10,061 research outputs found
A text-mining system for extracting metabolic reactions from full-text articles
Background: Increasingly biological text mining research is focusing on the extraction of complex relationships
relevant to the construction and curation of biological networks and pathways. However, one important category of
pathway—metabolic pathways—has been largely neglected.
Here we present a relatively simple method for extracting metabolic reaction information from free text that scores
different permutations of assigned entities (enzymes and metabolites) within a given sentence based on the presence
and location of stemmed keywords. This method extends an approach that has proved effective in the context of the
extraction of protein–protein interactions.
Results: When evaluated on a set of manually-curated metabolic pathways using standard performance criteria, our
method performs surprisingly well. Precision and recall rates are comparable to those previously achieved for the
well-known protein-protein interaction extraction task.
Conclusions: We conclude that automated metabolic pathway construction is more tractable than has often been
assumed, and that (as in the case of protein–protein interaction extraction) relatively simple text-mining approaches can prove surprisingly effective. It is hoped that these results will provide an impetus to further research and act as a useful benchmark for judging the performance of more sophisticated methods that are yet to be developed
The compositional and evolutionary logic of metabolism
Metabolism displays striking and robust regularities in the forms of
modularity and hierarchy, whose composition may be compactly described. This
renders metabolic architecture comprehensible as a system, and suggests the
order in which layers of that system emerged. Metabolism also serves as the
foundation in other hierarchies, at least up to cellular integration including
bioenergetics and molecular replication, and trophic ecology. The
recapitulation of patterns first seen in metabolism, in these higher levels,
suggests metabolism as a source of causation or constraint on many forms of
organization in the biosphere.
We identify as modules widely reused subsets of chemicals, reactions, or
functions, each with a conserved internal structure. At the small molecule
substrate level, module boundaries are generally associated with the most
complex reaction mechanisms and the most conserved enzymes. Cofactors form a
structurally and functionally distinctive control layer over the small-molecule
substrate. Complex cofactors are often used at module boundaries of the
substrate level, while simpler ones participate in widely used reactions.
Cofactor functions thus act as "keys" that incorporate classes of organic
reactions within biochemistry.
The same modules that organize the compositional diversity of metabolism are
argued to have governed long-term evolution. Early evolution of core
metabolism, especially carbon-fixation, appears to have required few
innovations among a small number of conserved modules, to produce adaptations
to simple biogeochemical changes of environment. We demonstrate these features
of metabolism at several levels of hierarchy, beginning with the small-molecule
substrate and network architecture, continuing with cofactors and key conserved
reactions, and culminating in the aggregation of multiple diverse physical and
biochemical processes in cells.Comment: 56 pages, 28 figure
Structural Kinetic Modeling of Metabolic Networks
To develop and investigate detailed mathematical models of cellular metabolic
processes is one of the primary challenges in systems biology. However, despite
considerable advance in the topological analysis of metabolic networks,
explicit kinetic modeling based on differential equations is still often
severely hampered by inadequate knowledge of the enzyme-kinetic rate laws and
their associated parameter values. Here we propose a method that aims to give a
detailed and quantitative account of the dynamical capabilities of metabolic
systems, without requiring any explicit information about the particular
functional form of the rate equations. Our approach is based on constructing a
local linear model at each point in parameter space, such that each element of
the model is either directly experimentally accessible, or amenable to a
straightforward biochemical interpretation. This ensemble of local linear
models, encompassing all possible explicit kinetic models, then allows for a
systematic statistical exploration of the comprehensive parameter space. The
method is applied to two paradigmatic examples: The glycolytic pathway of yeast
and a realistic-scale representation of the photosynthetic Calvin cycle.Comment: 14 pages, 8 figures (color
The protein cost of metabolic fluxes: prediction from enzymatic rate laws and cost minimization
Bacterial growth depends crucially on metabolic fluxes, which are limited by
the cell's capacity to maintain metabolic enzymes. The necessary enzyme amount
per unit flux is a major determinant of metabolic strategies both in evolution
and bioengineering. It depends on enzyme parameters (such as kcat and KM
constants), but also on metabolite concentrations. Moreover, similar amounts of
different enzymes might incur different costs for the cell, depending on
enzyme-specific properties such as protein size and half-life. Here, we
developed enzyme cost minimization (ECM), a scalable method for computing
enzyme amounts that support a given metabolic flux at a minimal protein cost.
The complex interplay of enzyme and metabolite concentrations, e.g. through
thermodynamic driving forces and enzyme saturation, would make it hard to solve
this optimization problem directly. By treating enzyme cost as a function of
metabolite levels, we formulated ECM as a numerically tractable, convex
optimization problem. Its tiered approach allows for building models at
different levels of detail, depending on the amount of available data.
Validating our method with measured metabolite and protein levels in E. coli
central metabolism, we found typical prediction fold errors of 3.8 and 2.7,
respectively, for the two kinds of data. ECM can be used to predict enzyme
levels and protein cost in natural and engineered pathways, establishes a
direct connection between protein cost and thermodynamics, and provides a
physically plausible and computationally tractable way to include enzyme
kinetics into constraint-based metabolic models, where kinetics have usually
been ignored or oversimplified
Dynamic optimization of metabolic networks coupled with gene expression
The regulation of metabolic activity by tuning enzyme expression levels is
crucial to sustain cellular growth in changing environments. Metabolic networks
are often studied at steady state using constraint-based models and
optimization techniques. However, metabolic adaptations driven by changes in
gene expression cannot be analyzed by steady state models, as these do not
account for temporal changes in biomass composition. Here we present a dynamic
optimization framework that integrates the metabolic network with the dynamics
of biomass production and composition, explicitly taking into account enzyme
production costs and enzymatic capacity. In contrast to the established dynamic
flux balance analysis, our approach allows predicting dynamic changes in both
the metabolic fluxes and the biomass composition during metabolic adaptations.
We applied our algorithm in two case studies: a minimal nutrient uptake
network, and an abstraction of core metabolic processes in bacteria. In the
minimal model, we show that the optimized uptake rates reproduce the empirical
Monod growth for bacterial cultures. For the network of core metabolic
processes, the dynamic optimization algorithm predicted commonly observed
metabolic adaptations, such as a diauxic switch with a preference ranking for
different nutrients, re-utilization of waste products after depletion of the
original substrate, and metabolic adaptation to an impending nutrient
depletion. These examples illustrate how dynamic adaptations of enzyme
expression can be predicted solely from an optimization principle
Use and abuse of the quasi-steady-state approximation
The transient kinetic behaviour of an open single enzyme, single substrate reaction is examined. The reaction follows the Van Slyke–Cullen mechanism, a spacial case of the Michaelis–Menten reaction. The analysis is performed both with and without applying the quasi-steady-state approximation. The analysis of the full system shows conditions for biochemical pathway coupling, which yield sustained oscillatory behaviour in the enzyme reaction. The reduced model does not demonstrate this behaviour. The results have important implications in the analysis of open biochemical reactions and the modelling of metabolic systems
Metabolite concentrations, fluxes and free energies imply efficient enzyme usage.
In metabolism, available free energy is limited and must be divided across pathway steps to maintain a negative ΔG throughout. For each reaction, ΔG is log proportional both to a concentration ratio (reaction quotient to equilibrium constant) and to a flux ratio (backward to forward flux). Here we use isotope labeling to measure absolute metabolite concentrations and fluxes in Escherichia coli, yeast and a mammalian cell line. We then integrate this information to obtain a unified set of concentrations and ΔG for each organism. In glycolysis, we find that free energy is partitioned so as to mitigate unproductive backward fluxes associated with ΔG near zero. Across metabolism, we observe that absolute metabolite concentrations and ΔG are substantially conserved and that most substrate (but not inhibitor) concentrations exceed the associated enzyme binding site dissociation constant (Km or Ki). The observed conservation of metabolite concentrations is consistent with an evolutionary drive to utilize enzymes efficiently given thermodynamic and osmotic constraints
The economic basis of periodic enzyme dynamics
Periodic enzyme activities can improve the metabolic performance of cells. As
an adaptation to periodic environments or by driving metabolic cycles that can
shift fluxes and rearrange metabolic processes in time to increase their
efficiency. To study what benefits can ensue from rhythmic gene expression or
posttranslational modification of enzymes, I propose a theory of optimal enzyme
rhythms in periodic or static environments. The theory is based on kinetic
metabolic models with predefined metabolic objectives, scores the effects of
harmonic enzyme oscillations, and determines amplitudes and phase shifts that
maximise cell fitness. In an expansion around optimal steady states, the
optimal enzyme profiles can be computed by solving a quadratic optimality
problem. The formulae show how enzymes can increase their efficiency by
oscillating in phase with their substrates and how cells can benefit from
adapting to external rhythms and from spontaneous, intrinsic enzyme rhythms.
Both types of behaviour may occur different parameter regions of the same
model. Optimal enzyme profiles are not passively adapted to existing substrate
rhythms, but shape them actively to create opportunities for further fitness
advantage: in doing so, they reflect the dynamic effects that enzymes can exert
in the network. The proposed theory combines the dynamics and economics of
metabolic systems and shows how optimal enzyme profiles are shaped by network
structure, dynamics, external rhythms, and metabolic objectives. It covers
static enzyme adaptation as a special case, reveals the conditions for
beneficial metabolic cycles, and predicts optimally combinations of gene
expression and posttranslational modification for creating enzyme rhythms
A structured approach for the engineering of biochemical network models, illustrated for signalling pathways
http://dx.doi.org/10.1093/bib/bbn026Quantitative models of biochemical networks (signal transduction cascades, metabolic pathways, gene regulatory circuits) are a central component of modern systems biology. Building and managing these complex models is a major challenge that can benefit from the application of formal methods adopted from theoretical computing science. Here we provide a general introduction to the field of formal modelling, which emphasizes the intuitive biochemical basis of the modelling process, but is also accessible for an audience with a background in computing science and/or model engineering. We show how signal transduction cascades can be modelled in a modular fashion, using both a qualitative approach { Qualitative Petri nets, and quantitative approaches { Continuous Petri Nets and Ordinary Differential Equations. We review the major elementary building blocks of a cellular signalling model, discuss which critical design decisions have to be made during model building, and present ..
Constrained Allocation Flux Balance Analysis
New experimental results on bacterial growth inspire a novel top-down
approach to study cell metabolism, combining mass balance and proteomic
constraints to extend and complement Flux Balance Analysis. We introduce here
Constrained Allocation Flux Balance Analysis, CAFBA, in which the biosynthetic
costs associated to growth are accounted for in an effective way through a
single additional genome-wide constraint. Its roots lie in the experimentally
observed pattern of proteome allocation for metabolic functions, allowing to
bridge regulation and metabolism in a transparent way under the principle of
growth-rate maximization. We provide a simple method to solve CAFBA efficiently
and propose an "ensemble averaging" procedure to account for unknown protein
costs. Applying this approach to modeling E. coli metabolism, we find that, as
the growth rate increases, CAFBA solutions cross over from respiratory,
growth-yield maximizing states (preferred at slow growth) to fermentative
states with carbon overflow (preferred at fast growth). In addition, CAFBA
allows for quantitatively accurate predictions on the rate of acetate excretion
and growth yield based on only 3 parameters determined by empirical growth
laws.Comment: 21 pages, 6 figures (main) + 33 pages, various figures and tables
(supporting); for the supplementary MatLab code, see
http://tinyurl.com/h763es
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