droplet-forming proteins associated with amyotrophic lateral sclerosis (ALS) can be predicted.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Cristina Olivieri, Geoffrey C. Li, Yingjie Wang, V. S. Manu, Caitlin Walker, Jonggul Kim, Carlo Camilloni, Alfonso De Simone, Michele Vendruscolo, David A. Bernlohr, Susan S. Taylor, Gianluigi Veglia
Summary: ATP-competitive inhibitors are a major class of drugs for protein kinases. Using protein kinase A as a model system, this study shows that different ATP-competitive inhibitors modulate substrate binding cooperativity by tuning the conformational entropy of the kinase. The findings propose a new paradigm for the discovery of ATP-competitive inhibitors based on their ability to modulate the allosteric coupling between nucleotide and substrate-binding sites.
Review
Multidisciplinary Sciences
Michele Vendruscolo, Monika Fuxreiter
Summary: Condensed states of proteins play crucial roles in the organization and function of cells, and disruptions of these states can lead to various diseases. This review analyzes the identification of targets for pharmacological interventions and explores opportunities for regulating aberrant protein condensation.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Attila Horvath, Michele Vendruscolo, Monika Fuxreiter
Summary: Mutations in TDP-43 can impact its cytotoxicity and facilitate the conversion between droplets and amyloid-containing aggregates.
Article
Biochemical Research Methods
Marc Oeller, Ryan Kang, Rosie Bell, Hannes Ausserwoger, Pietro Sormanni, Michele Vendruscolo
Summary: This article describes a computational method that incorporates the effect of pH on protein solubility predictions. The accuracy of these predictions is comparable to experimental methods, as demonstrated on various antibodies and proteins. This method, named CamSol 3.0, is now publicly available at https://www-cohsoftware.ch.cam.ac.uk/index.php/camsolph.
BRIEFINGS IN BIOINFORMATICS
(2023)
Article
Multidisciplinary Sciences
Alyssa Miller, Sean Chia, Zenon Toprakcioglu, Tuuli Hakala, Roman Schmid, Yaduo Feng, Tadas Kartanas, Ayaka Kamada, Michele Vendruscolo, Francesco Simone Ruggeri, Tuomas P. J. Knowles
Summary: In this study, a lab-on-a-chip spray approach was developed to combine rapid sample preparation, mixing, and deposition with nanoanalytical methods in chemistry and biology. This method provides enhanced spectroscopic sensitivity and single-molecule spatial resolution, allowing for multidimensional studies of heterogeneous biomolecular systems.
Article
Multidisciplinary Sciences
Mauricio Aguilar Rangel, Alice Bedwell, Elisa Costanzi, Ross J. Taylor, Rosaria Russo, Goncalo J. L. Bernardes, Stefano Ricagno, Judith Frydman, Michele Vendruscolo, Pietro Sormanni
Summary: De novo design methods enable the rapid generation of lead antibodies binding to preselected epitopes without in vitro affinity maturation, and high-resolution input antigen structure is not required.
Review
Chemistry, Multidisciplinary
Ryan Limbocker, Nunilo Cremades, Roberta Cascella, Peter M. Tessier, Michele Vendruscolo, Fabrizio Chiti
Summary: The misfolding and aggregation of peptides and proteins into amyloid aggregates is a common feature of various protein misfolding diseases, including Alzheimer's disease and Parkinson's disease. Misfolded protein oligomers, which can form intermediates in the fibril formation process or be released by mature fibrils, are increasingly recognized as central to the development of these diseases. Despite challenges in studying these oligomers, researchers have developed methods to produce stable and reproducible populations for experimentation. These tools have provided insights into the structural determinants of oligomer toxicity and potential therapeutic strategies.
ACCOUNTS OF CHEMICAL RESEARCH
(2023)
Review
Pharmacology & Pharmacy
Michele Vendruscolo
Summary: Protein misfolding diseases, such as Alzheimer's and Parkinson's diseases, have a major impact on our healthcare systems and societies. This paper discusses drug discovery strategies to target protein misfolding and aggregation, including thermodynamic and kinetic approaches. There is a need for disease-modifying treatments to address the over 50 human disorders associated with protein misfolding and aggregation.
EXPERT OPINION ON DRUG DISCOVERY
(2023)
Review
Clinical Neurology
Mark R. Wilson, Sandeep Satapathy, Michele Vendruscolo
Summary: The proteostasis system regulates cellular processes of protein synthesis, folding, concentration, trafficking, and degradation. The mechanisms of extracellular proteostasis, particularly in the context of neurodegenerative diseases, are not well understood, but growing evidence suggests that impairment of this system may contribute to neuronal death.
NATURE REVIEWS NEUROLOGY
(2023)
Article
Biochemistry & Molecular Biology
Andras Hatos, Joao M. C. Teixeira, Susana Barrera-Vilarmau, Attila Horvath, Silvio C. E. Tosatto, Michele Vendruscolo, Monika Fuxreiter
Summary: Proteins form complex interactions in the cellular environment. The FuzPred server predicts their binding modes based on sequence without specifying the binding partners. The server also estimates the multiplicity of binding modes and visualizes different interaction behaviors on protein structures.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Multidisciplinary Sciences
Alyssa Miller, Jiapeng Wei, Sarah Meehan, Christopher M. Dobson, Mark E. Welland, David Klenerman, Michele Vendruscolo, Francesco Simone Ruggeri, Tuomas P. J. Knowles
Summary: Neurodegenerative diseases such as Alzheimer's disease are caused by protein misfolding and aggregation into amyloid fibrils. This study uses atomic force microscopy and statistical theory to characterize amyloid ring structures derived from the brains of AD patients and explains the diversity in the structures formed from protein aggregation. The results show that ex vivo protofibril chains possess greater flexibility than mature amyloid fibrils, allowing them to form end-to-end connections and shedding light on their role in disease.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biochemistry & Molecular Biology
Z. Faidon Brotzakis, Thomas Lohr, Steven Truong, Samuel Hoff, Massimiliano Bonomi, Michele Vendruscolo
Summary: In recent years, cryo-electron microscopy has made significant advancements in determining biomolecular structures at the atomic level. However, studying large systems with continuous dynamics using this method has been a challenge. To address this, the metadynamic electron microscopy metainference (MEMMI) method was developed, which combines cryo-EM density maps with prior information to determine the structure and dynamics of large heterogeneous systems. This method was applied to study the amyloid fibril dynamics of the islet amyloid polypeptide (IAPP), revealing interesting characteristics of the fibril's structural variability and liquid-like dynamics in the core region.
Article
Multidisciplinary Sciences
Christine M. Lim, Alicia Gonzalez Diaz, Monika Fuxreiter, Frank W. Pun, Alex Zhavoronkov, Michele Vendruscolo
Summary: This study presents an approach that combines the PandaOmics platform with the FuzDrop method to identify disease-associated proteins prone to protein phase separation (PPS). The validated targets for Alzheimer's disease suggest the potential of this approach in identifying therapeutic targets for diseases involving dysregulation of PPS.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Review
Physics, Applied
Thomas C. T. Michaels, Daoyuan Qian, Andela Saric, Michele Vendruscolo, Sara Linse, Tuomas P. J. Knowles
Summary: This Review discusses the general protein self-assembly behavior of amyloid fibrils, which is associated with functional biology and the development of diseases such as Alzheimer and Parkinson diseases. It summarizes recent progress in describing the biophysical features of amyloid self-assembly as a nucleation-and-growth process, highlighting the role of secondary nucleation. The Review also outlines non-classical aspects of aggregate formation and discusses their implications for understanding and modulating protein assembly pathways.
NATURE REVIEWS PHYSICS
(2023)