@article{RianoPachonKleessenNeigenfindetal.2010, author = {Ria{\~n}o-Pach{\´o}n, Diego Mauricio and Kleessen, Sabrina and Neigenfind, Jost and Durek, Pawel and Weber, Elke and Engelsberger, Wolfgang R. and Walther, Dirk and Selbig, Joachim and Schulze, Waltraud X. and Kersten, Birgit}, title = {Proteome-wide survey of phosphorylation patterns affected by nuclear DNA polymorphisms in Arabidopsis thaliana}, series = {BMC Genomics}, volume = {11}, journal = {BMC Genomics}, publisher = {Biomed Central}, address = {London}, issn = {1471-2164}, doi = {10.1186/1471-2164-11-411}, pages = {19}, year = {2010}, abstract = {Background: Protein phosphorylation is an important post-translational modification influencing many aspects of dynamic cellular behavior. Site-specific phosphorylation of amino acid residues serine, threonine, and tyrosine can have profound effects on protein structure, activity, stability, and interaction with other biomolecules. Phosphorylation sites can be affected in diverse ways in members of any species, one such way is through single nucleotide polymorphisms (SNPs). The availability of large numbers of experimentally identified phosphorylation sites, and of natural variation datasets in Arabidopsis thaliana prompted us to analyze the effect of non-synonymous SNPs (nsSNPs) onto phosphorylation sites. Results: From the analyses of 7,178 experimentally identified phosphorylation sites we found that: (i) Proteins with multiple phosphorylation sites occur more often than expected by chance. (ii) Phosphorylation hotspots show a preference to be located outside conserved domains. (iii) nsSNPs affected experimental phosphorylation sites as much as the corresponding non-phosphorylated amino acid residues. (iv) Losses of experimental phosphorylation sites by nsSNPs were identified in 86 A. thaliana proteins, among them receptor proteins were overrepresented. These results were confirmed by similar analyses of predicted phosphorylation sites in A. thaliana. In addition, predicted threonine phosphorylation sites showed a significant enrichment of nsSNPs towards asparagines and a significant depletion of the synonymous substitution. Proteins in which predicted phosphorylation sites were affected by nsSNPs (loss and gain), were determined to be mainly receptor proteins, stress response proteins and proteins involved in nucleotide and protein binding. Proteins involved in metabolism, catalytic activity and biosynthesis were less affected. Conclusions: We analyzed more than 7,100 experimentally identified phosphorylation sites in almost 4,300 protein-coding loci in silico, thus constituting the largest phosphoproteomics dataset for A. thaliana available to date. Our findings suggest a relatively high variability in the presence or absence of phosphorylation sites between different natural accessions in receptor and other proteins involved in signal transduction. Elucidating the effect of phosphorylation sites affected by nsSNPs on adaptive responses represents an exciting research goal for the future.}, language = {en} } @misc{RianoPachonKleessenNeigenfindetal.2010, author = {Ria{\~n}o-Pach{\´o}n, Diego Mauricio and Kleessen, Sabrina and Neigenfind, Jost and Durek, Pawel and Weber, Elke and Engelsberger, Wolfgang R. and Walther, Dirk and Selbig, Joachim and Schulze, Waltraud X. and Kersten, Birgit}, title = {Proteome-wide survey of phosphorylation patterns affected by nuclear DNA polymorphisms in Arabidopsis thaliana}, series = {Zweitver{\"o}ffentlichungen der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, journal = {Zweitver{\"o}ffentlichungen der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, number = {1328}, issn = {1866-8372}, doi = {10.25932/publishup-43118}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-431181}, pages = {19}, year = {2010}, abstract = {Background: Protein phosphorylation is an important post-translational modification influencing many aspects of dynamic cellular behavior. Site-specific phosphorylation of amino acid residues serine, threonine, and tyrosine can have profound effects on protein structure, activity, stability, and interaction with other biomolecules. Phosphorylation sites can be affected in diverse ways in members of any species, one such way is through single nucleotide polymorphisms (SNPs). The availability of large numbers of experimentally identified phosphorylation sites, and of natural variation datasets in Arabidopsis thaliana prompted us to analyze the effect of non-synonymous SNPs (nsSNPs) onto phosphorylation sites. Results: From the analyses of 7,178 experimentally identified phosphorylation sites we found that: (i) Proteins with multiple phosphorylation sites occur more often than expected by chance. (ii) Phosphorylation hotspots show a preference to be located outside conserved domains. (iii) nsSNPs affected experimental phosphorylation sites as much as the corresponding non-phosphorylated amino acid residues. (iv) Losses of experimental phosphorylation sites by nsSNPs were identified in 86 A. thaliana proteins, among them receptor proteins were overrepresented. These results were confirmed by similar analyses of predicted phosphorylation sites in A. thaliana. In addition, predicted threonine phosphorylation sites showed a significant enrichment of nsSNPs towards asparagines and a significant depletion of the synonymous substitution. Proteins in which predicted phosphorylation sites were affected by nsSNPs (loss and gain), were determined to be mainly receptor proteins, stress response proteins and proteins involved in nucleotide and protein binding. Proteins involved in metabolism, catalytic activity and biosynthesis were less affected. Conclusions: We analyzed more than 7,100 experimentally identified phosphorylation sites in almost 4,300 protein-coding loci in silico, thus constituting the largest phosphoproteomics dataset for A. thaliana available to date. Our findings suggest a relatively high variability in the presence or absence of phosphorylation sites between different natural accessions in receptor and other proteins involved in signal transduction. Elucidating the effect of phosphorylation sites affected by nsSNPs on adaptive responses represents an exciting research goal for the future.}, language = {en} } @misc{KleessenNikoloski2012, author = {Kleessen, Sabrina and Nikoloski, Zoran}, title = {Dynamic regulatory on/off minimization for biological systems under internal temporal perturbations}, series = {Postprints der Universit{\"a}t Potsdam : Mathematisch Naturwissenschaftliche Reihe}, journal = {Postprints der Universit{\"a}t Potsdam : Mathematisch Naturwissenschaftliche Reihe}, number = {852}, issn = {1866-8372}, doi = {10.25932/publishup-43112}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-431128}, pages = {15}, year = {2012}, abstract = {Background: Flux balance analysis (FBA) together with its extension, dynamic FBA, have proven instrumental for analyzing the robustness and dynamics of metabolic networks by employing only the stoichiometry of the included reactions coupled with adequately chosen objective function. In addition, under the assumption of minimization of metabolic adjustment, dynamic FBA has recently been employed to analyze the transition between metabolic states. Results: Here, we propose a suite of novel methods for analyzing the dynamics of (internally perturbed) metabolic networks and for quantifying their robustness with limited knowledge of kinetic parameters. Following the biochemically meaningful premise that metabolite concentrations exhibit smooth temporal changes, the proposed methods rely on minimizing the significant fluctuations of metabolic profiles to predict the time-resolved metabolic state, characterized by both fluxes and concentrations. By conducting a comparative analysis with a kinetic model of the Calvin-Benson cycle and a model of plant carbohydrate metabolism, we demonstrate that the principle of regulatory on/off minimization coupled with dynamic FBA can accurately predict the changes in metabolic states. Conclusions: Our methods outperform the existing dynamic FBA-based modeling alternatives, and could help in revealing the mechanisms for maintaining robustness of dynamic processes in metabolic networks over time.}, language = {en} } @article{KleessenNikoloski2012, author = {Kleessen, Sabrina and Nikoloski, Zoran}, title = {Dynamic regulatory on/off minimization for biological systems under internal temporal perturbations}, series = {BMC systems biology}, volume = {6}, journal = {BMC systems biology}, publisher = {BioMed Central}, address = {London}, issn = {1752-0509}, doi = {10.1186/1752-0509-6-16}, pages = {13}, year = {2012}, abstract = {Background: Flux balance analysis (FBA) together with its extension, dynamic FBA, have proven instrumental for analyzing the robustness and dynamics of metabolic networks by employing only the stoichiometry of the included reactions coupled with adequately chosen objective function. In addition, under the assumption of minimization of metabolic adjustment, dynamic FBA has recently been employed to analyze the transition between metabolic states. Results: Here, we propose a suite of novel methods for analyzing the dynamics of (internally perturbed) metabolic networks and for quantifying their robustness with limited knowledge of kinetic parameters. Following the biochemically meaningful premise that metabolite concentrations exhibit smooth temporal changes, the proposed methods rely on minimizing the significant fluctuations of metabolic profiles to predict the time-resolved metabolic state, characterized by both fluxes and concentrations. By conducting a comparative analysis with a kinetic model of the Calvin-Benson cycle and a model of plant carbohydrate metabolism, we demonstrate that the principle of regulatory on/off minimization coupled with dynamic FBA can accurately predict the changes in metabolic states. Conclusions: Our methods outperform the existing dynamic FBA-based modeling alternatives, and could help in revealing the mechanisms for maintaining robustness of dynamic processes in metabolic networks over time.}, language = {en} } @article{KleessenAraujoFernieetal.2012, author = {Kleessen, Sabrina and Araujo, Wagner L. and Fernie, Alisdair R. and Nikoloski, Zoran}, title = {Model-based Confirmation of Alternative Substrates of Mitochondrial Electron Transport Chain}, series = {The journal of biological chemistry}, volume = {287}, journal = {The journal of biological chemistry}, number = {14}, publisher = {American Society for Biochemistry and Molecular Biology}, address = {Bethesda}, issn = {0021-9258}, doi = {10.1074/jbc.M111.310383}, pages = {11122 -- 11131}, year = {2012}, abstract = {Background: There are alternative substrates to the mitochondrial respiration. Results: Data-driven model-based analysis renders predictions of alternative substrates to the mitochondrial respiration. Conclusion: Metabolomics data in conjunction with flux-based models can discriminate among hypotheses based on enzymology alone. Significance: This analysis provides a basic framework for in silico studies of alternative pathways in metabolism.}, language = {en} } @article{SulpiceNikoloskiTschoepetal.2013, author = {Sulpice, Ronan and Nikoloski, Zoran and Tschoep, Hendrik and Antonio, Carla and Kleessen, Sabrina and Larhlimi, Abdelhalim and Selbig, Joachim and Ishihara, Hirofumi and Gibon, Yves and Fernie, Alisdair R. and Stitt, Mark}, title = {Impact of the Carbon and Nitrogen Supply on Relationships and Connectivity between Metabolism and Biomass in a Broad Panel of Arabidopsis Accessions(1[W][OA])}, series = {Plant physiology : an international journal devoted to physiology, biochemistry, cellular and molecular biology, biophysics and environmental biology of plants}, volume = {162}, journal = {Plant physiology : an international journal devoted to physiology, biochemistry, cellular and molecular biology, biophysics and environmental biology of plants}, number = {1}, publisher = {American Society of Plant Physiologists}, address = {Rockville}, issn = {0032-0889}, doi = {10.1104/pp.112.210104}, pages = {347 -- 363}, year = {2013}, abstract = {Natural genetic diversity provides a powerful tool to study the complex interrelationship between metabolism and growth. Profiling of metabolic traits combined with network-based and statistical analyses allow the comparison of conditions and identification of sets of traits that predict biomass. However, it often remains unclear why a particular set of metabolites is linked with biomass and to what extent the predictive model is applicable beyond a particular growth condition. A panel of 97 genetically diverse Arabidopsis (Arabidopsis thaliana) accessions was grown in near-optimal carbon and nitrogen supply, restricted carbon supply, and restricted nitrogen supply and analyzed for biomass and 54 metabolic traits. Correlation-based metabolic networks were generated from the genotype-dependent variation in each condition to reveal sets of metabolites that show coordinated changes across accessions. The networks were largely specific for a single growth condition. Partial least squares regression from metabolic traits allowed prediction of biomass within and, slightly more weakly, across conditions (cross-validated Pearson correlations in the range of 0.27-0.58 and 0.21-0.51 and P values in the range of <0.001-<0.13 and <0.001-<0.023, respectively). Metabolic traits that correlate with growth or have a high weighting in the partial least squares regression were mainly condition specific and often related to the resource that restricts growth under that condition. Linear mixed-model analysis using the combined metabolic traits from all growth conditions as an input indicated that inclusion of random effects for the conditions improves predictions of biomass. Thus, robust prediction of biomass across a range of conditions requires condition-specific measurement of metabolic traits to take account of environment-dependent changes of the underlying networks.}, language = {en} } @article{AlseekhTohgeWendenbergetal.2015, author = {Alseekh, Saleh and Tohge, Takayuki and Wendenberg, Regina and Scossa, Federico and Omranian, Nooshin and Li, Jie and Kleessen, Sabrina and Giavalisco, Patrick and Pleban, Tzili and M{\"u}ller-R{\"o}ber, Bernd and Zamir, Dani and Nikoloski, Zoran and Fernie, Alisdair R.}, title = {Identification and Mode of Inheritance of Quantitative Trait Loci for Secondary Metabolite Abundance in Tomato}, series = {The plant cell}, volume = {27}, journal = {The plant cell}, number = {3}, publisher = {American Society of Plant Physiologists}, address = {Rockville}, issn = {1040-4651}, doi = {10.1105/tpc.114.132266}, pages = {485 -- 512}, year = {2015}, abstract = {A large-scale metabolic quantitative trait loci (mQTL) analysis was performed on the well-characterized Solanum pennellii introgression lines to investigate the genomic regions associated with secondary metabolism in tomato fruit pericarp. In total, 679 mQTLs were detected across the 76 introgression lines. Heritability analyses revealed that mQTLs of secondary metabolism were less affected by environment than mQTLs of primary metabolism. Network analysis allowed us to assess the interconnectivity of primary and secondary metabolism as well as to compare and contrast their respective associations with morphological traits. Additionally, we applied a recently established real-time quantitative PCR platform to gain insight into transcriptional control mechanisms of a subset of the mQTLs, including those for hydroxycinnamates, acyl-sugar, naringenin chalcone, and a range of glycoalkaloids. Intriguingly, many of these compounds displayed a dominant-negative mode of inheritance, which is contrary to the conventional wisdom that secondary metabolite contents decreased on domestication. We additionally performed an exemplary evaluation of two candidate genes for glycolalkaloid mQTLs via the use of virus-induced gene silencing. The combined data of this study were compared with previous results on primary metabolism obtained from the same material and to other studies of natural variance of secondary metabolism.}, language = {en} } @misc{OmranianKleessenTohgeetal.2015, author = {Omranian, Nooshin and Kleessen, Sabrina and Tohge, Takayuki and Klie, Sebastian and Basler, Georg and M{\"u}ller-R{\"o}ber, Bernd and Fernie, Alisdair R. and Nikoloski, Zoran}, title = {Differential metabolic and coexpression networks of plant metabolism}, series = {Trends in plant science}, volume = {20}, journal = {Trends in plant science}, number = {5}, publisher = {Elsevier}, address = {London}, issn = {1360-1385}, doi = {10.1016/j.tplants.2015.02.002}, pages = {266 -- 268}, year = {2015}, abstract = {Recent analyses have demonstrated that plant metabolic networks do not differ in their structural properties and that genes involved in basic metabolic processes show smaller coexpression than genes involved in specialized metabolism. By contrast, our analysis reveals differences in the structure of plant metabolic networks and patterns of coexpression for genes in (non)specialized metabolism. Here we caution that conclusions concerning the organization of plant metabolism based on network-driven analyses strongly depend on the computational approaches used.}, language = {en} } @article{SmithDupontMcCarthyetal.2019, author = {Smith, Sarah R. and Dupont, Chris L. and McCarthy, James K. and Broddrick, Jared T. and Obornik, Miroslav and Horak, Ales and F{\"u}ssy, Zolt{\´a}n and Cihlar, Jaromir and Kleessen, Sabrina and Zheng, Hong and McCrow, John P. and Hixson, Kim K. and Araujo, Wagner L. and Nunes-Nesi, Adriano and Fernie, Alisdair R. and Nikoloski, Zoran and Palsson, Bernhard O. and Allen, Andrew E.}, title = {Evolution and regulation of nitrogen flux through compartmentalized metabolic networks in a marine diatom}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, publisher = {Nature Publ. Group}, address = {London}, issn = {2041-1723}, doi = {10.1038/s41467-019-12407-y}, pages = {14}, year = {2019}, abstract = {Diatoms outcompete other phytoplankton for nitrate, yet little is known about the mechanisms underpinning this ability. Genomes and genome-enabled studies have shown that diatoms possess unique features of nitrogen metabolism however, the implications for nutrient utilization and growth are poorly understood. Using a combination of transcriptomics, proteomics, metabolomics, fluxomics, and flux balance analysis to examine short-term shifts in nitrogen utilization in the model pennate diatom in Phaeodactylum tricornutum, we obtained a systems-level understanding of assimilation and intracellular distribution of nitrogen. Chloroplasts and mitochondria are energetically integrated at the critical intersection of carbon and nitrogen metabolism in diatoms. Pathways involved in this integration are organelle-localized GS-GOGAT cycles, aspartate and alanine systems for amino moiety exchange, and a split-organelle arginine biosynthesis pathway that clarifies the role of the diatom urea cycle. This unique configuration allows diatoms to efficiently adjust to changing nitrogen status, conferring an ecological advantage over other phytoplankton taxa.}, language = {en} }