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Small airways vs large airways in asthma: time for a new perspective

JOURNAL OF APPLIED PHYSIOLOGY 2021年第6期131卷 1839-1841页

作者： Donovan, Graham M. Noble, Peter B. Univ Auckland Dept Math Auckland New Zealand Univ Western Australia Sch Human Sci Crawley WA Australia

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Fluorescent substrates enable specific detection and structure-function insights into human aldehyde dehydrogenase isoforms

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Chemico-biological interactions 2025年 418卷

作者： Raquel Pequerul Daniela Covaleda Andrés S Sánchez-Vaca Laura Torres Andrada Constantinescu Mileidys Perez-Alea Xavier Parés Jaume Farrés Department of Biochemistry and Molecular Biology Faculty of Biosciences Universitat Autònoma de Barcelona Bellaterra Cerdanyola del Vallès Barcelona 08193 Spain. Electronic address: raquel.pequerul@uab.cat. Department of Biochemistry and Molecular Biology Faculty of Biosciences Universitat Autònoma de Barcelona Bellaterra Cerdanyola del Vallès Barcelona 08193 Spain. Unit of Research in Cellular and Molecular Biology Advanced BioDesign-ABD Saint Priest France. Department of Biochemistry and Molecular Biology Faculty of Biosciences Universitat Autònoma de Barcelona Bellaterra Cerdanyola del Vallès Barcelona 08193 Spain. Electronic address: jaume.farres@uab.cat.

Aldehyde dehydrogenase (ALDH) isoforms are widely used as biomarkers and potential drug targets in cancer research. Quantitation of ALDH enzymatic activity in biological samples often relies on the use of commercially available assays that are quite unspecific and do not discriminate between the various ALDH isoforms. The availability of highly purified recombinant ALDH isoforms allowed us to perform a full kinetic characterization of ALDH isoforms with fluorogenic substrates, BODIPY™-aminoacetaldehyde (BAAA), the ALDEFLUOR™ assay reagent, and two naphthaldedyde derivatives, 6-methoxy-2-naphthaldehyde (MONAL-62) and 7-methoxy-1-naphthaldehyde (MONAL-71). All ALDH1A isoforms were active to different extend with BAAA, while ALDH3A1 did not show any activity. Remarkable kinetic differences between ALDH1A1, ALDH1A2, ALDH1A3, ALDH2 and ALDH3A1 were observed with naphthaldehyde derivatives. Exquisite sensitivity was attained with MONAL-62 with a lower detection limit of 2 amol or 10 molecules of enzyme per microliter for ALDH1A1. The high substrate specificity of ALDH1A1 for MONAL-71 provides an alternative assay for the unambiguous identification of this isoform. Enzymatic properties of isoforms were accounted for by in silico simulations of substrate docking to the active site of ALDH structures. In addition to substrate specificity, inhibitor selectivity of each isoform, as assessed by incubation with DIMATE and ABD0171 inhibitors, provided additional information about isoform composition in low-activity samples isolated from cell extracts. The method was successfully applied to the detection of ALDH isoform activity in triple-negative breast cancer cells.

关键词： Breast cancer Enzyme inhibition Fluorescence Kinetic properties Oxidoreductases structure-function relationships

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Deciphering structure, function and mechanism of Plasmodium IspD homologs from their evolutionary imprints

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JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN 2019年第4期33卷 419-436页

作者： Chellapandi, P. Prathiviraj, R. Prisilla, A. Bharathidasan Univ Sch Life Sci Dept Bioinformat Mol Syst Engn Lab Tiruchirappalli 620024 Tamil Nadu India

Malaria is a life-threatening mosquito-borne blood disease caused by infection with Plasmodium parasites. Anti-malarial drug resistance is a global threat to control and eliminate malaria and therefore, it is very important to discover and evaluate new drug targets. The 2-C-methyl-d-erythritol 4-phosphate cytidylyltransferase (IspD) homolog is a second in vivo target for fosmidomycin within isoprenoid biosynthesis in malarial parasites. In the present study, we have deciphered the sequence-structure-function integrity of IspD homologs based on their evolutionary imprints. The function and catalytic mechanism of them were also intensively studied by using sequence-structure homology, molecular modeling, and docking approach. Results of our study indicated that substrate-binding and dimer interface motifs in their structures were extensively conserved and part of them closely related to eubacterial origins. Amino acid substitutions in their coiled-coil regions found to bring a radical change in secondary structural elements, which in turn may change the local structural environment. Arg or Asp was identified as a catalytic site in plasmodium IspD homologs, contributing a direct role in the cytidylyltransferase activity similar to bacterial IspD. Results of molecular docking studies demonstrated how anti-malarial drugs such as fosmidomycin and FR-900098 have competitively interacted with the substrate-binding site of these homologs. As shown by our analysis, species-specific evolutionary imprints in these homologs determine the sequence-structure-function-virulence integrity and binding site alterations in order to confer anti-malarial drug resistance.

关键词： IspD Fosmidomycin Evolutionary imprints Non-mevalonate pathway Apicoplast structure-function relationships Drug target

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Computational Predictions and Experimental Validation of Alkane Oxidative Dehydrogenation by Fe2M MOF Nodes

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ACS CATALYSIS 2020年第2期10卷 1460-1469页

作者： Barona, Melissa Ahn, Sol Morris, William Hoover, William Notestein, Justin M. Farha, Omar K. Snurr, Randall Q. Northwestern Univ Dept Chem & Biol Engn 2145 Sheridan Rd Evanston IL 60208 USA Northwestern Univ Dept Chem 2145 Sheridan Rd Evanston IL 60208 USA NuMat Technol 8025 Lamon Ave Skokie IL 60077 USA

The modular structure of metal organic frameworks (MOFs) makes them promising platforms for catalyst design and for elucidating structure/performance relationships in catalysis. In this work, we systematically varied the composition of the metal nodes (Fe2M) of the MOF PCN-250 and used density functional theory (DFT) to identify promising catalysts for light alkane C-H bond activation. Oxidative dehydrogenation (ODH) of alkanes was studied using N2O as the oxidant to understand the reactivity of the oxocentered Fe2M nodes found in PCN-250, where the Fe ions are in the +3 oxidation state and M is a metal with the oxidation state of +2. We show that the N2O activation barrier is positively correlated with the oxygen-binding energy at the metal center, and the C-H activation barrier is negatively correlated with this same quantity. For clusters containing early transition metals, oxygen binds strongly, facilitating N2O activation but hindering C-H activation. To validate the DFT predictions, we synthesized and tested PCN-250(Fe2M) with M = Mn, Fe, Co, and Ni and found that PCN-250(Fe2Mn) and PCN-250(Fe-3) are more active than PCN-250(Fe2Co) and PCN-250(Fe2Ni) in agreement with the DFT predictions, demonstrating the power of DFT calculations to predict and identify promising MOF catalysts for alkane C-H bond activation in advance of experiments.

关键词： metal-organic frameworks C-H bond activation oxidation catalysis structure-function relationships density functional theory PCN-250 oxidative dehydrogenation

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Crucial Roles of Two Hydrated Mg²⁺ Ions in Reaction Catalysis of the Pistol Ribozyme

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ANGEWANDTE CHEMIE-INTERNATIONAL EDITION 2020年第7期59卷 2837-2843页

作者： Teplova, Marianna Falschlunger, Christoph Krasheninina, Olga Egger, Michaela Ren, Aiming Patel, Dinshaw J. Micura, Ronald Leopold Franzens Univ Inst Organ Chem Innrain 80-82 A-6020 Innsbruck Austria Leopold Franzens Univ Ctr Mol Biosci Innrain 80-82 A-6020 Innsbruck Austria Mem Sloan Kettering Canc Ctr Struct Biol Program New York NY 10065 USA Zhejiang Univ Life Sci Inst Hangzhou 310058 Zhejiang Peoples R China

Pistol ribozymes constitute a new class of small self-cleaving RNAs. Crystal structures have been solved, providing three-dimensional snapshots along the reaction coordinate of pistol phosphodiester cleavage, corresponding to the pre-catalytic state, a vanadate mimic of the transition state, and the product. The results led to the proposed underlying chemical mechanism. Importantly, a hydrated Mg2+ ion remains innersphere-coordinated to N7 of G33 in all three states, and is consistent with its likely role as acid in general acid base catalysis (delta and beta catalysis). Strikingly, the new structures shed light on a second hydrated Mg2+ ion that approaches the scissile phosphate from its binding site in the pre-cleavage state to reach out for water-mediated hydrogen bonding in the cyclophosphate product. The major role of the second Mg2+ ion appears to be the stabilization of product conformation. This study delivers a mechanistic understanding of ribozyme-catalyzed backbone cleavage.

关键词： magnesium oligonucleotides reaction mechanisms RNA structure-function relationships

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Usage ofin situexopolysaccharide-forming lactic acid bacteria in food production: Meat products-A new field of application?

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COMPREHENSIVE REVIEWS IN FOOD SCIENCE AND FOOD SAFETY 2020年第6期19卷 2932-2954页

作者： Loeffler, Myriam Hilbig, Jonas Velasco, Lina Weiss, Jochen Univ Hohenheim Inst Food Sci & Biotechnol Dept Food Mat Sci Garbenstr 21-25 D-70599 Stuttgart Germany

In the meat industry, hydrocolloids and phosphates are used to improve the quality attributes of meat products. However, latest research results revealed that the usage of exopolysaccharide (EPS)-forming lactic acid bacteria (LAB), which are able to produce EPSin situduring processing could be an interesting alternative. The current review aims to give a better understanding of bacterial EPS production in food matrices with a special focus on meat products. This includes an introduction to microbial EPS production (homopolysaccharides as well as heteropolysaccharides) and an overview of parameters affecting EPS formation and yield depending on LAB used. This is followed by a summary of methods to detect and characterize EPS to facilitate a rational selection of starter cultures and fermentation conditions based on desired structure-function relationships in different food matrices. The mechanism of action ofin situgenerated EPS is then highlighted with an emphasis on different meat products. In the process, this review also highlights food additives currently used in meat production that could in the future be replaced byin situEPS-forming LAB.

关键词： exopolysaccharide detection in situexopolysaccharide production lactic acid bacteria meat quality structure-function relationships

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functional implications of pH-induced conformational changes in the Sphingosine kinase 1

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SPECTROCHIMICA ACTA PART A-MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2020年 225卷 117453页

作者： Gupta, Preeti Khan, Faez Iqbal Roy, Sonam Anwar, Saleha Dahiya, Rashmi Alajmi, Mohammed F. Hussain, Afzal Rehman, Md. Tabish Lai, Dakun Hassan, Md. Imtaiyaz Jamia Millia Islamia Ctr Interdisciplinary Res Basic Sci New Delhi 110025 India Univ Elect Sci & Technol China Sch Elect Sci & Engn Chengdu Sichuan Peoples R China King Saud Univ Coll Pharm Dept Pharmacognosy Riyadh Saudi Arabia

Sphingosine kinase 1 (SphK1) catalyzes the conversion of sphingosine to sphingosine-1-phosphate that acts as a bioactive signalling molecule, and regulates various cellular processes including lymphocyte trafficking, angiogenesis and response to apoptotic stimuli. Abnormal expression of SphK1 has been observed in a wide range of cancers highlighting their role in tumour growth and metastasis. This enzyme also plays a critical role in metabolic and inflammatory diseases, including pulmonary fibrosis, diabetic neuropathy and Alzheimer's disease. In the present study, we have investigated the structural and conformational changes in SphK1 at varying pH using various spectroscopic techniques. Consistent results were observed with the function of SphK1 at corresponding pH values. SphK1 maintains its secondary and tertiary structure in the pH range of 7.5-10.0. However, protein aggregation was observed in the acidic pH range (4.0-6.5). At pH 2.0, the SphK1 exists in the molten-globule state. Kinase assay also shows that SphK1 activity was optimal in the pH range of 7.5-8.5. To complement in vitro results, we have performed 100 ns molecular dynamics simulation to examine the effect of pH on the structural stability of SphK1 at molecular level. SphK1 maintains its native conformation in the alkaline pH range with some residual fluctuations detected at acidic pH. A considerable correlation was noticed between spectroscopic, enzymatic activity and MD simulation studies. pH dependent structural changes can be further implicated to understand its association with disease condition, and cellular homeostasis with respect to protein function under variable pH conditions. (C) 2019 Elsevier B.V. All rights reserved.

关键词： Sphingosine kinase 1 structure-function relationships Kinase activity Molecular dynamics simulation Structural genomics pH-induced denaturation

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Accurate and efficient structure-based computational mutagenesis for modeling fluorescence levels of Aequorea victoria green fluorescent protein mutants

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PROTEIN ENGINEERING DESIGN & SELECTION 2020年第33期33卷 gzaa022页

作者： Masso, Majid George Mason Univ Sch Syst Biol Lab Struct Bioinformat 10900 Univ Blvd MS 5B3 Manassas VA 20110 USA

A computational mutagenesis technique was used to characterize the structural effects associated with over 46 000 single and multiple amino acid variants of Aequorea victoria green fluorescent protein (GFP), whose functional effects (fluorescence levels) were recently measured by experimental researchers. For each GFP mutant, the approach generated a single score reflecting the overall change in sequence-structure compatibility relative to native GFP, as well as a vector of environmental perturbation (EP) scores characterizing the impact at all GFP residue positions. A significant GFP structure-function relationship (P < 0.0001) was elucidated by comparing the sequence-structure compatibility scores with the functional data. Next, the computed vectors for GFP mutants were used to train predictive models of fluorescence by implementing random forest (RF) classification and tree regression machine learning algorithms. Classification performance reached 0.93 for sensitivity, 0.91 for precision and 0.90 for balanced accuracy, and regression models led to Pearson's correlation as high as r = 0.83 between experimental and predicted GFP mutant fluorescence. An RF model trained on a subset of over 1000 experimental single residue GFP mutants with measured fluorescence was used for predicting the 3300 remaining unstudied single residue mutants, with results complementing known GFP biochemical and biophysical properties. In addition, models trained on the subset of experimental GFP mutants harboring multiple residue replacements successfully predicted fluorescence of the single residue GFP mutants. The models developed for this study were accurate and efficient, and their predictions outperformed those of several related state-of-the-art methods.

关键词： GFP machine learning prediction structure-function relationships

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structure and kinetic properties of human d-aspartate oxidase, the enzyme-controlling d-aspartate levels in brain

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FASEB JOURNAL 2020年第1期34卷 1182-1197页

作者： Molla, Gianluca Chaves-Sanjuan, Antonio Savinelli, Antonio Nardini, Marco Pollegioni, Loredano Univ Insubria Dipartimento Biotecnol & Sci Vita Via JH Dunant 3 I-21100 Varese Italy Univ Milan Dipartimento Biosci Via Celoria 26 I-20133 Milan Italy

d-Amino acids are the "wrong" enantiomers of amino acids as they are not used in proteins synthesis but evolved in selected functions. On this side, d-aspartate (d-Asp) plays several significant roles in mammals, especially as an agonist of N-methyl-d-aspartate receptors (NMDAR), and is involved in relevant diseases, such as schizophrenia and Alzheimer's disease. In vivo modulation of d-Asp levels represents an intriguing task to cope with such pathological states. As little is known about d-Asp synthesis, the only option for modulating the levels is via degradation, which is due to the flavoenzyme d-aspartate oxidase (DASPO). Here we present the first three-dimensional structure of a DASPO enzyme (from human) which belongs to the d-amino acid oxidase family. Notably, human DASPO differs from human d-amino acid oxidase (attributed to d-serine degradation, the main coagonist of NMDAR) showing peculiar structural features (a specific active site charge distribution), oligomeric state and kinetic mechanism, and a higher FAD affinity and activity. These results provide useful insights into the structure-function relationships of human DASPO: modulating its activity represents now a feasible novel therapeutic target.

关键词： d-aspartate d-aspartate oxidase flavoprotein NMDA receptor structure-function relationships

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functional analysis of BRCA1 RING domain variants: computationally derived structural data can improve upon experimental features for training predictive models

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INTEGRATIVE BIOLOGY 2020年第9期12卷 233-239页

作者： Masso, Majid George Mason Univ Coll Sci Sch Syst Biol 10900 Univ BlvdMS 5B3 Manassas VA 20110 USA

Advancements in the interpretation of variants of unknown significance are critical for improving clinical outcomes. In a recent study, massive parallel assays were used to experimentally quantify the effects of missense substitutions in the RING domain of BRCA1 on E3 ubiquitin ligase activity as well as BARD1 RING domain binding. These attributes were subsequently used for training a predictive model of homology-directed DNA repair levels for these BRCA1 variants relative to wild type, which is critical for tumor suppression. Here, relative structural changes characterizing BRCA1 variants were quantified by using an efficient and cost-free computational mutagenesis technique, and we show that these features lead to improvements in model performance. This work underscores the potential for bench researchers to gain valuable insights from computational tools, prior to implementing costly and time-consuming experiments.

关键词： structure-function relationships computational mutagenesis variants homology-directed DNA repair machine learning prediction

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