اشترك بالحزمة الذهبية واحصل على وصول غير محدود شمرا أكاديميا
تسجيل مستخدم جديدSpontaneous Reaction Silencing in Metabolic Optimization
141
0
0.0
(
0
)
اسأل ChatGPT حول البحث
ﻻ يوجد ملخص باللغة العربية
Metabolic reactions of single-cell organisms are routinely observed to become dispensable or even incapable of carrying activity under certain circumstances. Yet, the mechanisms as well as the range of conditions and phenotypes associated with this behavior remain very poorly understood. Here we predict computationally and analytically that any organism evolving to maximize growth rate, ATP production, or any other linear function of metabolic fluxes tends to significantly reduce the number of active metabolic reactions compared to typical non-optimal states. The reduced number appears to be constant across the microbial species studied and just slightly larger than the minimum number required for the organism to grow at all. We show that this massive spontaneous reaction silencing is triggered by the irreversibility of a large fraction of the metabolic reactions and propagates through the network as a cascade of inactivity. Our results help explain existing experimental data on intracellular flux measurements and the usage of latent pathways, shedding new light on microbial evolution, robustness, and versatility for the execution of specific biochemical tasks. In particular, the identification of optimal reaction activity provides rigorous ground for an intriguing knockout-based method recently proposed for the synthetic recovery of metabolic function.
قيم البحث
اقرأ أيضاً
Understanding the system level adaptive changes taking place in an organism in response to variations in the environment is a key issue of contemporary biology. Current modeling approaches such as the constraint-based flux balance analyses (FBA) have
proved highly successful in analyzing the capabilities of cellular metabolism, including its capacity to predict deletion phenotypes, the ability to calculate the relative flux values of metabolic reactions and the properties of alternate optimal growth states. Here, we use FBA to thoroughly assess the activity of the Escherichia coli, Helicobacter pylori, and Saccharomyces cerevisiae metabolism in 30,000 diverse simulated environments. We identify a set of metabolic reactions forming a connected metabolic core that carry non-zero fluxes under all growth conditions, and whose flux variations are highly correlated. Furthermore, we find that the enzymes catalyzing the core reactions display a considerably higher fraction of phenotypic essentiality and evolutionary conservation than those catalyzing non-core reactions. Cellular metabolism is characterized by a large number of species-specific conditionally-active reactions organized around an evolutionary conserved always active metabolic core. Finally, we find that most current antibiotics interfering with the bacterial metabolism target the core enzymes, indicating that our findings may have important implications for antimicrobial drug target discovery.
An important goal of medical research is to develop methods to recover the loss of cellular function due to mutations and other defects. Many approaches based on gene therapy aim to repair the defective gene or to insert genes with compensatory funct
ion. Here, we propose an alternative, network-based strategy that aims to restore biological function by forcing the cell to either bypass the functions affected by the defective gene, or to compensate for the lost function. Focusing on the metabolism of single-cell organisms, we computationally study mutants that lack an essential enzyme, and thus are unable to grow or have a significantly reduced growth rate. We show that several of these mutants can be turned into viable organisms through additional gene deletions that restore their growth rate. In a rather counterintuitive fashion, this is achieved via additional damage to the metabolic network. Using flux balance-based approaches, we identify a number of synthetically viable gene pairs, in which the removal of one enzyme-encoding gene results in a nonviable phenotype, while the deletion of a second enzyme-encoding gene rescues the organism. The systematic network-based identification of compensatory rescue effects may open new avenues for genetic interventions.
Cellular metabolism, the integrated interconversion of thousands of metabolic substrates through enzyme-catalyzed biochemical reactions, is the most investigated complex intercellular web of molecular interactions. While the topological organization
of individual reactions into metabolic networks is increasingly well understood, the principles governing their global functional utilization under different growth conditions pose many open questions. We implement a flux balance analysis of the E. coli MG1655 metabolism, finding that the network utilization is highly uneven: while most metabolic reactions have small fluxes, the metabolisms activity is dominated by several reactions with very high fluxes. E. coli responds to changes in growth conditions by reorganizing the rates of selected fluxes predominantly within this high flux backbone. The identified behavior likely represents a universal feature of metabolic activity in all cells, with potential implications to metabolic engineering.
Understanding the organization of reaction fluxes in cellular metabolism from the stoichiometry and the topology of the underlying biochemical network is a central issue in systems biology. In this task, it is important to devise reasonable approxima
tion schemes that rely on the stoichiometric data only, because full-scale kinetic approaches are computationally affordable only for small networks (e.g. red blood cells, about 50 reactions). Methods commonly employed are based on finding the stationary flux configurations that satisfy mass-balance conditions for metabolites, often coupling them to local optimization rules (e.g. maximization of biomass production) to reduce the size of the solution space to a single point. Such methods have been widely applied and have proven able to reproduce experimental findings for relatively simple organisms in specific conditions. Here we define and study a constraint-based model of cellular metabolism where neither mass balance nor flux stationarity are postulated, and where the relevant flux configurations optimize the global growth of the system. In the case of E. coli, steady flux states are recovered as solutions, though mass-balance conditions are violated for some metabolites, implying a non-zero net production of the latter. Such solutions furthermore turn out to provide the correct statistics of fluxes for the bacterium E. coli in different environments and compare well with the available experimental evidence on individual fluxes. Conserved metabolic pools play a key role in determining growth rate and flux variability. Finally, we are able to connect phenomenological gene essentiality with `frozen fluxes (i.e. fluxes with smaller allowed variability) in E. coli metabolism.
Metabolic networks are known to be scale free but the evolutionary origin of this structural property is not clearly understood. One way of studying the dynamical process is to compare the metabolic networks of species that have arisen at different p
oints in evolution and hence are related to each other to varying extents. We have compared the reaction sets of each metabolite across and within 15 groups of species. For a given pair of species and a given metabolite, the number $Delta k$ of reactions of the metabolite that appear in the metabolic network of only one species and not the other is a measure of the distance between the two networks. While $Delta k$ is small within groups of related species and large across groups, we find its probability distribution to be $sim (Delta k)^{-gamma}$ where $gamma$ is a universal exponent that is the same within and across groups. This exponent equals, upto statistical uncertainties, the exponent $gamma$ in the scale free degree distribution $sim k^{-gamma}$. We argue that this, as well as our finding that $Delta k$ is approximately linearly correlated with the degree $k$ of the metabolite, is evidence of a `proportionate change process in evolution. We also discuss some molecular mechanisms that might be responsible for such an evolutionary process.
سجل دخول لتتمكن من نشر تعليقات
التعليقات
جاري جلب التعليقات
سجل دخول لتتمكن من متابعة معايير البحث التي قمت باختيارها
