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32 Publications visible to you, out of a total of 32
Co-expression of cytochrome P450 reductases modulates the activity and selectivity of human cytochrome P450 enzymes transiently expressed in Nicotiana benthamiana

Abstract (Expand)

The transient co-expression of various redox partners affects the efficiency of human hepatic cytochrome P450 enzymes (CYP) in a plant-based biotransformation system. Using Nicotiana benthamiana as a … host, we investigated the interaction of CYP1A2, CYP2D6, and CYP3A4 with different cytochrome P450 reductases (CPRs) derived from animal and plant sources. While human CPR typically enhance or maintain CYP activity, plant-derived CPRs can either enhance or significantly inhibit the metabolism of specific drugs. Additionally, the co-expression of an alternative redox partner, cytochrome b5, can enhance, inhibit, or have no effect on human CYP catalysis, depending on the specific CYP involved. For the majority of CYP/CPR/substrate combinations, we selected variants beneficial for CYP-mediated biotransformation, resulting in a 1.8-4.3-fold increase in product accumulation. We also developed chimeric human-plant CPR variants by swapping structural domains, thereby allowing identification of specific regions responsible for different levels of CYP2D6 productivity. This approach led to the creation of an enhanced CPR variant with a modified transmembrane domain and improved characteristics compared to the native versions.

Authors: Yuriy V. Sheludko, Iryna M. Gerasymenko, Heribert Warzecha

Date Published: 2026

Publication Type: Preprint

Efficient accumulation of new irregular monoterpene malonyl glucosides in Nicotiana benthamiana achieved by co-expression of isoprenyl diphosphate synthases and substrate-producing enzymes

Abstract (Expand)

Irregular monoterpenes have limited natural sources but possess unique activities applicable in medicine and agriculture. To enable sustainable plant-based production of these compounds, we established … a transient expression procedure to enhance the biosynthetic flux in Nicotiana benthamiana toward dimethylallyl diphosphate (DMAPP), a substrate for isopentenyl diphosphate synthases (IDSs) that generate irregular monoterpene skeletons. Considering the benefits of glycosylation for accumulating and storing monoterpenes in extractable form, we focused on developing a platform for the production of non-volatile glycosylated irregular monoterpenes using three IDS that form branched and cyclic structures. The analysis of methanolic leaf extracts from transiently transformed N. benthamiana plants revealed six major new components, 6-O-malonyl-β-D-glucopyranoside and 6-O-malonyl-β-D-glucopyranosyl-(1→2)-β-D-glucopyranoside derivatives of chrysanthemol, lavandulol and cyclolavandulol, five of which are novel compounds. Alleviating two bottlenecks in the DMAPP formation in plastids by co-expressing 1-deoxyxylulose 5-phosphate synthase and isopentenyl diphosphate isomerases increased the yield of chrysantemyl and lavandulyl glucosides produced by plant-derived IDS to 1.7 ± 0.4 μmol g-1 FW and 1.4 ± 0.3 μmol g-1 FW, respectively. A bacterial cyclolavandulyl diphosphate synthase operated efficiently in chloroplasts and cytoplasm. The highest irregular monoterpene concentrations were achieved in cytoplasm by co-expression of hydroxymethylglutaryl-CoA reductase, the bottleneck enzyme of the mevalonate pathway for DMAPP biosynthesis. The mean level of cyclolavandulyl glucosides reached 3.9 ± 1.5 μmol g-1 FW; the top-performing plants contained 6.6 μmol g-1 FW. This yield represents the highest amount of irregular monoterpenes produced in plant systems.

Authors: Iryna Gerasymenko, Yuriy V. Sheludko, Volker Schmidts, Heribert Warzecha

Date Published: 6th Oct 2025

Publication Type: Journal Article

Diverse Metabolic Control of Phosphoglucomutases by Bisphosphorylated Sugars in Heterotrophic Bacteria

Abstract (Expand)

Introduction: Phosphoglucomutases (PGM) are crucial for bacterial fitness, environmental survival, pathogenicity, and cell envelope stability, making them potential new targets for combating bacterial … infection and transmission. PGM functionality relies on initial phosphorylation by the activator glucose-1,6-bisphosphate (glucose-1,6-BP). While the origin of glucose-1,6-BP in vertebrates is well investigated, a bacterial glucose-1,6-BP synthase was only recently identified in the cyanobacterium Synechocystis. In this photoautotroph, a secondary PGM (SynPGM2) efficiently catalyzes glucose-1,6-BP synthesis from fructose-1,6-bisphosphate (fructose-1,6-BP) and glucose-1-phosphate or glucose-6-phosphate . A homologous PGM from the heterotrophic Bacteroides salyersiae, belonging to the same conserved domain subfamily (cd05800) as SynPGM2, exhibited similar activity, suggesting that bacterial glucose-1,6-BP synthesis is a feature of this specific subfamily. Methods: To investigate the specificity and regulation of various PGM enzymes from different heterotrophic bacteria, recombinant enzymes were purified and analyzed using enzymatic assays and HPLC-MS. Results: We demonstrate that glucose-1,6-BP synthesis extends beyond the cd5800 subfamily to the cd05801, cd05799, and cd03089 subfamilies. PGMs from Escherichia coli (cd05801 and cd03089), Enterococcus faecium (cd05799), Yersinia enterocolitica (cd05801), and Candidatus Gastranaerophilales (cd05800) catalyze the same fructose-1,6-BP-dependent synthesis reaction of glucose-1,6-BP as SynPGM2. Notably, fructose-1,6-BP, a known inhibitor of some PGM, does not inhibit these bacterial PGMs. Moreover, E. faecium PGM, belonging to the same subfamily as the mammalian glucose 1,6 BP synthase, efficiently catalyzes the mammalian-type 1,3-bisphosphoglycerate-dependent glucose 1,6-BP synthesis reaction. Conclusion: All investigated heterotrophic bacteria appear to use their primary PGM for both PGM activity and activator synthesis, suggesting a more versatile and less specialized role for PGMs in heterotrophic bacteria.

Authors: Janette T. Alford, Marina Borisova-Mayer, Christoph Mayer, Karl Forchhammer

Date Published: 16th Jul 2025

Publication Type: Journal Article

The race with microbial factories: Metabolic and protein engineering for production small molecules in plants

Abstract

Not specified

Authors: Iryna Gerasymenko, • Sheludko YV, Heribert Warzecha

Date Published: 5th Mar 2025

Publication Type: Conference Proceeding

Choosing the right partner: Maximizing the efficiency of foreign P450s in plant cells

Abstract

Not specified

Authors: • Sheludko YV, Gerasymenko I

Date Published: 7th Oct 2024

Publication Type: Conference Paper

In situ Product Recovery of Microbially Synthesized Ethyl Acetate from the Exhaust Gas of a Bioreactor by Membrane Technology

Abstract (Expand)

Ethyl acetate is at present exclusively produced from fossil resources. Microbial synthesis of this ester from sugar‐rich waste as an alternative is an aerobic process. Ethyl acetate is highly volatile … and therefore stripped with the exhaust gas from the bioreactor which enables in situ product recovery. Previous research on microbial formation of ethyl acetate has focused on the kinetics of ester synthesis and in part on the ester stripping, while the separation of the ester from the exhaust gas has hardly been investigated. A mixed matrix membrane was developed consisting of Silikalite‐1 embedded in polydimethylsiloxane which was installed in a radial–symmetrical membrane module. Evaluation of the separation of ethyl acetate was based on the analysis of the composition of the feed and retentate gas by mass spectrometry. The separation efficiency of the membrane was first tested with varied flows of artificial exhaust gas, containing defined amounts of ethyl acetate. A model for describing the separation process was parametrized by the measured data and used to design a real separation experiment. Ethyl acetate produced from delactosed whey permeate by Kluyveromyces marxianus DSM 5422 in a stirred bioreactor gassed with 0.5 vvm air was successfully separated from the exhaust gas by membranes; 93.6% of the stripped ester was separated. Liquid ethyl acetate was recovered by cooling the permeate gas to ‒78°C, whereby 99.75% of the condensed organic compounds were ethyl acetate. This study demonstrates for the first time that microbially produced and stripped ethyl acetate can be effectively separated from the exhaust gas of bioreactors by membrane technology to obtain the ester in high yield and purity.

Authors: Andreas Hoffmann, Alexander Franz, Christian Löser, Thomas Hoyer, Marcus Weyd, Thomas Walther

Date Published: 30th Sep 2024

Publication Type: Journal Article

Bayesian modelling of time series data (BayModTS)—a FAIR workflow to process sparse and highly variable data

Abstract (Expand)

Abstract Motivation Systems biology aims to better understand living systems through mathematical modelling of experimental and clinical data. A pervasive challenge in quantitative dynamical modelling …vasive challenge in quantitative dynamical modelling is the integration of time series measurements, which often have high variability and low sampling resolution. Approaches are required to utilize such information while consistently handling uncertainties. Results We present BayModTS (Bayesian modelling of time series data), a new FAIR (findable, accessible, interoperable, and reusable) workflow for processing and analysing sparse and highly variable time series data. BayModTS consistently transfers uncertainties from data to model predictions, including process knowledge via parameterized models. Further, credible differences in the dynamics of different conditions can be identified by filtering noise. To demonstrate the power and versatility of BayModTS, we applied it to three hepatic datasets gathered from three different species and with different measurement techniques: (i) blood perfusion measurements by magnetic resonance imaging in rat livers after portal vein ligation, (ii) pharmacokinetic time series of different drugs in normal and steatotic mice, and (iii) CT-based volumetric assessment of human liver remnants after clinical liver resection. Availability and implementation The BayModTS codebase is available on GitHub at https://github.com/Systems-Theory-in-Systems-Biology/BayModTS. The repository contains a Python script for the executable BayModTS workflow and a widely applicable SBML (systems biology markup language) model for retarded transient functions. In addition, all examples from the paper are included in the repository. Data and code of the application examples are stored on DaRUS: https://doi.org/10.18419/darus-3876. The raw MRI ROI voxel data were uploaded to DaRUS: https://doi.org/10.18419/darus-3878. The steatosis metabolite data are published on FairdomHub: 10.15490/fairdomhub.1.study.1070.1.

Authors: Sebastian Höpfl, Mohamed Albadry, Uta Dahmen, Karl-Heinz Herrmann, Eva Marie Kindler, Matthias König, Jürgen Rainer Reichenbach, Hans-Michael Tautenhahn, Weiwei Wei, Wan-Ting Zhao, Nicole Erika Radde

Date Published: 1st May 2024

Publication Type: Journal Article

Kinetic modeling identifies targets for engineering improved photosynthetic efficiency in potato (Solanum tuberosum cv. Solara).

Abstract (Expand)

Potato (Solanum tuberosum) is a significant non-grain food crop in terms of global production. However, its yield potential might be raised by identifying means to release bottlenecks within photosynthetic … metabolism, from the capture of solar energy to the synthesis of carbohydrates. Recently, engineered increases in photosynthetic rates in other crops have been directly related to increased yield - how might such increases be achieved in potato? To answer this question, we derived the photosynthetic parameters V(cmax) and J(max) to calibrate a kinetic model of leaf metabolism (e-Photosynthesis) for potato. This model was then used to simulate the impact of manipulating the expression of genes and their protein products on carbon assimilation rates in silico through optimizing resource investment among 23 photosynthetic enzymes, predicting increases in photosynthetic CO(2) uptake of up to 67%. However, this number of manipulations would not be practical with current technologies. Given a limited practical number of manipulations, the optimization indicated that an increase in amounts of three enzymes - Rubisco, FBP aldolase, and SBPase - would increase net assimilation. Increasing these alone to the levels predicted necessary for optimization increased photosynthetic rate by 28% in potato.

Authors: S. Vijayakumar, Y. Wang, G. Lehretz, S. Taylor, E. Carmo-Silva, S. Long

Date Published: 30th Jan 2024

Publication Type: Journal Article

Regulation of Rubisco activity in crops.

Abstract (Expand)

Efficient plant acclimation to changing environmental conditions relies on fast adjustments of the transcriptome, proteome, and metabolome. Regulation of enzyme activity depends on the activity of … specific chaperones, chemical post-translational modifications (PTMs) of amino acid residues, and changes in the cellular and organellar microenvironment. Central to carbon assimilation, and thus plant growth and yield, Rubisco activity is regulated by its chaperone Rubisco activase (Rca) and by adjustments in the chloroplast stroma environment. Focused on crops, this review highlights the main PTMs and stromal ions and metabolites affecting Rubisco and Rca in response to environmental stimuli. Rca isoforms differ in regulatory properties and heat sensitivity, with expression changing according to the surrounding environment. Much of the physiological relevance of Rubisco and Rca PTMs is still poorly understood, though some PTMs have been associated with Rubisco regulation in response to stress. Ion and metabolite concentrations in the chloroplast change in response to variations in light and temperature. Some of these changes promote Rubisco activation while others inhibit activation, deactivate the enzyme, or change the rates of catalysis. Understanding these regulatory mechanisms will aid the development of strategies to improve carbon fixation by Rubisco under rapidly changing environments as experienced by crop plants.

Authors: J. Amaral, A. K. M. Lobo, E. Carmo-Silva

Date Published: 11th Dec 2023

Publication Type: Journal Article

Chemical identification and indexing in full-text articles: an overview of the NLM-Chem track at BioCreative VII

Abstract (Expand)

Abstract The BioCreative National Library of Medicine (NLM)-Chem track calls for a community effort to fine-tune automated recognition of chemical names in the biomedical literature. Chemicals are one …cals are one of the most searched biomedical entities in PubMed, and—as highlighted during the coronavirus disease 2019 pandemic—their identification may significantly advance research in multiple biomedical subfields. While previous community challenges focused on identifying chemical names mentioned in titles and abstracts, the full text contains valuable additional detail. We, therefore, organized the BioCreative NLM-Chem track as a community effort to address automated chemical entity recognition in full-text articles. The track consisted of two tasks: (i) chemical identification and (ii) chemical indexing. The chemical identification task required predicting all chemicals mentioned in recently published full-text articles, both span [i.e. named entity recognition (NER)] and normalization (i.e. entity linking), using Medical Subject Headings (MeSH). The chemical indexing task required identifying which chemicals reflect topics for each article and should therefore appear in the listing of MeSH terms for the document in the MEDLINE article indexing. This manuscript summarizes the BioCreative NLM-Chem track and post-challenge experiments. We received a total of 85 submissions from 17 teams worldwide. The highest performance achieved for the chemical identification task was 0.8672 F-score (0.8759 precision and 0.8587 recall) for strict NER performance and 0.8136 F-score (0.8621 precision and 0.7702 recall) for strict normalization performance. The highest performance achieved for the chemical indexing task was 0.6073 F-score (0.7417 precision and 0.5141 recall). This community challenge demonstrated that (i) the current substantial achievements in deep learning technologies can be utilized to improve automated prediction accuracy further and (ii) the chemical indexing task is substantially more challenging. We look forward to further developing biomedical text–mining methods to respond to the rapid growth of biomedical literature. The NLM-Chem track dataset and other challenge materials are publicly available at https://ftp.ncbi.nlm.nih.gov/pub/lu/BC7-NLM-Chem-track/. Database URL https://ftp.ncbi.nlm.nih.gov/pub/lu/BC7-NLM-Chem-track/

Authors: Robert Leaman, Rezarta Islamaj, Virginia Adams, Mohammed A Alliheedi, João Rafael Almeida, Rui Antunes, Robert Bevan, Yung-Chun Chang, Arslan Erdengasileng, Matthew Hodgskiss, Ryuki Ida, Hyunjae Kim, Keqiao Li, Robert E Mercer, Lukrécia Mertová, Ghadeer Mobasher, Hoo-Chang Shin, Mujeen Sung, Tomoki Tsujimura, Wen-Chao Yeh, Zhiyong Lu

Date Published: 2023

Publication Type: Journal Article

Cardiac PI3K p110alpha attenuation delays aging and extends lifespan.

Abstract (Expand)

Phosphoinositide 3-kinase (PI3K) is a key component of the insulin signaling pathway that controls cellular me-tabolism and growth. Loss-of-function mutations in PI3K signaling and other downstream … effectors of the insulin signaling pathway extend the lifespan of various model organisms. However, the pro-longevity effect appears to be sex-specific and young mice with reduced PI3K signaling have increased risk of cardiac disease. Hence, it remains elusive as to whether PI3K inhibition is a valid strategy to delay aging and extend healthspan in humans. We recently demonstrated that reduced PI3K activity in cardiomyocytes delays cardiac growth, causing subnormal contractility and cardiopulmonary functional capacity, as well as increased risk of mortality at young age. In stark contrast, in aged mice, experi-mental attenuation of PI3K signaling reduced the age-dependent decline in cardiac function and extended maximal lifespan, suggesting a biphasic effect of PI3K on cardiac health and survival. The cardiac anti-aging effects of reduced PI3K activity coincided with enhanced oxida-tive phosphorylation and required increased autophagic flux. In humans, explanted failing hearts showed in-creased PI3K signaling, as indicated by increased phos-phorylation of the serine/threonine-protein kinase AKT. Hence, late-life cardiac-specific targeting of PI3K might have a therapeutic potential in cardiac aging and related diseases.

Authors: M. Abdellatif, T. Eisenberg, A. M. Heberle, K. Thedieck, G. Kroemer, S. Sedej

Date Published: 30th Nov 2022

Publication Type: Journal Article

High non-photochemical quenching of VPZ transgenic potato plants limits CO(2) assimilation under high light conditions and reduces tuber yield under fluctuating light.

Abstract (Expand)

Under natural conditions, photosynthesis has to be adjusted to fluctuating light intensities. Leaves exposed to high light dissipate excess light energy in form of heat at photosystem II (PSII) by a … process called non-photochemical quenching (NPQ). Upon fast transition from light to shade, plants lose light energy by a relatively slow relaxation from photoprotection. Combined overexpression of violaxanthin de-epoxidase (VDE), PSII subunit S (PsbS) and zeaxanthin epoxidase (ZEP) in tobacco accelerates relaxation from photoprotection, and increases photosynthetic productivity. In Arabidopsis, expression of the same three genes (VPZ) resulted in a more rapid photoprotection but growth of the transgenic plants was impaired. Here we report on VPZ expressing potato plants grown under various light regimes. Similar to tobacco and Arabidopsis, induction and relaxation of NPQ was accelerated under all growth conditions tested, but did not cause an overall increased photosynthetic rate or growth of transgenic plants. Tuber yield of VPZ expressing plants was unaltered as compared to control plants under constant light conditions and even decreased under fluctuating light conditions. Under control conditions, levels of the phytohormone abscisic acid (ABA) were found to be elevated, indicating an increased violaxanthin availability in VPZ plants. However, the increased basal ABA levels did not improve drought tolerance of VPZ transgenic potato plants under greenhouse conditions. The failure to benefit from improved photoprotection is most likely caused by a reduced radiation use efficiency under high light conditions resulting from a too strong NPQ induction. Mitigating this negative effect in the future might help to improve photosynthetic performance in VPZ expressing potato plants.

Authors: G. G. Lehretz, A. Schneider, D. Leister, U. Sonnewald

Date Published: 29th Jun 2022

Publication Type: Journal Article

Combining dictionary- and rule-based approximate entity linking with tuned BioBERT

Abstract (Expand)

Chemical named entity recognition (NER) is a significant step for many downstream applications like entity linking for the chemical text-mining pipeline. However, the identification of chemical entities … in a biomedical text is a challenging task due to the diverse morphology of chemical entities and the different types of chemical nomenclature. In this work, we describe our approach that was submitted for BioCreative version 7 challenge Track 2, focusing on the ‘Chemical Identification’ task for identifying chemical entities and entity linking, using MeSH. For this purpose, we have applied a two-stage approach as follows (a) usage of fine-tuned BioBERT for identification of chemical entities (b) semantic approximate search in MeSH and PubChem databases for entity linking. There was some friction between the two approaches, as our rule-based approach did not harmonise optimally with partially recognized words forwarded by the BERT component. For our future work, we aim to resolve the issue of the artefacts arising from BERT tokenizers and develop joint learning of chemical named entity recognition and entity linking using pre-trained transformer-based models and compare their performance with our preliminary approach. Next, we will improve the efficiency of our approximate search in reference databases during entity linking. This task is non-trivial as it entails determining similarity scores of large sets of trees with respect to a query tree. Ideally, this will enable flexible parametrization and rule selection for the entity linking search.

Authors: Ghadeer Mobasher, Lukrécia Mertová, Sucheta Ghosh, Olga Krebs, Bettina Heinlein, Wolfgang Müller

Date Published: 11th Nov 2021

Publication Type: Conference Proceeding

Assimilate highway to sink organs - Physiological consequences of SP6A overexpression in transgenic potato (Solanum tuberosum L.).

Abstract (Expand)

Leaf/stem-specific overexpression of SP6A, the FLOWERING LOCUS T homolog in potato (Solanum tuberosum), was previously shown to induce tuberization leading to higher tuber numbers and yield under ambient … and abiotic stress conditions. In this study, we investigated the mechanism underlying SP6A action. Overexpression of SP6A reduced shoot growth, mainly by inhibition of stem elongation and secondary growth, and by repression of apical bud outgrowth. In contrast, root growth and lateral shoot emergence from basal nodes was promoted. Tracer experiments using the fluorescent sucrose analogue esculin revealed that stems of SP6A overexpressing plants transport assimilates more efficiently to belowground sinks, e.g. roots and tubers, compared to wild-type plants. This was accompanied by a lower level of sucrose leakage from the transport phloem into neighboring parenchyma cells and the inhibition of flower formation. We demonstrate the ability of SP6A to control assimilate allocation to belowground sinks and postulate that selection of beneficial SP6A alleles will enable potato breeding to alter plant architecture and to increase tuber yield under conditions of expected climate change.

Authors: G. G. Lehretz, S. Sonnewald, U. Sonnewald

Date Published: 6th Oct 2021

Publication Type: Journal Article

Quality control in scRNA-Seq can discriminate pacemaker cells: the mtRNA bias.

Abstract (Expand)

Single-cell RNA-sequencing (scRNA-seq) provides high-resolution insights into complex tissues. Cardiac tissue, however, poses a major challenge due to the delicate isolation process and the large size … of mature cardiomyocytes. Regardless of the experimental technique, captured cells are often impaired and some capture sites may contain multiple or no cells at all. All this refers to "low quality" potentially leading to data misinterpretation. Common standard quality control parameters involve the number of detected genes, transcripts per cell, and the fraction of transcripts from mitochondrial genes. While cutoffs for transcripts and genes per cell are usually user-defined for each experiment or individually calculated, a fixed threshold of 5% mitochondrial transcripts is standard and often set as default in scRNA-seq software. However, this parameter is highly dependent on the tissue type. In the heart, mitochondrial transcripts comprise almost 30% of total mRNA due to high energy demands. Here, we demonstrate that a 5%-threshold not only causes an unacceptable exclusion of cardiomyocytes but also introduces a bias that particularly discriminates pacemaker cells. This effect is apparent for our in vitro generated induced-sinoatrial-bodies (iSABs; highly enriched physiologically functional pacemaker cells), and also evident in a public data set of cells isolated from embryonal murine sinoatrial node tissue (Goodyer William et al. in Circ Res 125:379-397, 2019). Taken together, we recommend omitting this filtering parameter for scRNA-seq in cardiovascular applications whenever possible.

Authors: A. M. Galow, S. Kussauer, M. Wolfien, R. M. Brunner, T. Goldammer, R. David, A. Hoeflich

Date Published: 24th Aug 2021

Publication Type: Text

Welcome to the Family: Identification of the NAD(+) Transporter of Animal Mitochondria as Member of the Solute Carrier Family SLC25.

Abstract (Expand)

Subcellular compartmentation is a fundamental property of eukaryotic cells. Communication and metabolic and regulatory interconnectivity between organelles require that solutes can be transported across … their surrounding membranes. Indeed, in mammals, there are hundreds of genes encoding solute carriers (SLCs) which mediate the selective transport of molecules such as nucleotides, amino acids, and sugars across biological membranes. Research over many years has identified the localization and preferred substrates of a large variety of SLCs. Of particular interest has been the SLC25 family, which includes carriers embedded in the inner membrane of mitochondria to secure the supply of these organelles with major metabolic intermediates and coenzymes. The substrate specificity of many of these carriers has been established in the past. However, the route by which animal mitochondria are supplied with NAD(+) had long remained obscure. Only just recently, the existence of a human mitochondrial NAD(+) carrier was firmly established. With the realization that SLC25A51 (or MCART1) represents the major mitochondrial NAD(+) carrier in mammals, a long-standing mystery in NAD(+) biology has been resolved. Here, we summarize the functional importance and structural features of this carrier as well as the key observations leading to its discovery.

Authors: M. Ziegler, M. Monne, A. Nikiforov, G. Agrimi, I. Heiland, F. Palmieri

Date Published: 14th Jun 2021

Publication Type: Journal Article

Finding new edges: systems approaches to MTOR signaling.

Abstract (Expand)

Cells have evolved highly intertwined kinase networks to finely tune cellular homeostasis to the environment. The network converging on the mechanistic target of rapamycin (MTOR) kinase constitutes a … central hub that integrates metabolic signals and adapts cellular metabolism and functions to nutritional changes and stress. Feedforward and feedback loops, crosstalks and a plethora of modulators finely balance MTOR-driven anabolic and catabolic processes. This complexity renders it difficult - if not impossible - to intuitively decipher signaling dynamics and network topology. Over the last two decades, systems approaches have emerged as powerful tools to simulate signaling network dynamics and responses. In this review, we discuss the contribution of systems studies to the discovery of novel edges and modulators in the MTOR network in healthy cells and in disease.

Authors: A. M. Heberle, U. Rehbein, M. Rodriguez Peiris, K. Thedieck

Date Published: 26th Feb 2021

Publication Type: Journal Article

Future-Proofing Potato for Drought and Heat Tolerance by Overexpression of Hexokinase and SP6A.

Abstract (Expand)

Crop yield is largely affected by global climate change. Especially periods of heat and drought limit crop productivity worldwide. According to current models of future climate scenarios, heatwaves and … periods of drought are likely to increase. Potato, as an important food crop of temperate latitudes, is very sensitive to heat and drought which impact tuber yield and quality. To improve abiotic stress resilience of potato plants, we aimed at co-expressing hexokinase 1 from Arabidopsis thaliana (AtHXK1) in guard cells and SELF-PRUNING 6A (SP6A) using the leaf/stem-specific StLS1 promoter in order to increase water use efficiency as well as tuberization under drought and heat stress. Guard cell-specific expression of AtHXK1 decreased stomatal conductance and improved water use efficiency of transgenic potato plants as has been shown for other crop plants. Additionally, co-expression with the FT-homolog SP6A stimulated tuberization and improved assimilate allocation to developing tubers under control as well as under single and combined drought and heat stress conditions. Thus, co-expression of both proteins provides a novel strategy to improve abiotic stress tolerance of potato plants.

Authors: G. G. Lehretz, S. Sonnewald, N. Lugassi, D. Granot, U. Sonnewald

Date Published: 29th Jan 2021

Publication Type: Journal Article

Identification of evolutionary and kinetic drivers of NAD-dependent signaling

Abstract

Not specified

Authors: Mathias Bockwoldt, Dorothée Houry, Marc Niere, Toni I. Gossmann, Ines Reinartz, Alexander Schug, Mathias Ziegler, Ines Heiland

Date Published: 6th Aug 2019

Publication Type: Journal Article

Predicting strain engineering strategies using iKS1317: a genome‐scale metabolic model of Streptomyces coelicolor

Abstract

Not specified

Authors: Tjaša Kumelj, Snorre Sulheim, Alexander Wentzel, Eivind Almaas

Date Published: 7th Dec 2018

Publication Type: Not specified

Comparison of 432 Pseudomonas strains through integration of genomic, functional, metabolic and expression data.

Abstract (Expand)

Pseudomonas is a highly versatile genus containing species that can be harmful to humans and plants while others are widely used for bioengineering and bioremediation. We analysed 432 sequenced Pseudomonas … strains by integrating results from a large scale functional comparison using protein domains with data from six metabolic models, nearly a thousand transcriptome measurements and four large scale transposon mutagenesis experiments. Through heterogeneous data integration we linked gene essentiality, persistence and expression variability. The pan-genome of Pseudomonas is closed indicating a limited role of horizontal gene transfer in the evolutionary history of this genus. A large fraction of essential genes are highly persistent, still non essential genes represent a considerable fraction of the core-genome. Our results emphasize the power of integrating large scale comparative functional genomics with heterogeneous data for exploring bacterial diversity and versatility.

Authors: J. J. Koehorst, J. C. van Dam, R. G. van Heck, E. Saccenti, V. A. Dos Santos, M. Suarez-Diez, P. J. Schaap

Date Published: 6th Dec 2016

Publication Type: Journal Article

Subcellular Distribution of NAD+ between Cytosol and Mitochondria Determines the Metabolic Profile of Human Cells.

Abstract (Expand)

The mitochondrial NAD pool is particularly important for the maintenance of vital cellular functions. Although at least in some fungi and plants, mitochondrial NAD is imported from the cytosol by carrier … proteins, in mammals, the mechanism of how this organellar pool is generated has remained obscure. A transporter mediating NAD import into mammalian mitochondria has not been identified. In contrast, human recombinant NMNAT3 localizes to the mitochondrial matrix and is able to catalyze NAD(+) biosynthesis in vitro. However, whether the endogenous NMNAT3 protein is functionally effective at generating NAD(+) in mitochondria of intact human cells still remains to be demonstrated. To modulate mitochondrial NAD(+) content, we have expressed plant and yeast mitochondrial NAD(+) carriers in human cells and observed a profound increase in mitochondrial NAD(+). None of the closest human homologs of these carriers had any detectable effect on mitochondrial NAD(+) content. Surprisingly, constitutive redistribution of NAD(+) from the cytosol to the mitochondria by stable expression of the Arabidopsis thaliana mitochondrial NAD(+) transporter NDT2 in HEK293 cells resulted in dramatic growth retardation and a metabolic shift from oxidative phosphorylation to glycolysis, despite the elevated mitochondrial NAD(+) levels. These results suggest that a mitochondrial NAD(+) transporter, similar to the known one from A. thaliana, is likely absent and could even be harmful in human cells. We provide further support for the alternative possibility, namely intramitochondrial NAD(+) synthesis, by demonstrating the presence of endogenous NMNAT3 in the mitochondria of human cells.

Authors: M. R. VanLinden, C. Dolle, I. K. Pettersen, V. A. Kulikova, M. Niere, G. Agrimi, S. E. Dyrstad, F. Palmieri, A. A. Nikiforov, K. J. Tronstad, M. Ziegler

Date Published: 13th Nov 2015

Publication Type: Not specified

RobOKoD: microbial strain design for (over)production of target compounds

Abstract (Expand)

Sustainable production of target compounds such as biofuels and high-value chemicals for pharmaceutical, agrochemical, and chemical industries is becoming an increasing priority given their current … dependency upon diminishing petrochemical resources. Designing these strains is difficult, with current methods focusing primarily on knocking-out genes, dismissing other vital steps of strain design including the overexpression and dampening of genes. The design predictions from current methods also do not translate well-into successful strains in the laboratory. Here, we introduce RobOKoD (Robust, Overexpression, Knockout and Dampening), a method for predicting strain designs for overproduction of targets. The method uses flux variability analysis to profile each reaction within the system under differing production percentages of target-compound and biomass. Using these profiles, reactions are identified as potential knockout, overexpression, or dampening targets. The identified reactions are ranked according to their suitability, providing flexibility in strain design for users. The software was tested by designing a butanol-producing Escherichia coli strain, and was compared against the popular OptKnock and RobustKnock methods. RobOKoD shows favorable design predictions, when predictions from these methods are compared to a successful butanol-producing experimentally-validated strain. Overall RobOKoD provides users with rankings of predicted beneficial genetic interventions with which to support optimized strain design.

Authors: N. J. Stanford, P. Millard, N. Swainston

Date Published: 24th Mar 2015

Publication Type: Not specified

Large-scale metabolome analysis and quantitative integration with genomics and proteomics data in Mycoplasma pneumoniae.

Abstract (Expand)

Systems metabolomics, the identification and quantification of cellular metabolites and their integration with genomics and proteomics data, promises valuable functional insights into cellular biology. … However, technical constraints, sample complexity issues and the lack of suitable complementary quantitative data sets prevented accomplishing such studies in the past. Here, we present an integrative metabolomics study of the genome-reduced bacterium Mycoplasma pneumoniae. We experimentally analysed its metabolome using a cross-platform approach. We explain intracellular metabolite homeostasis by quantitatively integrating our results with the cellular inventory of proteins, DNA and other macromolecules, as well as with available building blocks from the growth medium. We calculated in vivo catalytic parameters of glycolytic enzymes, making use of measured reaction velocities, as well as enzyme and metabolite pool sizes. A quantitative, inter-species comparison of absolute and relative metabolite abundances indicated that metabolic pathways are regulated as functional units, thereby simplifying adaptive responses. Our analysis demonstrates the potential for new scientific insight by integrating different types of large-scale experimental data from a single biological source.

Authors: T. Maier, J. Marcos, J. A. Wodke, B. Paetzold, M. Liebeke, R. Gutierrez-Gallego, L. Serrano

Date Published: 20th Apr 2013

Publication Type: Not specified

Dissecting the energy metabolism in Mycoplasma pneumoniae through genome-scale metabolic modeling.

Abstract (Expand)

Mycoplasma pneumoniae, a threatening pathogen with a minimal genome, is a model organism for bacterial systems biology for which substantial experimental information is available. With the goal of … understanding the complex interactions underlying its metabolism, we analyzed and characterized the metabolic network of M. pneumoniae in great detail, integrating data from different omics analyses under a range of conditions into a constraint-based model backbone. Iterating model predictions, hypothesis generation, experimental testing, and model refinement, we accurately curated the network and quantitatively explored the energy metabolism. In contrast to other bacteria, M. pneumoniae uses most of its energy for maintenance tasks instead of growth. We show that in highly linear networks the prediction of flux distributions for different growth times allows analysis of time-dependent changes, albeit using a static model. By performing an in silico knock-out study as well as analyzing flux distributions in single and double mutant phenotypes, we demonstrated that the model accurately represents the metabolism of M. pneumoniae. The experimentally validated model provides a solid basis for understanding its metabolic regulatory mechanisms.

Authors: J. A. Wodke, J. Puchalka, M. Lluch-Senar, J. Marcos, E. Yus, M. Godinho, R. Gutierrez-Gallego, V. A. dos Santos, L. Serrano, E. Klipp, T. Maier

Date Published: 4th Apr 2013

Publication Type: Not specified

Engineering an anaerobic metabolic regime in Pseudomonas putida KT2440 for the anoxic biodegradation of 1,3-dichloroprop-1-ene

Abstract

Not specified

Authors: Pablo I. Nikel, Víctor de Lorenzo

Date Published: 2013

Publication Type: Not specified

Modelling reveals novel roles of two parallel signalling pathways and homeostatic feedbacks in yeast

Abstract (Expand)

The high osmolarity glycerol (HOG) pathway in yeast serves as a prototype signalling system for eukaryotes. We used an unprecedented amount of data to parameterise 192 models capturing different … hypotheses about molecular mechanisms underlying osmo-adaptation and selected a best approximating model. This model implied novel mechanisms regulating osmo-adaptation in yeast. The model suggested that (i) the main mechanism for osmo-adaptation is a fast and transient non-transcriptional Hog1-mediated activation of glycerol production, (ii) the transcriptional response serves to maintain an increased steady-state glycerol production with low steady-state Hog1 activity, and (iii) fast negative feedbacks of activated Hog1 on upstream signalling branches serves to stabilise adaptation response. The best approximating model also indicated that homoeostatic adaptive systems with two parallel redundant signalling branches show a more robust and faster response than single-branch systems. We corroborated this notion to a large extent by dedicated measurements of volume recovery in single cells. Our study also demonstrates that systematically testing a model ensemble against data has the potential to achieve a better and unbiased understanding of molecular mechanisms.

Authors: J. Schaber, R. Baltanas, A. Bush, E. Klipp, A. Colman-Lerner

Date Published: 15th Nov 2012

Publication Type: Not specified

Reconciliation of Genome-Scale Metabolic Reconstructions for Comparative Systems Analysis

Abstract

Not specified

Authors: Matthew A. Oberhardt, Jacek Puchałka, Vítor A. P. Martins dos Santos, Jason A. Papin

Date Published: 31st Mar 2011

Publication Type: Not specified

In silico genome-scale metabolic analysis of Pseudomonas putida KT2440 for polyhydroxyalkanoate synthesis, degradation of aromatics and anaerobic survival

Abstract

Not specified

Authors: Seung Bum Sohn, Tae Yong Kim, Jong Myoung Park, Sang Yup Lee

Date Published: 1st Jul 2010

Publication Type: Not specified

Nested autoinhibitory feedbacks alter the resistance of homeostatic adaptive biochemical networks

Abstract (Expand)

Negative feedback control is a ubiquitous feature of biochemical systems, as is time delay between a signal and its response. Negative feedback in conjunction with time delay can lead to oscillations. … In a cellular context, it might be beneficial to mitigate oscillatory behaviour to avoid recurring stress situations. This can be achieved by increasing the distance between the parameters of the system and certain thresholds, beyond which oscillations occur. This distance has been termed resistance. Here, we prove that in a generic three-dimensional negative feedback system the resistance of the system is modified by nested autoinhibitory feedbacks. Our system features negative feedbacks through both input-inhibition as well as output-activation, a signalling component with mass conservation and perfect adaptation. We show that these features render the system applicable to biological data, exemplified by the high osmolarity glycerol system in yeast and the mammalian p53 system. Output-activation is better supported by data than input-inhibition and also shows distinguished properties with respect to the system's stimulus. Our general approach might be useful in designing synthetic systems in which oscillations can be tuned by synthetic autoinhibitory feedbacks.

Authors: J. Schaber, A. Lapytsko, D. Flockerzi

Date Published: No date defined

Publication Type: Not specified

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