Petra Matt

European Medicines Agency

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Mark Stitt

Max Planck Institute of Molecular Plant Physiology

Anne Krapp

Institut Jean-Pierre Bourgin

M. Geiger

Heidelberg University

Pia Walch‐Liu

Lancaster University

Christof Engels

Humboldt-Universität zu Berlin

Volker Haake

Biobyte Solutions (Germany)

Uli Schurr

Forschungszentrum Jülich

Diana Klein

Heidelberg University

Regina Feil

Max Planck Institute of Molecular Plant Physiology

Francesco Pignatti

European Medicines Agency

Cooperative Institutions

Max Planck Institute of Molecular Plant Physiology

Heidelberg University

University of Bayreuth

University of Hohenheim

Max Planck Society

European Medicines Agency

University of Nebraska–Lincoln

Consejo Superior de Investigaciones Científicas

Danish Medicines Agency

Utrecht University

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Decreased Rubisco activity leads to dramatic changes of nitrate metabolism, amino acid metabolism and the levels of phenylpropanoids and nicotine in tobacco antisense RBCS transformants

The Plant Journal (2002)

Petra Matt Anne Krapp Volker Haake Hans‐Peter Mock Mark Stitt

Summary Tobacco transformants that express an antisense RBCS construct were used to investigate the consequences of a lesion in photosynthetic carbon metabolism for nitrogen metabolism and secondary metabolism. The results show that an inhibition of photosynthesis and decrease in sugar levels leads to a general inhibition of nitrogen metabolism, and dramatic changes in the levels of secondary metabolites. The response was particularly clear in plants that received excess nitrogen. In these conditions, a decrease of Rubisco activity led to an inhibition of nitrate reductase activity, accumulation of nitrate, a decrease of amino acid levels that was larger than the decrease of sugars, and a large decrease of chlorogenic acid and of nicotine, which are the major carbon‐ and nitrogen‐rich secondary metabolites in tobacco leaves, respectively. Similar changes were seen when nitrogen‐replete wild‐type tobacco was grown in low light. The inhibition of nitrogen metabolism was partly masked when wild‐type plants and antisense RBCS transformants were compared in marginal or in limiting nitrogen, because the lower growth rate of the transformants alleviated the nitrogen deficiency, leading to an increase of amino acids. In these conditions, chlorogenic acid always decreased but the decrease of nicotine was ameliorated or reversed. When the changes in internal pools are compared across all the genotypes and growth conditions, two conclusions emerge. First, decreased levels of primary metabolites lead to a dramatic decrease in the levels of secondary metabolites. Second, changes of the amino acid : sugar ratio are accompanied by changes of the nicotine:chlorogenic acid ratio.

Chlorogenic Acid

Secondary metabolism

Nitrogen deficiency

10.1046/j.1365-313x.2002.01323.x

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Citations (115)

The immediate cause of the diurnal changes of nitrogen metabolism in leaves of nitrate‐replete tobacco: a major imbalance between the rate of nitrate reduction and the rates of nitrate uptake and ammonium metabolism during the first part of the light period

Plant Cell & Environment (2001)

Petra Matt M. Geiger Pia Walch‐Liu Christof Engels Annemarie Krapp

ABSTRACT To assess how diurnal changes of nitrate reductase ( NIA ) expression in leaves interact with upstream and downstream processes during nitrate utilization, nitrate uptake, and nitrate and ammonium metabolism were investigated at several times during the diurnal cycle in wild‐type tobacco. Plants were grown hydroponically on 2 m M nitrate to exclude possible complications due to changes in the external availability of nitrate, and to allow nitrate uptake to be measured in the growth conditions. (a) In leaves, the NIA transcript decreases during the day and recovers at night, and NIA activity increases three‐fold during the first part and declines during the second part of the light period. Nitrate decreases during the day and recovers at night, ammonium, glutamine, glycine and serine increase during the day and decrease at night, and 2‐oxoglutarate increases three‐fold after illumination and decreases during the last part of the light period. The amplitudes of the diurnal changes are similar to or larger than in tobacco grown on high nitrate in sand. The transcript for plastid glutamine synthetase ( GLN2 ) is low at the end of the night and increases during the day, and glutamine synthetase activity increases to a peak at the end of the day and decreases at night. (b) In the roots, transcript levels for the high affinity nitrate transporter ( NRT2 ) increase in the day and decrease at night. Nitrate uptake is about 40% higher during the day than at night. (c) Comparison of the diurnal changes of the leaf metabolite pools with the rate of nitrate uptake allows diurnal changes in fluxes to be estimated. During the first part of the light, the rate of nitrate assimilation is about two‐fold higher than the rate of nitrate uptake, and also exceeds the rate at which reduced nitrogen is metabolized in the GOGAT pathway. The resulting decrease of leaf nitrate and accumulation of nitrogen in intermediates of ammonium metabolism and photorespiration represent about 40 and 15%, respectively, of the total nitrate that enters the plant in 24 h. Later in the diurnal cycle as NIA expression and activity decline, this imbalance is reversed. NRT2 expression and nitrate uptake remain relatively high, and nitrate taken up during the night is used to replenish the leaf nitrate pool. Increased GLN2 expression in leaves during the second part of the light period allows continued assimilation of ammonium released during photorespiration and remobilization of the reduced nitrogen that accumulated earlier in the diurnal cycle.

Nitrogen Cycle

10.1111/j.1365-3040.2001.00676.x

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Citations (139)

The European Medicines Agency Review of Tegafur/Gimeracil/Oteracil (Teysuno™) for the Treatment of Advanced Gastric Cancer When Given in Combination with Cisplatin: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use (CHMP)

The Oncologist (2011)

Petra Matt Barbara van Zwieten‐Boot Gonzalo Calvo Rojas Hadewych ter Hofstede Rocio García‐Carbonero

Abstract The product Teysuno™ (S-1) contains tegafur, a prodrug of 5-fluorouracil (5-FU), and two modulators of 5-FU metabolism, gimeracil and oteracil. The main clinical study in this application was a randomized controlled study comparing S-1 plus cisplatin with 5-FU plus cisplatin. In this study, median overall survival times of 8.6 months and 7.9 months for S-1 plus cisplatin and 5-FU plus cisplatin, respectively, were observed (hazard ratio, 0.92; 95% confidence interval, 0.80–1.05). The Committee for Medicinal Products for Human Use of the European Medicines Agency concluded that S-1 in combination with cisplatin (75 mg/m2) was noninferior to 5-FU plus cisplatin (100 mg/m2) in patients with advanced gastric cancer and adopted a positive opinion recommending the marketing authorization for this product for the treatment of advanced gastric cancer when given in combination with cisplatin. The recommended dose of S-1 is 25 mg/m2 (expressed as tegafur content) twice a day, for 21 consecutive days followed by 7 days rest (one treatment cycle), in combination with 75 mg/m2 cisplatin i.v. administered on day 1. This treatment cycle is repeated every 4 weeks. The most common side effects reported in the pivotal study were anemia, neutropenia, vomiting, diarrhea, abdominal pain, weight decrease, anorexia, and fatigue. The objective of this paper is to summarize the scientific review of the application leading to approval in the EU. The full scientific assessment report and the summary of product characteristics are available on the European Medicines Agency website (http://www.ema.europa.eu).

Tegafur

10.1634/theoncologist.2011-0224

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Citations (32)

Impact of the C–N status on the amino acid profile in tobacco source leaves

Plant Cell & Environment (2006)

Christina Fritz C. Mueller Petra Matt Regina Feil Mark Stitt

ABSTRACT This paper investigates the influence of the carbon (C) and nitrogen (N) status on the amino acid profile in tobacco source leaves. Treatments used included growing plants at different light intensities, using an antisense RBCS (small subunit of ribulose‐1,5‐bisphosphate carboxylase/oxygenase) construct to inhibit Rubisco activity, growing plants on 12 or 0.5 mM nitrate, comparing wild‐types with genotypes that have small and large decreases in nitrate reductase (NIA) activity, and sampling plants at different times during the diurnal cycle. This combination of experiments provides information on how amino acid levels respond to several inputs including the C and N status, nitrate, excess light and light–dark transitions. The data set was analysed using principal component analysis, regression analysis and by normalizing the level of each individual amino acid on the total amino acid pool. Most amino acids show a downward trend when the C or the N status is decreased, and rise during day and fall at night during the diurnal cycle. However, individual amino acids often showed deviating responses. Furthermore, no evidence was found for feedback inhibition of minor amino acid synthesis, either within or between pathways, when 18 individual amino acids were supplied to detached leaves. Results indicate that regulation of amino acid metabolism, for example by the C and N status, leads to qualitatively similar responses of many amino acids, but homeostatic mechanisms involving feedback inhibition within or between individual amino acid biosynthesis pathways are not stringent. All of the above inputs affect the level of phenylalanine, an amino acid that is also the substrate for an important sector of secondary metabolism. The levels of glutamate were remarkably constant, indicating that unknown mechanisms stabilize the concentration of this key central amino acid. Analyses of metabolite levels and feeding experiments indicated that 2‐oxoglutarate plays an important role in regulating glutamate levels. Glutamate was the most effective inhibitor of NIA activity when 18 individual amino acids were supplied to detached leaves. Feeding glutamate, and other downstream amino acids, led to an increase of glutamine, indicating glutamate exerts feedback regulation on ammonium metabolism.

Amino acid synthesis

10.1111/j.1365-3040.2006.01580.x

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Citations (92)

Elevated carbon dioxide increases nitrate uptake and nitrate reductase activity when tobacco is growing on nitrate, but increases ammonium uptake and inhibits nitrate reductase activity when tobacco is growing on ammonium nitrate

Plant Cell & Environment (2001)

Petra Matt M. Geiger Pia Walch‐Liu Christof Engels Anne Krapp

Abstract The influence of elevated [CO 2 ] on the uptake and assimilation of nitrate and ammonium was investigated by growing tobacco plants in hydroponic culture with 2 m m nitrate or 1 m m ammonium nitrate and ambient or 800 p.p.m. [CO 2 ]. Leaves and roots were harvested at several times during the diurnal cycle to investigate the levels of the transcripts for a high‐affinity nitrate transporter ( NRT2 ), nitrate reductase ( NIA ), cytosolic and plastidic glutamine synthetase ( GLN1 , GLN2 ), the activity of NIA and glutamine synthetase, the rate of 15 N‐nitrate and 15 N‐ammonium uptake, and the levels of nitrate, ammonium, amino acids, 2‐oxoglutarate and carbohydrates. (i) In source leaves of plants growing on 2 m m nitrate in ambient [CO 2 ], NIA transcript is high at the end of the night and NIA activity increases three‐fold after illumination. The rate of nitrate reduction during the first part of the light period is two‐fold higher than the rate of nitrate uptake and exceeds the rate of ammonium metabolism in the glutamate: oxoglutarate aminotransferase (GOGAT) pathway, resulting in a rapid decrease of nitrate and the accumulation of ammonium, glutamine and the photorespiratory intermediates glycine and serine. This imbalance is reversed later in the diurnal cycle. The level of the NIA transcript falls dramatically after illumination, and NIA activity and the rate of nitrate reduction decline during the second part of the light period and are low at night. NRT2 transcript increases during the day and remains high for the first part of the night and nitrate uptake remains high in the second part of the light period and decreases by only 30% at night. The nitrate absorbed at night is used to replenish the leaf nitrate pool. GLN2 transcript and glutamine synthetase activity rise to a maximum at the end of the day and decline only gradually after darkening, and ammonium and amino acids decrease during the night. (ii) In plants growing on ammonium nitrate, about 30% of the nitrogen is derived from ammonium. More ammonium accumulates in leaves during the day, and glutamine synthetase activity and glutamine levels remain high through the night. There is a corresponding 30% inhibition of nitrate uptake, a decrease of the absolute nitrate level, and a 15–30% decrease of NIA activity in the leaves and roots. The diurnal changes of leaf nitrate and the absolute level and diurnal changes of the NIA transcript are, however, similar to those in nitrate‐grown plants. (iii) Plants growing on nitrate adjust to elevated [CO 2 ] by a coordinate change in the diurnal regulation of NRT2 and NIA , which allows maximum rates of nitrate uptake and maximum NIA activity to be maintained for a larger part of the 24 h diurnal cycle. In contrast, tobacco growing on ammonium nitrate adjusts by selectively increasing the rate of ammonium uptake, and decreasing the expression of NRT2 and NIA and the rate of nitrate assimilation. In both conditions, the overall rate of inorganic nitrogen utilization is increased in elevated [CO 2 ] due to higher rates of uptake and assimilation at the end of the day and during the night, and amino acids are maintained at levels that are comparable to or even higher than in ambient [CO 2 ]. (iv) Comparison of the diurnal changes of transcripts, enzyme activities and metabolite pools across the four growth conditions reveals that these complex diurnal changes are due to transcriptional and post‐transcriptional mechanisms, which act several steps and are triggered by various signals depending on the condition and organ. The results indicate that nitrate and ammonium uptake and root NIA activity may be regulated by the sugar supply, that ammonium uptake and assimilation inhibit nitrate uptake and root NIA activity, that the balance between the influx and utilization of nitrate plays a key role in the diurnal changes of the NIA transcript in leaves, that changes of glutamine do not play a key role in transcriptional regulation of NIA in leaves but instead inhibit NIA activity via uncharacterized post‐transcriptional or post‐translational mechanisms, and that high ammonium acts via uncharacterized post‐transcriptional or post‐translational mechanisms to stabilize glutamine synthetase activity during the night.

Nitrogen Assimilation

10.1046/j.1365-3040.2001.00771.x

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Citations (149)

Growth of tobacco in short-day conditions leads to high starch, low sugars, altered diurnal changes in the Nia transcript and low nitrate reductase activity, and inhibition of amino acid synthesis

Planta (1998)

Petra Matt Uli Schurr Diana Klein Anne Krapp Mark Stitt

Darkness

Diurnal temperature variation

10.1007/s004250050452

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Citations (96)

The immediate cause of the diurnal changes of nitrogen metabolism in leaves of nitrate-replete tobacco: a major imbalance between the rate of nitrate reduction and the rates of nitrate uptake and ammonium metabolism during the first part of the light period

Plant Cell & Environment (2001)

Petra Matt M. Geiger Pia Walch‐Liu Christof Engels Anne Krapp

To assess how diurnal changes of nitrate reductase (NIA) expression in leaves interact with upstream and downstream processes during nitrate utilization, nitrate uptake, and nitrate and ammonium metabolism were investigated at several times during the diurnal cycle in wild-type tobacco. Plants were grown hydroponically on 2 mM nitrate to exclude possible complications due to changes in the external availability of nitrate, and to allow nitrate uptake to be measured in the growth conditions. (a) In leaves, the NIA transcript decreases during the day and recovers at night, and NIA activity increases three-fold during the first part and declines during the second part of the light period. Nitrate decreases during the day and recovers at night, ammonium, glutamine, glycine and serine increase during the day and decrease at night, and 2-oxoglutarate increases three-fold after illumination and decreases during the last part of the light period. The amplitudes of the diurnal changes are similar to or larger than in tobacco grown on high nitrate in sand. The transcript for plastid glutamine synthetase (GLN2) is low at the end of the night and increases during the day, and glutamine synthetase activity increases to a peak at the end of the day and decreases at night. (b) In the roots, transcript levels for the high affinity nitrate transporter (NRT2) increase in the day and decrease at night. Nitrate uptake is about 40% higher during the day than at night. (c) Comparison of the diurnal changes of the leaf metabolite pools with the rate of nitrate uptake allows diurnal changes in fluxes to be estimated. During the first part of the light, the rate of nitrate assimilation is about two-fold higher than the rate of nitrate uptake, and also exceeds the rate at which reduced nitrogen is metabolized in the GOGAT pathway. The resulting decrease of leaf nitrate and accumulation of nitrogen in intermediates of ammonium metabolism and photorespiration represent about 40 and 15%, respectively, of the total nitrate that enters the plant in 24 h. Later in the diurnal cycle as NIA expression and activity decline, this imbalance is reversed. NRT2 expression and nitrate uptake remain relatively high, and nitrate taken up during the night is used to replenish the leaf nitrate pool. Increased GLN2 expression in leaves during the second part of the light period allows continued assimilation of ammonium released during photorespiration and remobilization of the reduced nitrogen that accumulated earlier in the diurnal cycle.

Nitrogen Cycle

10.1046/j.1365-3040.2001.00676.x

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Citations (4)