61604
2020
2020
eng
1949
1972
24
6
32
article
Oxford University Press
Oxford
1
2020-04-10
2020-04-10
--
Functional features of Trehalose-6-Phosphate Synthase 1
Tre6P synthesis by TPS1 is essential for embryogenesis and postembryonic growth in Arabidopsis, and appropriate Suc signaling by Tre6P is dependent on the noncatalytic domains of TPS1. In Arabidopsis (Arabidopsis thaliana), TREHALOSE-6-PHOSPHATE SYNTHASE1 (TPS1) catalyzes the synthesis of the sucrose-signaling metabolite trehalose 6-phosphate (Tre6P) and is essential for embryogenesis and normal postembryonic growth and development. To understand its molecular functions, we transformed the embryo-lethal tps1-1 null mutant with various forms of TPS1 and with a heterologous TPS (OtsA) from Escherichia coli, under the control of the TPS1 promoter, and tested for complementation. TPS1 protein localized predominantly in the phloem-loading zone and guard cells in leaves, root vasculature, and shoot apical meristem, implicating it in both local and systemic signaling of Suc status. The protein is targeted mainly to the nucleus. Restoring Tre6P synthesis was both necessary and sufficient to rescue the tps1-1 mutant through embryogenesis. However, postembryonic growth and the sucrose-Tre6P relationship were disrupted in some complementation lines. A point mutation (A119W) in the catalytic domain or truncating the C-terminal domain of TPS1 severely compromised growth. Despite having high Tre6P levels, these plants never flowered, possibly because Tre6P signaling was disrupted by two unidentified disaccharide-monophosphates that appeared in these plants. The noncatalytic domains of TPS1 ensure its targeting to the correct subcellular compartment and its catalytic fidelity and are required for appropriate signaling of Suc status by Tre6P.
The Plant Cell
an essential enzyme in Arabidopsis
10.1105/tpc.19.00837
0032-0781
1471-9053
John Edward Lunn
International Max Planck Research School, Primary Metabolism and Plant Growth; Max Planck Society
2020758-X
<a href="https://doi.org/10.25932/publishup-51653">Zweitveröffentlichung in der Schriftenreihe Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe ; 1432</a>
CC-BY - Namensnennung 4.0 International
Franziska Fichtner
Justyna Jadwiga Olas
Regina Feil
Mutsumi Watanabe
Ursula Krause
Rainer Hoefgen
Mark Stitt
John Edward Lunn
eng
uncontrolled
cyanobacterial sucrose-phosphatase
eng
uncontrolled
trehalose 6-phosphate
eng
uncontrolled
vegetative growth
eng
uncontrolled
crystal-structure
eng
uncontrolled
gene-expression
eng
uncontrolled
thaliana
eng
uncontrolled
metabolism
eng
uncontrolled
phosphorylation
eng
uncontrolled
reveals
eng
uncontrolled
proteins
Biowissenschaften; Biologie
Pflanzen (Botanik)
Institut für Biochemie und Biologie
Referiert
Hybrid Open-Access
61689
2021
2021
eng
14
4
33
article
Wiley
Hoboken
1
2021-01-28
2021-01-28
--
Untangling the effect of insulin action on brain mitochondria and metabolism
The regulation of energy homeostasis is controlled by the brain and, besides requiring high amounts of energy, it relies on functional insulin/insulin-like growth factor (IGF)-1 signalling in the central nervous system. This energy is mainly provided by mitochondria in form of ATP. Thus, there is an intricate interplay between mitochondrial function and insulin/IGF-1 action to enable functional brain signalling and, accordingly, propagate a healthy metabolism. To adapt to different nutritional conditions, the brain is able to sense the current energy status via mitochondrial and insulin signalling-dependent pathways and exerts an appropriate metabolic response. However, regional, cell type and receptor-specific consequences of this interaction occur and are linked to diverse outcomes such as altered nutrient sensing, body weight regulation or even cognitive function. Impairments of this cross-talk can lead to obesity and glucose intolerance and are linked to neurodegenerative diseases, yet they also induce a self-sustainable, dysfunctional 'metabolic triangle' characterised by insulin resistance, mitochondrial dysfunction and inflammation in the brain. The identification of causal factors deteriorating insulin action, mitochondrial function and concomitantly a signature of metabolic stress in the brain is of utter importance to offer novel mechanistic insights into development of the continuously rising prevalence of non-communicable diseases such as type 2 diabetes and neurodegeneration. This review aims to determine the effect of insulin action on brain mitochondrial function and energy metabolism. It precisely outlines the interaction and differences between insulin action, insulin-like growth factor (IGF)-1 signalling and mitochondrial function; distinguishes between causality and association; and reveals its consequences for metabolism and cognition. We hypothesise that an improvement of at least one signalling pathway can overcome the vicious cycle of a self-perpetuating metabolic dysfunction in the brain present in metabolic and neurodegenerative diseases.
Journal of neuroendocrinology
10.1111/jne.12932
33506556
0953-8194
1365-2826
outputup:dataSource:PubMed:2021
e12932
WOS:000612334100001
Kleinridders, A (corresponding author), Univ Potsdam, Dept Mol & Expt Nutr Med, Inst Nutr Sci, Arthur Scheunert Allee 114-116, D-14558 Nuthetal, Germany., kleinridders@uni-potsdam.de
Deutsche Forschungsgemeinschaft (DFG)German Research Foundation (DFG) [KL 2399/6-1]; State of Brandenburg [82DZD00302]; BMBFFederal Ministry of Education & Research (BMBF) [031B0569]
Kleinridders, André
2023-12-04T07:58:04+00:00
sword
importub
filename=package.tar
b4fee0417c7517a00c0a9ae234f4b70e
2007386-0
1007517-3
false
true
CC-BY-NC-ND - Namensnennung, nicht kommerziell, keine Bearbeitungen 4.0 International
Mareike Schell
Kristina Wardelmann
Andre Kleinridders
eng
uncontrolled
brain
eng
uncontrolled
energy homeostasis
eng
uncontrolled
inflammation
eng
uncontrolled
insulin signalling
eng
uncontrolled
metabolism
eng
uncontrolled
mitochondrial function
Chemie und zugeordnete Wissenschaften
Institut für Ernährungswissenschaft
Referiert
Import
Hybrid Open-Access
52400
2021
2021
eng
11
14
11
article
John Wiley & Sons, Inc.
New Jersey
1
2021-06-30
2021-05-26
--
Intra-specific differences in metabolic rates shape carbon stable isotope trophic discrimination factors of muscle tissue in the common teleost Eurasian perch (Perca fluviatilis)
Stable isotopes represent a unique approach to provide insights into the ecology of organisms. δ13C and δ15N have specifically been used to obtain information on the trophic ecology and food-web interactions. Trophic discrimination factors (TDF, Δ13C and Δ15N) describe the isotopic fractionation occurring from diet to consumer tissue, and these factors are critical for obtaining precise estimates within any application of δ13C and δ15N values. It is widely acknowledged that metabolism influences TDF, being responsible for different TDF between tissues of variable metabolic activity (e.g., liver vs. muscle tissue) or species body size (small vs. large). However, the connection between the variation of metabolism occurring within a single species during its ontogeny and TDF has rarely been considered. Here, we conducted a 9-month feeding experiment to report Δ13C and Δ15N of muscle and liver tissues for several weight classes of Eurasian perch (Perca fluviatilis), a widespread teleost often studied using stable isotopes, but without established TDF for feeding on a natural diet. In addition, we assessed the relationship between the standard metabolic rate (SMR) and TDF by measuring the oxygen consumption of the individuals. Our results showed a significant negative relationship of SMR with Δ13C, and a significant positive relationship of SMR with Δ15N of muscle tissue, but not with TDF of liver tissue. SMR varies inversely with size, which translated into a significantly different TDF of muscle tissue between size classes. In summary, our results emphasize the role of metabolism in shaping-specific TDF (i.e., Δ13C and Δ15N of muscle tissue) and especially highlight the substantial differences between individuals of different ontogenetic stages within a species. Our findings thus have direct implications for the use of stable isotope data and the applications of stable isotopes in food-web studies.
Ecology and Evolution
2045-7758
Universität Potsdam
PA 2021_091
1713.60
<a href="https://doi.org/10.25932/publishup-52401">Zweitveröffentlichung in der Schriftenreihe Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe ; 1179</a>
false
false
CC-BY - Namensnennung 4.0 International
Kristin Scharnweber
Matilda L. Andersson
Fernando Chaguaceda
Peter Eklöv
eng
uncontrolled
fractionation factors
eng
uncontrolled
metabolism
eng
uncontrolled
ontogeny
eng
uncontrolled
standard metabolic rate
eng
uncontrolled
tissue types
eng
uncontrolled
δ13C
eng
uncontrolled
δ15N
Biowissenschaften; Biologie
Institut für Biochemie und Biologie
Referiert
Publikationsfonds der Universität Potsdam
Gold Open-Access
51266
2021
2021
2021
eng
xvii, 134
doctoralthesis
1
--
--
2021-07-01
Analysis of the effects of age-related changes of metabolic flux on brown adipocyte formation and function
Brown adipose tissue (BAT) is responsible for non-shivering thermogenesis, thereby allowing mammals to maintain a constant body temperature in a cold environment. Thermogenic capacity of this tissue is due to a high mitochondrial density and expression of uncoupling protein 1 (UCP1), a unique brown adipocyte marker which dissipates the mitochondrial proton gradient to produce heat instead of ATP. BAT is actively involved in whole-body metabolic homeostasis and during aging there is a loss of classical brown adipose tissue with concomitantly reduced browning capacity of white adipose tissue. Therefore, an age-dependent decrease of BAT-related energy expenditure capacity may exacerbate the development of metabolic diseases, including obesity and type 2 diabetes mellitus. Given that direct effects of age-related changes of BAT-metabolic flux have yet to be unraveled, the aim of the current thesis is to investigate potential metabolic mechanisms involved in BAT-dysfunction during aging and to identify suitable metabolic candidates as functional biomarkers of BAT-aging. To this aim, integration of transcriptomic, metabolomic and proteomic data analyses of BAT from young and aged mice was performed, and a group of candidates with age-related changes was revealed. Metabolomic analysis showed age-dependent alterations of metabolic intermediates involved in energy, nucleotide and vitamin metabolism, with major alterations regarding the purine nucleotide pool. These data suggest a potential role of nucleotide intermediates in age-related BAT defects. In addition, the screening of transcriptomic and proteomic data sets from BAT of young and aged mice allowed identification of a 60-kDa lysophospholipase, also known as L-asparaginase (Aspg), whose expression declines during BAT-aging. Involvement of Aspg in brown adipocyte thermogenic function was subsequently analyzed at the molecular level using in vitro approaches and animal models. The findings revealed sensitivity of Aspg expression to β3-adrenergic activation via different metabolic cues, including cold exposure and treatment with β3-adrenergic agonist CL. To further examine ASPG function in BAT, an over-expression model of Aspg in a brown adipocyte cell line was established and showed that these cells were metabolically more active compared to controls, revealing increased expression of the main brown-adipocyte specific marker UCP1, as well as higher lipolysis rates. An in vitro loss-of-function model of Aspg was also functionally analyzed, revealing reduced brown adipogenic characteristics and an impaired lipolysis, thus confirming physiological relevance of Aspg in brown adipocyte function. Characterization of a transgenic mouse model with whole-body inactivation of the Aspg gene (Aspg-KO) allowed investigation of the role of ASPG under in vivo conditions, indicating a mild obesogenic phenotype, hypertrophic white adipocytes, impairment of the early thermogenic response upon cold-stimulation and dysfunctional insulin sensitivity. Taken together, these data show that ASPG may represent a new functional biomarker of BAT-aging that regulates thermogenesis and therefore a potential target for the treatment of age-related metabolic disease.
10.25932/publishup-51266
online registration
publish
Dissertation, Universität Potsdam, 2021
true
true
Carola Mancini
eng
uncontrolled
adipose tissue
eng
uncontrolled
aging
eng
uncontrolled
nutrients
eng
uncontrolled
metabolism
deu
uncontrolled
Fettgewebe
deu
uncontrolled
Alterung
deu
uncontrolled
Stoffwechsel
deu
uncontrolled
Nährstoffe
Naturwissenschaften und Mathematik
Institut für Ernährungswissenschaft
Universität Potsdam
Universität Potsdam
49822
2021
2021
eng
224
habilitation
1
--
--
2021-02-26
Protein-dependent regulation of feeding, metabolism, and development of type 2 diabetes
Proteinabhängige Regulation der Nahrungsaufnahme und des Metabolismus sowie Entstehung des Typ-2-Diabetes
Food intake is driven by the need for energy but also by the demand for essential nutrients such as protein. Whereas it was well known how diets high in protein mediate satiety, it remained unclear how diets low in protein induce appetite. Therefore, this thesis aims to contribute to the research area of the detection of restricted dietary protein and adaptive responses.
This thesis provides clear evidence that the liver-derived hormone fibroblast growth factor 21 (FGF21) is an endocrine signal of a dietary protein restriction, with the cellular amino acid sensor general control nonderepressible 2 (GCN2) kinase acting as an upstream regulator of FGF21 during protein restriction. In the brain, FGF21 is mediating the protein-restricted metabolic responses, e.g. increased energy expenditure, food intake, insulin sensitivity, and improved glucose homeostasis. Furthermore, endogenous FGF21 induced by dietary protein or methionine restriction is preventing the onset of type 2 diabetes in the New Zealand Obese mouse.
Overall, FGF21 plays an important role in the detection of protein restriction and macronutrient imbalance in rodents and humans, and mediates both the behavioral and metabolic responses to dietary protein restriction. This makes FGF21 a critical physiological signal of dietary protein restriction, highlighting the important but often overlooked impact of dietary protein on metabolism and eating behavior, independent of dietary energy content.
Die Nahrungsaufnahme wird nicht nur durch den Bedarf an Energie, sondern auch durch den Bedarf an essenziellen Nährstoffen wie z. B. Protein bestimmt. Es war zwar bekannt, wie proteinreiche Nahrung eine Sättigung vermittelt, jedoch war unklar, wie eine proteinarme Ernährung den Appetit anregt. Ziel dieser Arbeit ist es daher, zu untersuchen, wie Nahrung mit einem niedrigen Proteingehalt detektiert wird und die Anpassung des Organismus im Hinblick auf den Metabolismus und das Ernährungsverhalten erfolgt.
Diese Arbeit liefert klare Beweise dafür, dass das aus der Leber stammende Hormon Fibroblast growth factor 21 (FGF21) ein endokrines Signal einer Nahrungsproteinrestriktion ist, wobei der zelluläre Aminosäuresensor general control nonderepressible 2 kinase (GCN2) als Regulator von FGF21 während der Proteinrestriktion fungiert. Im Gehirn vermittelt FGF21 die durch Proteinrestriktion induzierten Stoffwechselreaktionen, z.B. den Anstieg des Energieverbrauches, die Erhöhung der Nahrungsaufnahme und eine Verbesserung der Insulinsensitivität sowie der Glukosehomöostase. Darüber hinaus schützt das durch eine protein- oder methioninarme Diät induzierte FGF21 New Zealand Obese (NZO)-Mäuse, einem Tiermodell für den humanen Typ-2-Diabetes, vor einer Diabetesentstehung.
FGF21 spielt bei Nagetieren und Menschen eine wichtige Rolle hinsichtlich der Detektion einer diätetischen Proteinrestriktion sowie eines Ungleichgewichtes der Makronährstoffe zueinander und vermittelt die adaptiven Verhaltens- und Stoffwechselreaktionen. Dies macht FGF21 zu einem kritischen physiologischen Signal der Nahrungsproteinrestriktion und unterstreicht den wichtigen, aber oft übersehenen Einfluss der Nahrungsproteine auf den Stoffwechsel und das Nahrungsaufnahmeverhalten, unabhängig vom Energiegehalt der Nahrung.
FGF21’s biological role
die Rolle von FGF21
online registration
publish
Habilitation, Universität Potsdam, 2021
false
false
Thomas Laeger
eng
uncontrolled
protein restriction
eng
uncontrolled
autophagy
eng
uncontrolled
thermogenesis
eng
uncontrolled
appetite
eng
uncontrolled
hyperglycemia
eng
uncontrolled
methionine restriction
eng
uncontrolled
bone
eng
uncontrolled
FGF21
eng
uncontrolled
energy expenditure
eng
uncontrolled
GCN2
eng
uncontrolled
metabolism
eng
uncontrolled
food choice
eng
uncontrolled
type 2 diabetes
Naturwissenschaften und Mathematik
Institut für Ernährungswissenschaft
Universität Potsdam
Universität Potsdam
46867
2020
2020
eng
116, A-16, B-7, C-8
doctoralthesis
1
--
--
2020-02-14
Predictions from constraint-based approaches including enzyme kinetics
The metabolic state of an organism reflects the entire phenotype that is jointly affected by genetic and environmental changes. Due to the complexity of metabolism, system-level modelling approaches have become indispensable tools to obtain new insights into biological functions. In particular, simulation and analysis of metabolic networks using constraint-based modelling approaches have helped the analysis of metabolic fluxes. However, despite ongoing improvements in prediction of reaction flux through a system, approaches to directly predict metabolite concentrations from large-scale metabolic networks remain elusive. In this thesis, we present a computational approach for inferring concentration ranges from genome-scale metabolic models endowed with mass action kinetics. The findings specify a molecular mechanism underling facile control of concentration ranges for components in large-scale metabolic networks. Most importantly, an extended version of the approach can be used to predict concentration ranges without knowledge of kinetic parameters, provided measurements of concentrations in a reference state. We show that the approach is applicable with large-scale kinetic and stoichiometric metabolic models of organisms from different kingdoms of life. By challenging the predictions of concentration ranges in the genome-scale metabolic network of Escherichia coli with real-world data sets, we further demonstrate the prediction power and limitations of the approach. To predict concentration ranges in other species, e.g. model plant species Arabidopsis thaliana, we would rely on estimates of kinetic parameters (i.e. enzyme catalytic rates) since plant-specific enzyme catalytic rates are poorly documented. Using the constraint-based approach of Davidi et al. for estimation of enzyme catalytic rates, we obtain values for 168 plant enzymes. The approach depends on quantitative proteomics data and flux estimates obtained from constraint-based model of plant leaf metabolism integrating maximal rates of selected enzymes, plant-specific constraints on fluxes through canonical pathways, and growth measurements from Arabidopsis thaliana rosette under ten conditions. We demonstrate a low degree of plant enzyme saturation, supported by the agreement between concentrations of nicotinamide adenine dinucleotide, adenosine triphosphate, and glyceraldehyde 3-phosphate, based on our maximal in vivo catalytic rates, and available quantitative metabolomics data. Hence, our results show genome-wide estimation for plant-specific enzyme catalytic rates is feasible. These can now be readily employed to study resource allocation, to predict enzyme and metabolite concentrations using recent constrained-based modelling approaches. Constraint-based methods do not directly account for kinetic mechanisms and corresponding parameters. Therefore, a number of workflows have already been proposed to approximate reaction kinetics and to parameterize genome-scale kinetic models. We present a systems biology strategy to build a fully parameterized large-scale model of Chlamydomonas reinhardtii accounting for microcompartmentalization in the chloroplast stroma. Eukaryotic algae comprise a microcompartment, the pyrenoid, essential for the carbon concentrating mechanism (CCM) that improves their photosynthetic performance. Since the experimental study of the effects of microcompartmentation on metabolic pathways is challenging, we employ our model to investigate compartmentation of fluxes through the Calvin-Benson cycle between pyrenoid and stroma. Our model predicts that ribulose-1,5-bisphosphate, the substrate of Rubisco, and 3-phosphoglycerate, its product, diffuse in and out of the pyrenoid. We also find that there is no major diffusional barrier to metabolic flux between the pyrenoid and stroma. Therefore, our computational approach represents a stepping stone towards understanding of microcompartmentalized CCM in other organisms. This thesis provides novel strategies to use genome-scale metabolic networks to predict and integrate metabolite concentrations. Therefore, the presented approaches represent an important step in broadening the applicability of large-scale metabolic models to a range of biotechnological and medical applications.
Der Stoffwechsel eines Organismus spiegelt den gesamten Phänotyp wieder, welcher durch genetische und umweltbedingte Veränderungen beeinflusst wird. Aufgrund der Komplexität des Stoffwechsels sind Modellierungsansätze, welche das ganzheitliches System betrachten, zu unverzichtbaren Instrumenten geworden, um neue Einblicke in biologische Funktionen zu erhalten. Insbesondere die Simulation und Analyse von Stoffwechselnetzwerken mithilfe von Constraint-basierten Modellierungsansätzen hat die Analyse von Stoffwechselflüssen erleichtert. Trotz kontinuierlicher Verbesserungen bei der Vorhersage des Reaktionsflusses durch ein System, sind Ansätze zur direkten Vorhersage von Metabolitkonzentrationen aus metabolischen Netzwerken kaum vorhanden. In dieser Arbeit stellen wir einen Ansatz vor, mit welchem Konzentrationsbereiche aus genomweiten metabolischen Netzwerken, die mit einer Massenwirkungskinetik ausgestattet sind, abgeleitet werden können. Die Ergebnisse zeigen einen molekularen Mechanismus auf, welcher der Steuerung von Konzentrationsbereichen für Komponenten in metabolischen Netzwerken zugrunde liegt. Eine erweiterte Version des Ansatzes kann verwendet werden, um Konzentrationsbereiche ohne Kenntnis der kinetischen Parameter vorherzusagen, vorausgesetzt, dass Messungen von Konzentrationen in einem Referenzzustand vorhanden sind. Wir zeigen, dass der Ansatz mit kinetischen und stöchiometrischen Stoffwechselmodellen von Organismen aus verschiedenen taxonomischen Reichen anwendbar ist. Indem wir die Vorhersagen von Konzentrationsbereichen im genomweiten Stoffwechselnetzwerk von Escherichia coli mit realen Datensätzen validieren, demonstrieren wir die Vorhersagekraft und die Grenzen des Ansatzes. Um Konzentrationsbereiche in anderen Spezies vorherzusagen, z.B. der Modellpflanzenspezies Arabidopsis thaliana, stützen wir uns auf Schätzungen der kinetischen Parameter (d.h. der katalytischen Enzymraten), da tatsächlich gemessene, pflanzenspezifische katalytische Enzymraten nur unzureichend dokumentiert sind. Unter Verwendung des Constraint-basierten Ansatzes von Davidi et al. zur Abschätzung der katalytischen Enzymraten erhalten wir Werte für 168 pflanzliche Enzyme. Der Ansatz hängt von quantitativen Proteomikdaten und Schätzungen des Reaktionsflusses ab, die aus einem Constraint-basierten Modell des Pflanzenblattmetabolismus unter Einbeziehung der maximalen Raten ausgewählter Enzyme, pflanzenspezifischen Einschränkungen des Flusses durch kanonische Pfade und Wachstumsmessungen aus Rosetten von Arabidopsis thaliana unter zehn Bedingungen erhalten wurden. Wir fanden einen niedrigen Grad an Sättigung der Pflanzenenzyme, der durch die Übereinstimmung zwischen den Konzentrationen von Nicotinamidadenindinukleotid, Adenosintriphosphat und Glycerinaldehyd-3-phosphat auf der Grundlage unserer maximalen in vivo katalytischen Raten und den verfügbaren quantitativen Metabolomikdaten gestützt wird. Daher zeigen unsere Ergebnisse, dass genomweite Schätzungen für pflanzenspezifische Enzymkatalyseraten möglich sind. Diese können nun leicht verwendet werden, um die Ressourcenzuweisung zu untersuchen und die Enzym- und Metabolitenkonzentrationen unter Verwendung neuerer Constraint-basierter Modellierungsansätze vorherzusagen. Constraint-basierte Methoden berücksichtigen kinetische Mechanismen und entsprechende Parameter nicht direkt. Daher wurden einige Methoden entwickelt, welche die Reaktionskinetik approximieren und systemumfassende kinetische Modelle zu parametrisieren. Wir präsentieren eine systembiologische Strategie zur Erstellung eines vollständig parametrisierten Modells von Chlamydomonas reinhardtii, welches die Mikrokompartimentierung im Chloroplaststroma berücksichtigt. Eukaryotische Algen besitzen ein Mikrokompartiment, den Pyrenoiden, der für den Kohlenstoffkonzentrationsmechanismus (KKM) unerlässlich ist und die Photosyntheseleistung verbessert. Die experimentelle Untersuchung der Auswirkungen der Mikrokompartimentierung auf Stoffwechselwege stellt eine Herausforderung dar. Daher verwenden wir unser Modell um die Kompartimentierung von Reaktionsflüssen durch den Calvin-Benson-Zyklus zwischen Pyrenoid und Stroma zu untersuchen. Unser Modell sagt voraus, dass Ribulose-1,5-Bisphosphat, das Substrat von Rubisco, und 3-Phosphoglycerat , das Produkt, in den Pyrenoid hinein und aus ihm heraus diffundieren. Weiter stellen wir fest, dass es keine wesentliche Diffusionsbarriere zwischen dem Pyrenoid und dem Stroma gibt. Somit bietet unser Ansatz eine Möglichkeit um ein Verständnis des mikrokompartimentierten KKM auch in anderen Organismen zu erlangen. Diese Dissertation zeigt neue Strategien um metabolische Netzwerke zur Vorhersage von Metabolitkonzentrationen zu nutzen und selbige zu integrieren. Daher stellen die Ansätze einen wichtigen Schritt zur Anwendbarkeit von genomweiten Stoffwechselmodellen auf eine Reihe von biotechnologischen und medizinischen Anwendungen dar.
online registration
Dissertation, Universität Potsdam, 2020
Keine öffentliche Lizenz: Unter Urheberrechtsschutz
Anika Küken
eng
uncontrolled
constraint-based modeling
eng
uncontrolled
metabolism
eng
uncontrolled
metabolic networks
Biowissenschaften; Biologie
Institut für Biochemie und Biologie
Universität Potsdam
Universität Potsdam
46096
2017
2017
eng
12
8
article
Frontiers Research Foundation
Lausanne
1
--
--
--
Stoichiometric Correlation Analysis: Principles of Metabolic Functionality from Metabolomics Data
Recent advances in metabolomics technologies have resulted in high-quality (time-resolved) metabolic profiles with an increasing coverage of metabolic pathways. These data profiles represent read-outs from often non-linear dynamics of metabolic networks. Yet, metabolic profiles have largely been explored with regression-based approaches that only capture linear relationships, rendering it difficult to determine the extent to which the data reflect the underlying reaction rates and their couplings. Here we propose an approach termed Stoichiometric Correlation Analysis (SCA) based on correlation between positive linear combinations of log-transformed metabolic profiles. The log-transformation is due to the evidence that metabolic networks can be modeled by mass action law and kinetics derived from it. Unlike the existing approaches which establish a relation between pairs of metabolites, SCA facilitates the discovery of higherorder dependence between more than two metabolites. By using a paradigmatic model of the tricarboxylic acid cycle we show that the higher-order dependence reflects the coupling of concentration of reactant complexes, capturing the subtle difference between the employed enzyme kinetics. Using time-resolved metabolic profiles from Arabidopsis thaliana and Escherichia coli, we show that SCA can be used to quantify the difference in coupling of reactant complexes, and hence, reaction rates, underlying the stringent response in these model organisms. By using SCA with data from natural variation of wild and domesticated wheat and tomato accession, we demonstrate that the domestication is accompanied by loss of such couplings, in these species. Therefore, application of SCA to metabolomics data from natural variation in wild and domesticated populations provides a mechanistic way to understanding domestication and its relation to metabolic networks.
Frontiers in plant science
10.3389/fpls.2017.02152
29326746
1664-462X
wos:2017
2152
WOS:000418118500001
Nikoloski, Z (reprint author), Max Planck Inst Mol Plant Physiol, Syst Biol & Math Modeling Grp, Potsdam, Germany.; Nikoloski, Z (reprint author), Univ Potsdam, Bioinformat Grp, Inst Biochem & Biol, Potsdam, Germany.; Nikoloski, Z (reprint author), Ctr Plant Syst Biol & Biotechnol, Plovdiv, Bulgaria., nikoloski@mpimp-golm.mpg.de
International Max Planck Research School on Plant Growth at the Max Planck Institute of Molecular Plant Physiology, Potsdam-Golm, Germany;
importub
2020-04-19T22:37:01+00:00
filename=package.tar
0ec17e591395155ce9d682d1f7666b7c
Kevin Schwahn
Romina Beleggia
Nooshin Omranian
Zoran Nikoloski
eng
uncontrolled
metabolism
eng
uncontrolled
systems biology
eng
uncontrolled
maximal correlation
eng
uncontrolled
correlation analysis
eng
uncontrolled
domestication
Institut für Biochemie und Biologie
Referiert
Import
45777
2016
2016
eng
539
552
14
11
article
Routledge, Taylor & Francis Group
Philadelphia
1
--
--
--
Maternal eNOS deficiency determines a fatty liver phenotype of the offspring in a sex dependent manner
Maternal environmental factors can impact on the phenotype of the offspring via the induction of epigenetic adaptive mechanisms. The advanced fetal programming hypothesis proposes that maternal genetic variants may influence the offspring's phenotype indirectly via epigenetic modification, despite the absence of a primary genetic defect. To test this hypothesis, heterozygous female eNOS knockout mice and wild type mice were bred with male wild type mice. We then assessed the impact of maternal eNOS deficiency on the liver phenotype of wild type offspring. Birth weight of male wild type offspring born to female heterozygous eNOS knockout mice was reduced compared to offspring of wild type mice. Moreover, the offspring displayed a sex specific liver phenotype, with an increased liver weight, due to steatosis. This was accompanied by sex specific differences in expression and DNA methylation of distinct genes. Liver global DNA methylation was significantly enhanced in both male and female offspring. Also, hepatic parameters of carbohydrate metabolism were reduced in male and female offspring. In addition, male mice displayed reductions in various amino acids in the liver. Maternal genetic alterations, such as partial deletion of the eNOS gene, can affect liver metabolism of wild type offspring without transmission of the intrinsic defect. This occurs in a sex specific way, with more detrimental effects in females. This finding demonstrates that a maternal genetic defect can epigenetically alter the phenotype of the offspring, without inheritance of the defect itself. Importantly, these acquired epigenetic phenotypic changes can persist into adulthood.
Epigenetics : the official journal of the DNA Methylation Society
10.1080/15592294.2016.1184800
27175980
1559-2294
1559-2308
wos2016:2019
WOS:000380906200007
Hocher, B (reprint author), Hunan Normal Univ, Coll Med, Dept Basic Med, Changsha, Hunan, Peoples R China., hocher@uni-potsdam.de
Deutsche Forschungsgemeinschaft; chinese National Natural Science Foundation of China [81300557]; Robert Bosch Foundation
importub
2020-03-22T21:22:01+00:00
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3e78a1e92fc63c7d0ccd73489e8ae7c7
Berthold Hocher
Hannah Haumann
Jan Rahnenführer
Christoph Reichetzeder
Philipp Kalk
Thiemo Pfab
Oleg Tsuprykov
Stefan Winter
Ute Hofmann
Jian Li
Gerhard Paul Püschel
Florian Lang
Detlef Schuppan
Matthias Schwab
Elke Schaeffeler
eng
uncontrolled
Epigenetics
eng
uncontrolled
eNOS
eng
uncontrolled
Fetal programming
eng
uncontrolled
fatty liver
eng
uncontrolled
metabolism
Institut für Ernährungswissenschaft
Referiert
Import
41971
2018
2018
eng
vii, 153
doctoralthesis
1
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2018-11-05
Regulation of central carbon and nitrogen metabolism by Target of Rapamycin (TOR) kinase in Chlamydomonas reinhardtii
Regulation des zentralen Kohlen- und Stickstoff Stoffwechsels durch die Target of Rapamycin Kinase in der Grünalge Chlamydomonas reinhardtii
The highly conserved protein complex containing the Target of Rapamycin (TOR) kinase is known to integrate intra- and extra-cellular stimuli controlling nutrient allocation and cellular growth. This thesis describes three studies aimed to understand how TOR signaling pathway influences carbon and nitrogen metabolism in Chlamydomonas reinhardtii. The first study presents a time-resolved analysis of the molecular and physiological features across the diurnal cycle. The inhibition of TOR leads to 50% reduction in growth followed by nonlinear delays in the cell cycle progression. The metabolomics analysis showed that the growth repression is mainly driven by differential carbon partitioning between anabolic and catabolic processes. Furthermore, the high accumulation of nitrogen-containing compounds indicated that TOR kinase controls the carbon to nitrogen balance of the cell, which is responsible for biomass accumulation, growth and cell cycle progression. In the second study the cause of the high accumulation of amino acids is explained. For this purpose, the effect of TOR inhibition on Chlamydomonas was examined under different growth regimes using stable 13C- and 15N-isotope labeling. The data clearly showed that an increased nitrogen uptake is induced within minutes after the inhibition of TOR. Interestingly, this increased N-influx is accompanied by increased activities of nitrogen assimilating enzymes. Accordingly, it was concluded that TOR inhibition induces de-novo amino acid synthesis in Chlamydomonas. The recognition of this novel process opened an array of questions regarding potential links between central metabolism and TOR signaling. Therefore a detailed phosphoproteomics study was conducted to identify the potential substrates of TOR pathway regulating central metabolism. Interestingly, some of the key enzymes involved in carbon metabolism as well as amino acid synthesis exhibited significant changes in the phosphosite intensities immediately after TOR inhibition. Altogether, these studies provide a) detailed insights to metabolic response of Chlamydomonas to TOR inhibition, b) identification of a novel process causing rapid upshifts in amino acid levels upon TOR inhibition and c) finally highlight potential targets of TOR signaling regulating changes in central metabolism. Further biochemical and molecular investigations could confirm these observations and advance the understanding of growth signaling in microalgae.
Target of Rapamycin (TOR) ist das Zentralprotein eines hochkonservierten Proteinkomplexes, welcher Nährstoff- und Energie Ressourcen für zelluläre Wachstumsprozesse kontengiert. Diese Doktorarbeit beschreibt anhand dreier Studien, wie TOR zu diesem Zweck, in der Grünalge Chlamydomonas reinhardtii, den zentralen Stoffwechsel reguliert. Die erste Studie untersucht dazu das zeitaufgelöste Verhalten von Biomolekülen im Tagesverlauf synchronisiert wachsender Algen. Dabei konnte gezeigt werden, das der TOR Inhibitor Rapamycin das Wachstum um 50% reduziert und den Zellzyklus verzögert. Die Zellzyklus Verzögerung scheint dabei hauptsächlich durch veränderte Stoffwechselprozesse erklärt zu sein. Hierbei konnte gezeigt werden, dass TOR vor allem stickstoffhaltige Stoffwechselprodukte (z.B. Aminosäuren) kontrolliert, welche die Grundlage für Biomasseproduktion, Wachstum und den Zellzyklus bilden. Im Rahmen der zweiten Studie konnte dann der molekulare Mechanismus der Akkumulation der zellulären Aminosäuren aufgeklärt werden. Zu diesem Zweck wurden Fütterungsstudien mit 13C- und 15N-Isotopen durchgeführt. Die Ergebnisse dieser Fütterung konnten klar zeigen, dass die Inhibition von TOR zur verstärkten Aufnahme von Stickstoff in die Zelle und dessen Assimilierung in Aminosäuren führt. Die Aufdeckung dieses neuen, von TOR gesteuerten Prozesses eröffnete somit die Frage, wie die Signalkaskade von TOR zu den Enzymen der Aminosäuresynthese verläuft. Detaillierte phosphoproteomische Studien sollten dieser Frage nachgehen und Zielprotein der TOR Kinase zu identifizieren und regulierte Stoffwechselprozesses zu finden. Dabei stellte sich heraus, dass sowohl verschiedene Enzyme der Aminosäuresynthese als auch Enzyme des zentralen Stoffwechsels innerhalb weniger Minuten stark verändert wurden. Zusammenfassend kann man festhalten das die vorliegende Arbeit detaillierte Stoffwechselanalysen des Stoffwechsels nach einer TOR Inhibition aufdeckt. Hierbei ein neuer Mechanismus zur Regulation der Aminosäuresynthese, nach TOR Inhibition gezeigt werden konnte, welche durch systemische Regulation der Phosphorylierungsmuster zellulärer Proteine kontrolliert wird. Zusätzliche molekulare und biochemische Studien konnten weiterhin zeigen, dass wie TOR das zelluläre Wachstum der photosynthetischen Grünalge kontrolliert und somit steuert.
online registration
Dissertation, Universität Potsdam, 2018
Keine öffentliche Lizenz: Unter Urheberrechtsschutz
Umarah Mubeen
eng
uncontrolled
Target of Rapamycin kinase
eng
uncontrolled
Growth signaling
eng
uncontrolled
metabolism
eng
uncontrolled
phosphoproteomics
eng
uncontrolled
Chlamydomonas
deu
uncontrolled
Target of Rapamycin kinase
deu
uncontrolled
Wachstumssignale
deu
uncontrolled
Stoffwechsel
deu
uncontrolled
Phosphoproteomik
deu
uncontrolled
Chlamydomonas
Biowissenschaften; Biologie
Institut für Biochemie und Biologie
Extern
Universität Potsdam
Universität Potsdam
37196
2011
2011
eng
109
118
10
1
15
article
Wiley-Blackwell
Malden
1
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Metabolic profiling reveals key metabolic features of renal cell carcinoma
Recent evidence suggests that metabolic changes play a pivotal role in the biology of cancer and in particular renal cell carcinoma (RCC). Here, a global metabolite profiling approach was applied to characterize the metabolite pool of RCC and normal renal tissue. Advanced decision tree models were applied to characterize the metabolic signature of RCC and to explore features of metastasized tumours. The findings were validated in a second independent dataset. Vitamin E derivates and metabolites of glucose, fatty acid, and inositol phosphate metabolism determined the metabolic profile of RCC. alpha-tocopherol, hippuric acid, myoinositol, fructose-1-phosphate and glucose-1-phosphate contributed most to the tumour/normal discrimination and all showed pronounced concentration changes in RCC. The identified metabolic profile was characterized by a low recognition error of only 5% for tumour versus normal samples. Data on metastasized tumours suggested a key role for metabolic pathways involving arachidonic acid, free fatty acids, proline, uracil and the tricarboxylic acid cycle. These results illustrate the potential of mass spectroscopy based metabolomics in conjunction with sophisticated data analysis methods to uncover the metabolic phenotype of cancer. Differentially regulated metabolites, such as vitamin E compounds, hippuric acid and myoinositol, provide leads for the characterization of novel pathways in RCC.
Journal of cellular and molecular medicine : a journal of translational medicine
10.1111/j.1582-4934.2009.00939.x
1582-1838
wos:2011-2013
WOS:000286513900014
Weikert, S (reprint author), Charite, Dept Urol, Hindenburgdamm 30, D-12200 Berlin, Germany., steffen.weikert@charite.de
Gareth Catchpole
Alexander Platzer
Cornelia Weikert
Carsten Kempkensteffen
Manfred Johannsen
Hans Krause
Klaus Jung
Kurt Miller
Lothar Willmitzer
Joachim Selbig
Steffen Weikert
eng
uncontrolled
kidney cancer
eng
uncontrolled
metabolism
eng
uncontrolled
metabolomics
eng
uncontrolled
metastasis
Institut für Informatik und Computational Science
Referiert
Institut für Informatik