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47 Publications visible to you, out of a total of 55
Yeast-Based Biosynthesis of Natural Products From Xylose.

Abstract (Expand)

Xylose is the second most abundant sugar in lignocellulosic hydrolysates. Transformation of xylose into valuable chemicals, such as plant natural products, is a feasible and sustainable route to … industrializing biorefinery of biomass materials. Yeast strains, including Saccharomyces cerevisiae, Scheffersomyces stipitis, and Yarrowia lipolytica, display some paramount advantages in expressing heterologous enzymes and pathways from various sources and have been engineered extensively to produce natural products. In this review, we summarize the advances in the development of metabolically engineered yeasts to produce natural products from xylose, including aromatics, terpenoids, and flavonoids. The state-of-the-art metabolic engineering strategies and representative examples are reviewed. Future challenges and perspectives are also discussed on yeast engineering for commercial production of natural products using xylose as feedstocks.

Authors: J. Zha, M. Yuwen, W. Qian, X. Wu

Date Published: 22nd Feb 2021

Publication Type: Journal

Solvent Selection in Homogeneous Catalysis—Optimization of Kinetics and Reaction Performance

Abstract

Not specified

Authors: Fabian Huxoll, Froze Jameel, Jonas Bianga, Thomas Seidensticker, Matthias Stein, Gabriele Sadowski, Dieter Vogt

Date Published: 15th Jan 2021

Publication Type: Journal

Biased Ligands Differentially Shape the Conformation of the Extracellular Loop Region in 5-HT2B Receptors.

Abstract (Expand)

G protein-coupled receptors are linked to various intracellular transducers, each pathway associated with different physiological effects. Biased ligands, capable of activating one pathway over another, … are gaining attention for their therapeutic potential, as they could selectively activate beneficial pathways whilst avoiding those responsible for adverse effects. We performed molecular dynamics simulations with known beta-arrestin-biased ligands like lysergic acid diethylamide and ergotamine in complex with the 5-HT2B receptor and discovered that the extent of ligand bias is directly connected with the degree of closure of the extracellular loop region. Given a loose allosteric coupling of extracellular and intracellular receptor regions, we delineate a concept for biased signaling at serotonin receptors, by which conformational interference with binding pocket closure restricts the signaling repertoire of the receptor. Molecular docking studies of biased ligands gathered from the BiasDB demonstrate that larger ligands only show plausible docking poses in the ergotamine-bound structure, highlighting the conformational constraints associated with bias. This emphasizes the importance of selecting the appropriate receptor conformation on which to base virtual screening workflows in structure-based drug design of biased ligands. As this mechanism of ligand bias has also been observed for muscarinic receptors, our studies provide a general mechanism of signaling bias transferable between aminergic receptors.

Authors: K. Denzinger, T. N. Nguyen, T. Noonan, G. Wolber, M. Bermudez

Date Published: 20th Dec 2020

Publication Type: Journal

Cultivar-specific transcriptome and pan-transcriptome reconstruction of tetraploid potato.

Abstract (Expand)

Although the reference genome of Solanum tuberosum Group Phureja double-monoploid (DM) clone is available, knowledge on the genetic diversity of the highly heterozygous tetraploid Group Tuberosum, … representing most cultivated varieties, remains largely unexplored. This lack of knowledge hinders further progress in potato research. In conducted investigation, we first merged and manually curated the two existing partially-overlapping DM genome-based gene models, creating a union of genes in Phureja scaffold. Next, we compiled available and newly generated RNA-Seq datasets (cca. 1.5 billion reads) for three tetraploid potato genotypes (cultivar Desiree, cultivar Rywal, and breeding clone PW363) with diverse breeding pedigrees. Short-read transcriptomes were assembled using several de novo assemblers under different settings to test for optimal outcome. For cultivar Rywal, PacBio Iso-Seq full-length transcriptome sequencing was also performed. EvidentialGene redundancy-reducing pipeline complemented with in-house developed scripts was employed to produce accurate and complete cultivar-specific transcriptomes, as well as to attain the pan-transcriptome. The generated transcriptomes and pan-transcriptome represent a valuable resource for potato gene variability exploration, high-throughput omics analyses, and breeding programmes.

Authors: M. Petek, M. Zagorscak, Z. Ramsak, S. Sanders, S. Tomaz, E. Tseng, M. Zouine, A. Coll, K. Gruden

Date Published: 24th Jul 2020

Publication Type: Journal

Comparison of Three Xylose Pathways in Pseudomonas putida KT2440 for the Synthesis of Valuable Products

Abstract (Expand)

Pseudomonas putida KT2440 is a well-established chassis in industrial biotechnology. To increase the substrate spectrum, we implemented three alternative xylose utilization pathways, namely the Isomerase, … Weimberg, and Dahms pathways. The synthetic operons contain genes from Escherichia coli and Pseudomonas taiwanensis. For isolating the Dahms pathway in P. putida KT2440 two genes (PP_2836 and PP_4283), encoding an endogenous enzyme of the Weimberg pathway and a regulator for glycolaldehyde degradation, were deleted. Before and after adaptive laboratory evolution, these strains were characterized in terms of growth and synthesis of mono-rhamnolipids and pyocyanin. The engineered strain using the Weimberg pathway reached the highest maximal growth rate of 0.30 h−1. After adaptive laboratory evolution the lag phase was reduced significantly. The highest titers of 720mg L−1 mono-rhamnolipids and 30mg L−1 pyocyanin were reached by the evolved strain using the Weimberg or an engineered strain using the Isomerase pathway, respectively. The different stoichiometries of the three xylose utilization pathways may allow engineering of tailored chassis for valuable bioproduct synthesis.

Authors: Isabel Bator, Andreas Wittgens, Frank Rosenau, Till Tiso, Lars M. Blank

Date Published: 17th Jan 2020

Publication Type: Not specified

Computational characterization of the glutamate receptor antagonist perampanel and its close analogs: density functional exploration of conformational space and molecular docking study

Abstract (Expand)

Perampanel approved by FDA in 2012 is a first-in-class antiepileptic drug which inhibits α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor currents. It is markedly more active than … many of its close analogs, and the reasons for this activity difference are not quite clear. Recent crystallographic studies allowed the authors to identify the location of its binding site. Unfortunately, the resolution is low, and the detailed description of perampanel binding mode is still in part speculative. Here we provide a detailed DFT-level conformational analysis of perampanel in a vacuum and in the solvents, mimicking the protein environment, followed by quantum theory of atoms in molecules (QTAIM), non-covalent interactions (NCI), and natural bond orbital (NBO) analyses. The findings indicate the electrostatic nature of the intramolecular interactions which contribute to energy differences of the conformations in a vacuum whereas the increase of dielectric constant leads to the energy equalization of conformations. Based on these results, the docking study was performed to investigate possible binding modes of perampanel and its close analogs in AMPA receptors. The influence of the pyridine nitrogen and cyano group position was explained based on the results of conformational analysis and molecular docking. These findings may contribute to the design of novel antiepileptic drugs and the development of novel approaches to treat neurodegenerative diseases and major depressive disorder.

Authors: Abdul-Akim D. Guseynov, Sergey A. Pisarev, Dmitry A. Shulga, Vladimir A. Palyulin, Maxim V. Fedorov, Dmitry S. Karlov

Date Published: 1st Oct 2019

Publication Type: Journal

Residue-level determinants of angiopoietin-2 interactions with its receptor Tie2.

Abstract (Expand)

We combined computational and experimental methods to interrogate the binding determinants of angiopoietin-2 (Ang2) to its receptor tyrosine kinase (RTK) Tie2-a central signaling system in angiogenesis, … inflammation, and tumorigenesis. We used physics-based electrostatic and surface-area calculations to identify the subset of interfacial Ang2 and Tie2 residues that can affect binding directly. Using random and site-directed mutagenesis and yeast surface display (YSD), we validated these predictions and identified additional Ang2 positions that affected receptor binding. We then used burial-based calculations to classify the larger set of Ang2 residues that are buried in the Ang2 core, whose mutations can perturb the Ang2 structure and thereby affect interactions with Tie2 indirectly. Our analysis showed that the Ang2-Tie2 interface is dominated by nonpolar contributions, with only three Ang2 and two Tie2 residues that contribute electrostatically to intermolecular interactions. Individual interfacial residues contributed only moderately to binding, suggesting that engineering of this interface will require multiple mutations to reach major effects. Conversely, substitutions in substantially buried Ang2 residues were more prevalent in our experimental screen, reduced binding substantially, and are therefore more likely to have a deleterious effect that might contribute to oncogenesis. Computational analysis of additional RTK-ligand complexes, c-Kit-SCF and M-CSF-c-FMS, and comparison to previous YSD results, further show the utility of our combined methodology.

Authors: A. Bakhman, E. Rabinovich, T. Shlamkovich, N. Papo, M. Kosloff

Date Published: 7th Dec 2018

Publication Type: Journal

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