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Understanding the Control of Metabolism

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... In a linear pathway, the FCC value for a specific enzyme, which indicates the fractional change in flux due to a fractional change in that enzyme activity, has a range between 0 and 1. While an FCC value of 0 indicates that an alteration of enzyme activity will have no effect on flux, a value of 1 would correspond to a directly proportional relationship between enzyme concentration and pathway flux [79]. However, our experiments showed relatively low values for FCC of DXS under all environmental conditions tested (statistically indistinguishable from zero for all but the high light intensity-low temperature condition, where the FCC Table 1. ...
... In a linear pathway, the FCC value for a specific enzyme, which indicates the fractional change in flux due to a fractional change in that enzyme activity, has a range between 0 and 1. While an FCC value of 0 indicates that an alteration of enzyme activity will have no effect on flux, a value of 1 would correspond to a directly proportional relationship between enzyme concentration and pathway flux [79]. However, our experiments showed relatively low values for FCC of DXS under all environmental conditions tested (statistically indistinguishable from zero for all but the high light intensity-low temperature condition, where the FCC value was 0.18, see Supplemental Figure S3). ...
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The plastidic 2-C-methylerythritol 4-phosphate (MEP) pathway supplies the precursors of a large variety of essential plant isoprenoids, but its regulation is still not well understood. Using metabolic control analysis (MCA), we examined the first enzyme of this pathway, 1-deoxyxylulose 5-phosphate synthase (DXS), in multiple grey poplar (Populus × canescens) lines modified in their DXS activity. Single leaves were dynamically labeled with 13CO2 in an illuminated, climate-controlled gas exchange cuvette coupled to a proton transfer reaction mass spectrometer, and the carbon flux through the MEP pathway was calculated. Carbon was rapidly assimilated into MEP pathway intermediates and labeled both the isoprene released and the IDP+DMADP pool by up to 90%. DXS activity was increased by 25% in lines overexpressing the DXS gene and reduced by 50% in RNA interference lines, while the carbon flux in the MEP pathway was 25–35% greater in overexpressing lines and unchanged in RNA interference lines. Isoprene emission was also not altered in these different genetic backgrounds. By correlating absolute flux to DXS activity under different conditions of light and temperature, the flux control coefficient was found to be low. Among isoprenoid end products, isoprene itself was unchanged in DXS transgenic lines, but the levels of the chlorophylls and most carotenoids measured were 20–30% less in RNA interference lines than in overexpression lines. Our data thus demonstrate that DXS in the isoprene-emitting grey poplar plays only a minor part in controlling flux through the MEP pathway.
... This constraint satisfaction resource allocation approach is at the core of one of the most common approaches for modelling metabolism, known as stoichiometric modelling, constraint-based modelling or flux balance analysis (FBA; Box 1). The starting point for FBA is the construction of a stoichiometric matrix [34][35][36] , which encapsulates the detailed stoichiometry of all molecules (rows) participating in each metabolic reaction (columns in Fig. 2b,c). Next, as illustrated above, FBA makes the simplifying assumption that all fluxes are in steady state (that is, there are no changes over time in the concentrations of the metabolites; Fig. 2a). ...
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Metabolism is the complex network of chemical reactions occurring within every cell and organism, maintaining life, mediating ecosystem processes and affecting Earth's climate. Experiments and models of microbial metabolism often focus on one specific scale, overlooking the connectivity between molecules, cells and ecosystems. Here we highlight quantitative metabolic principles that exhibit commonalities across scales, which we argue could help to achieve an integrated perspective on microbial life. Mass, electron and energy balance provide quantitative constraints on their flow within metabolic networks, organisms and ecosystems, shaping how each responds to its environment. The mechanisms underlying these flows, such as enzyme-substrate interactions, often involve encounter and handling stages that are represented by equations similar to those for cells and resources, or predators and prey. We propose that these formal similarities reflect shared principles and discuss how their investigation through experiments and models may contribute to a common language for studying microbial metabolism across scales.
... PAL cannot react to an increased ATP demand, at least not for a [Ca 2+ ] c  0.27 µM. This is demonstrated in Fig. 1 C and D [25]. This behavior is explained by the following equation: ...
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A substantial aim of this study is to show how substrate utilization depends on power output. Metabolic reactions of demand and delivery in skeletal muscle are simulated. These are the pathways of coupled adenosine triphosphate (ATP) consumption of the sarcosol (demand), and those of glucose and/or glycogen and of palmitic acid oxidation (delivery). From respective ATP formation rates, substrate utilization of respective pathways can be calculated. Results are obtained from three types of muscle fibers, which differ in their mitochondrial content. Substrate utilization is shifted from palmitic acid at low and medium power outputs towards glucose/glycogen at higher power outputs. This is caused by an increase of the conductance of the glycolytic pathway through adenosine monophosphate (AMP) activation of phosphofructokinase, while on the contrary, the conductance of the fatty acid pathway remains unchanged. The flux through this latter pathway can be markedly increased only by an increase of its conductance for membrane transport. Interferences such as uncoupling of oxidative phosphorylation, or a change from isotonic to isometric contractions must be followed by an alteration of substrate utilization, because power output and the Cutting Edge Research in Biology Vol. 8 Power Output and Substrate Utilization in Skeletal Muscle: The Thermodynamics of Demand and Delivery Pathways 59 concentration of AMP are changed concomitantly. The entire flux of both substrates through demand and delivery reactions can be formulated by one single equation. Coupling between these parts of energy metabolism is achieved by ATP cycling through ATP forming and ATP splitting reactions. A negative entropy production can occur only with coupled reactions, when the negative output affinity is gone through by a flux. But this process is more than compensated for by the positive input affinity. From this it can be concluded that the Second Law of thermodynamics, i S   0, always remains fulfilled, even in the presence of negative entropy production.
... Homeostasis such as (3) is a case of such branching due to time dependent constraints. Metabolism [Fell (1997)] is an example of machresis in physiology and cells, as are brain plasticity effects associated with memory via gene regulation [Kandel (2001)] which determine what proteins will be present. Developmentally emergence takes place over timescales of between minutes to decades as an organism develops from a single cell to a cooperative ensemble of 10 11 to 10 13 cells of different types. ...
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Is there a single linearly evolving Wave Function of the Universe that is able to lead to all the nonlinearities we see around us? This proposal seems a priori highly implausible. I claim that instead, in the real Universe, generically only local wave functions exist. Non-local wave functions occur for carefully engineered contexts such as Bell experiments, but there is no single wave function for a cat or macroscopic object such as a brain, let alone for the Universe as a whole. Contextual wave function collapse leads to a defensible version of the Copenhagen interpretation of quantum theory, where classical macro levels provide the context for quantum events and biological emergence. Complexity arises via multiscale adaptive modular hierarchical structures that enable logical branching to emerge from the underlying linear physics. Each emergent level is causally effective because of the meshing of upwards and downwards causation that takes place consistently with that physics. Quantum chemistry approaches in biological contexts fit this local wavefunction picture.
... The summation laws have multiple implications for the control of dynamic phenomena [41]. We here mention only a few examples: When a concentration is at its time maximum, the corresponding summation law implies that this maximum concentration cannot just be determined by a single reaction activity in the system; there must be at least one additional controlling activity with an opposite sign. ...
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Dynamic variables in the non-equilibrium systems of life are determined by catalytic activities. These relate to the expression of the genome. The extent to which such a variable depends on the catalytic activity defined by a gene has become more and more important in view of the possibilities to modulate gene expression or intervene with enzyme function through the use of medicinal drugs. With all the complexity of cellular systems biology, there are still some very simple principles that guide the control of variables such as fluxes, concentrations, and half-times. Using time-unit invariance we here derive a multitude of laws governing the sums of the control coefficients that quantify the control of multiple variables by all the catalytic activities. We show that the sum of the control coefficients of any dynamic variable over all catalytic activities is determined by the control of the same property by time. When the variable is at a maximum, minimum or steady, this limits the sums to simple integers, such as 0, −1, 1, and −2, depending on the variable under consideration. Some of the implications for biological control are discussed as is the dependence of these results on the precise definition of control.
... Hence, although there is some evidence that PDH activation can elicit priming-like responses in some experimental preparations, all studies using a rigorous V O 2 kinetics analysis in humans have failed to find any impact of direct PDH activation via DCA on pulmonary V O 2 kinetics. However, studying the effects of an isolated aspect of mitochondrial metabolism in such a way is complex because the activities of all enzymes involved in oxidative metabolism influence the overall rate of mitochondrial ATP production to an extent that is dependent upon their individual flux control ratios [154]. Hence, if PDH is activated without a simultaneous increase in the activities of the enzymes of the electron transport system, for instance, it is unlikely that any effect on V O 2 kinetics would be observed. ...
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The observation that prior heavy or severe-intensity exercise speeds overall oxygen uptake ([Formula: see text]O2) kinetics, termed the "priming effect", has garnered significant research attention and its underpinning mechanisms have been hotly debated. In the first part of this review, the evidence for and against (1) lactic acidosis, (2) increased muscle temperature, (3) O2 delivery, (4) altered motor unit recruitment patterns and (5) enhanced intracellular O2 utilisation in underpinning the priming effect is discussed. Lactic acidosis and increased muscle temperature are most likely not key determinants of the priming effect. Whilst priming increases muscle O2 delivery, many studies have demonstrated that an increased muscle O2 delivery is not a prerequisite for the priming effect. Motor unit recruitment patterns are altered by prior exercise, and these alterations are consistent with some of the observed changes in [Formula: see text]O2 kinetics in humans. Enhancements in intracellular O2 utilisation likely play a central role in mediating the priming effect, probably related to elevated mitochondrial calcium levels and parallel activation of mitochondrial enzymes at the onset of the second bout. In the latter portion of the review, the implications of priming on the parameters of the power-duration relationship are discussed. The effect of priming on subsequent endurance performance depends critically upon which phases of the [Formula: see text]O2 response are altered. A reduced [Formula: see text]O2 slow component or increased fundamental phase amplitude tend to increase the work performable above critical power (i.e. W´), whereas a reduction in the fundamental phase time constant following priming results in an increased critical power.
... It enables direct and biologically contextualized interpretation of results, as the measurements can be related to biochemical parameters such as the Michaelis-Menten constant (KM) of relevant enzymes [54,55]. Further, these quantitative data can be exploited for relevant mathematical modeling, such as Metabolic Control Analysis [56] or thermodynamic calculations. As relating metabolite abundance to CDW or OD is less laborious, these alternative normalization strategies are also commonly applied in metabolomics [54,57,58]. ...
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Precise and accurate quantification is a prerequisite for interpretation of targeted metabolomics data, but this task is challenged by the inherent instability of the analytes. The sampling, quenching, extraction, and sample purification conditions required to recover and stabilize metabolites in representative extracts have also been proven highly dependent on species-specific properties. For Escherichia coli, unspecific leakage has been demonstrated for conventional microbial metabolomics sampling protocols. We herein present a fast filtration-based sampling protocol for this widely applied model organism, focusing on pitfalls such as inefficient filtration, selective loss of biomass, matrix contamination, and membrane permeabilization and leakage. We evaluate the effect of and need for removal of extracellular components and demonstrate how residual salts can challenge analytical accuracy of hyphenated mass spectrometric analyses, even when sophisticated correction strategies are applied. Laborious extraction procedures are bypassed by direct extraction in cold acetonitrile:water:methanol (3:5:2, v/v%), ensuring compatibility with sample concentration and thus, any downstream analysis. By applying this protocol, we achieve and demonstrate high precision and low metabolite turnover, and, followingly, minimal perturbation of the inherent metabolic state. This allows us to herein report absolute intracellular concentrations in E. coli and explore its central carbon metabolome at several commonly applied cultivation conditions.
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Kynurenic acid (KYNA) is an antioxidant degradation product of tryptophan that has been shown to have a variety of cytoprotective, neuroprotective and neuronal signalling properties. However, mammalian transporters and receptors display micromolar binding constants; these are consistent with its typically micromolar tissue concentrations but far above its serum/plasma concentration (normally tens of nanomolar), suggesting large gaps in our knowledge of its transport and mechanisms of action, in that the main influx transporters characterized to date are equilibrative, not concentrative. In addition, it is a substrate of a known anion efflux pump (ABCC4), whose in vivo activity is largely unknown. Exogeneous addition of L-tryptophan or L-kynurenine leads to the production of KYNA but also to that of many other co-metabolites (including some such as 3-hydroxy-L-kynurenine and quinolinic acid that may be toxic). With the exception of chestnut honey, KYNA exists at relatively low levels in natural foodstuffs. However, its bioavailability is reasonable, and as the terminal element of an irreversible reaction of most tryptophan degradation pathways, it might be added exogenously without disturbing upstream metabolism significantly. Many examples, which we review, show that it has valuable bioactivity. Given the above, we review its potential utility as a nutraceutical, finding it significantly worthy of further study and development.
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Selected-effects theories provide the most popular account of biological teleology. According to these theories, the purpose of a trait is to do whatever it was selected for. The vast majority of selected-effects theories consider biological teleology to be introduced by natural selection. We want to argue, however, that natural selection is not the only relevant selective process in biology. In particular, our proposal is that biological regulation is a form of biological selection. So, those who accept selected-effects theories should recognize biological regulation as a distinctive source of biological teleology. The purposes derived from biological regulation are of special interest for explaining and predicting the behavior of organisms, given that regulatory mechanisms directly modulate the behavior of the systems they regulate. This explanatory power, added to the fact that regulation is widespread in the biological world, makes the idea that regulation gives rise to its own form of teleology a substantial contribution to the debate on biological teleology.
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