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.
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.
Seed metabolites are critically important both for plant development and human nutrition; however, the natural variation in their levels remains poorly characterized. Here we profiled 121 metabolites in mature seeds of a wide panel Oryza sativa japonica and indica cultivars, revealing correlations between the metabolic phenotype and geographic origin of the rice seeds. Moreover, japonica and indica subspecies differed significantly not only in the relative abundances of metabolites but also in their corresponding metabolic association networks. These findings provide important insights into metabolic adaptation in rice subgroups, bridging the gap between genome and phenome, and facilitating the identification of genetic control of metabolic properties that can serve as a basis for the future improvement of rice quality via metabolic engineering.
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.
SUMMARYFlux phenotypes predicted by constraint-based methods can be refined by the inclusion of heterogeneous data. While recent advances facilitate the integration of transcriptomics and proteomics data, purely stoichiometry-based approaches for the prediction of flux phenotypes by considering metabolomics data are lacking. Here we propose a constraint-based method, termed TREM-Flux, for integrating time-resolved metabolomics and transcriptomics data. We demonstrate the applicability of TREM-Flux in the dissection of the metabolic response of Chlamydomonas reinhardtii to rapamycin treatment by integrating the expression levels of 982 genes and the content of 45 metabolites obtained from two growth conditions. The findings pinpoint cysteine and methionine metabolism to be most affected by the rapamycin treatment. Our study shows that the integration of time-resolved unlabeled metabolomics data in addition to transcriptomics data can specify the metabolic pathways involved in the system's response to a studied treatment.
Metabolite levels together with their corresponding metabolic fluxes are integrative outcomes of biochemical transformations and regulatory processes and they can be used to characterize the response of biological systems to genetic and/or environmental changes. However, while changes in transcript or to some extent protein levels can usually be traced back to one or several responsible genes, changes in fluxes and particularly changes in metabolite levels do not follow such rationale and are often the outcome of complex interactions of several components. The increasing quality and coverage of metabolomics technologies have fostered the development of computational approaches for integrating metabolic read-outs with large-scale models to predict the physiological state of a system. Constraint-based approaches, relying on the stoichiometry of the considered reactions, provide a modeling framework amenable to analyses of large-scale systems and to the integration of high-throughput data. Here we review the existing approaches that integrate metabolomics data in variants of constrained-based approaches to refine model reconstructions, to constrain flux predictions in metabolic models, and to relate network structural properties to metabolite levels. Finally, we discuss the challenges and perspectives in the developments of constraint-based modeling approaches driven by metabolomics data.
Supplementary data are available at Bioinformatics online.
BACKGROUND Aclonifen is a unique diphenyl ether herbicide. Despite its structural similarities to known inhibitors of the protoporphyrinogen oxidase (e.g. acifluorfen, bifenox or oxadiazon), which result in leaf necrosis, aclonifen causes a different phenotype that is described as bleaching. This also is reflected by the Herbicide Resistance Action Committee (HRAC) classification that categorizes aclonifen as an inhibitor of pigment biosynthesis with an unknown target. RESULTS A comprehensive Arabidopsis thaliana RNAseq dataset comprising 49 different inhibitor treatments and covering 40 known target pathways was used to predict the aclonifen mode of action (MoA) by a random forest classifier. The classifier predicts for aclonifen a MoA within the carotenoid biosynthesis pathway similar to the reference compound norflurazon that inhibits the phytoene desaturase. Upon aclonifen treatment, the phytoene desaturation reaction is disturbed, resulting in a characteristic phytoene accumulation in vivo. However, direct enzyme inhibition by the herbicide was excluded for known herbicidal targets such as phytoene desaturase, 4‐hydroxyphenylpyruvate dioxygenase and homogentisate solanesyltransferase. Eventually, the solanesyl diphosphate synthase (SPS), providing one of the two homogentisate solanesyltransferase substrate molecules, could be identified as the molecular target of aclonifen. Inhibition was confirmed using biochemical activity assays for the A. thaliana SPSs 1 and 2. Furthermore, a Chlamydomonas reinhardtii homolog was used for co‐crystallization of the enzyme–inhibitor complex, showing that one inhibitor molecule binds at the interface between two protein monomers. CONCLUSION Solanesyl diphosphate synthase was identified as the target of aclonifen, representing a novel mode of action for herbicides. © 2020 Society of Chemical Industry
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