3,870 research outputs found
Signatures of arithmetic simplicity in metabolic network architecture
Metabolic networks perform some of the most fundamental functions in living
cells, including energy transduction and building block biosynthesis. While
these are the best characterized networks in living systems, understanding
their evolutionary history and complex wiring constitutes one of the most
fascinating open questions in biology, intimately related to the enigma of
life's origin itself. Is the evolution of metabolism subject to general
principles, beyond the unpredictable accumulation of multiple historical
accidents? Here we search for such principles by applying to an artificial
chemical universe some of the methodologies developed for the study of genome
scale models of cellular metabolism. In particular, we use metabolic flux
constraint-based models to exhaustively search for artificial chemistry
pathways that can optimally perform an array of elementary metabolic functions.
Despite the simplicity of the model employed, we find that the ensuing pathways
display a surprisingly rich set of properties, including the existence of
autocatalytic cycles and hierarchical modules, the appearance of universally
preferable metabolites and reactions, and a logarithmic trend of pathway length
as a function of input/output molecule size. Some of these properties can be
derived analytically, borrowing methods previously used in cryptography. In
addition, by mapping biochemical networks onto a simplified carbon atom
reaction backbone, we find that several of the properties predicted by the
artificial chemistry model hold for real metabolic networks. These findings
suggest that optimality principles and arithmetic simplicity might lie beneath
some aspects of biochemical complexity
Irreversible thermodynamics of open chemical networks I: Emergent cycles and broken conservation laws
In this and a companion paper we outline a general framework for the
thermodynamic description of open chemical reaction networks, with special
regard to metabolic networks regulating cellular physiology and biochemical
functions. We first introduce closed networks "in a box", whose thermodynamics
is subjected to strict physical constraints: the mass-action law, elementarity
of processes, and detailed balance. We further digress on the role of solvents
and on the seemingly unacknowledged property of network independence of free
energy landscapes. We then open the system by assuming that the concentrations
of certain substrate species (the chemostats) are fixed, whether because
promptly regulated by the environment via contact with reservoirs, or because
nearly constant in a time window. As a result, the system is driven out of
equilibrium. A rich algebraic and topological structure ensues in the network
of internal species: Emergent irreversible cycles are associated to
nonvanishing affinities, whose symmetries are dictated by the breakage of
conservation laws. These central results are resumed in the relation between the number of fundamental affinities , that of broken
conservation laws and the number of chemostats . We decompose the
steady state entropy production rate in terms of fundamental fluxes and
affinities in the spirit of Schnakenberg's theory of network thermodynamics,
paving the way for the forthcoming treatment of the linear regime, of
efficiency and tight coupling, of free energy transduction and of thermodynamic
constraints for network reconstruction.Comment: 18 page
Genome-scale architecture of small molecule regulatory networks and the fundamental trade-off between regulation and enzymatic activity
Metabolic flux is in part regulated by endogenous small molecules that modulate the catalytic activity of an enzyme, e.g., allosteric inhibition. In contrast to transcriptional regulation of enzymes, technical limitations have hindered the production of a genome-scale atlas of small molecule-enzyme regulatory interactions. Here, we develop a framework leveraging the vast, but fragmented, biochemical literature to reconstruct and analyze the small molecule regulatory network (SMRN) of the model organism Escherichia coli, including the primary metabolite regulators and enzyme targets. Using metabolic control analysis, we prove a fundamental trade-off between regulation and enzymatic activity, and we combine it with metabolomic measurements and the SMRN to make inferences on the sensitivity of enzymes to their regulators. Generalizing the analysis to other organisms, we identify highly conserved regulatory interactions across evolutionarily divergent species, further emphasizing a critical role for small molecule interactions in the maintenance of metabolic homeostasis.P30 CA008748 - NCI NIH HHS; R01 GM121950 - NIGMS NIH HH
Characterization of growth and metabolism of the haloalkaliphile Natronomonas pharaonis
Natronomonas pharaonis is an archaeon adapted to two extreme conditions: high salt concentration and alkaline pH. It has become one of the model organisms for the study of extremophilic life. Here, we present a genome-scale, manually curated metabolic reconstruction for the microorganism. The reconstruction itself represents a knowledge base of the haloalkaliphile's metabolism and, as such, would greatly assist further investigations on archaeal pathways. In addition, we experimentally determined several parameters relevant to growth, including a characterization of the biomass composition and a quantification of carbon and oxygen consumption. Using the metabolic reconstruction and the experimental data, we formulated a constraints-based model which we used to analyze the behavior of the archaeon when grown on a single carbon source. Results of the analysis include the finding that Natronomonas pharaonis, when grown aerobically on acetate, uses a carbon to oxygen consumption ratio that is theoretically near-optimal with respect to growth and energy production. This supports the hypothesis that, under simple conditions, the microorganism optimizes its metabolism with respect to the two objectives. We also found that the archaeon has a very low carbon efficiency of only about 35%. This inefficiency is probably due to a very low P/O ratio as well as to the other difficulties posed by its extreme environment
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