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1.
PLoS Comput Biol ; 19(12): e1011711, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38079453

RESUMO

The Michaelis-Menten (MM) rate law has been the dominant paradigm of modeling biochemical rate processes for over a century with applications in biochemistry, biophysics, cell biology, systems biology, and chemical engineering. The MM rate law and its remedied form stand on the assumption that the concentration of the complex of interacting molecules, at each moment, approaches an equilibrium (quasi-steady state) much faster than the molecular concentrations change. Yet, this assumption is not always justified. Here, we relax this quasi-steady state requirement and propose the generalized MM rate law for the interactions of molecules with active concentration changes over time. Our approach for time-varying molecular concentrations, termed the effective time-delay scheme (ETS), is based on rigorously estimated time-delay effects in molecular complex formation. With particularly marked improvements in protein-protein and protein-DNA interaction modeling, the ETS provides an analytical framework to interpret and predict rich transient or rhythmic dynamics (such as autogenously-regulated cellular adaptation and circadian protein turnover), which goes beyond the quasi-steady state assumption.


Assuntos
Fenômenos Bioquímicos , Cinética , Proteólise , Enzimas/metabolismo
2.
STAR Protoc ; 2(4): 100958, 2021 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-34841277

RESUMO

Our backward simulation (BS) is an approach to infer the dynamics of individual components in ordinary differential equation (ODE) models, given the information on relatively downstream components or their sums. Here, we demonstrate the use of BS to infer protein synthesis rates with a given profile of protein concentrations over time in a circadian system. This protocol can also be applied to a wide range of problems with undetermined dynamics at the upstream levels. For complete details on the use and execution of this protocol, please refer to Lim et al. (2021).


Assuntos
Simulação por Computador , Modelos Biológicos , Biologia de Sistemas/métodos , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/metabolismo , Cinética
3.
iScience ; 24(7): 102726, 2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34355141

RESUMO

Circadian protein oscillations are maintained by the lifelong repetition of protein production and degradation in daily balance. It comes at the cost of ever-replayed, futile protein synthesis each day. This biosynthetic cost with a given oscillatory protein profile is relievable by a rhythmic, not constant, degradation rate that selectively peaks at the right time of day but remains low elsewhere, saving much of the gross protein loss and of the replenishing protein synthesis. Here, our mathematical modeling reveals that the rhythmic degradation rate of proteins with circadian production spontaneously emerges under steady and limited activity of proteolytic mediators and does not necessarily require rhythmic post-translational regulation of previous focus. Additional (yet steady) post-translational modifications in a proteolytic pathway can further facilitate the degradation's rhythmicity in favor of the biosynthetic cost saving. Our work is supported by animal and plant circadian data, offering a generic mechanism for potentially widespread, time-dependent protein turnover.

4.
Sci Data ; 7(1): 272, 2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32788577

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

5.
Sci Data ; 7(1): 204, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32591517

RESUMO

The role of our gut microbiota in health and disease is largely attributed to the collective metabolic activities of the inhabitant microbes. A system-level framework of the microbial community structure, mediated through metabolite transport, would provide important insights into the complex microbe-microbe and host-microbe chemical interactions. This framework, if adaptable to both mouse and human systems, would be useful for mechanistic interpretations of the vast amounts of experimental data from gut microbiomes in murine animal models, whether humanized or not. Here, we constructed a literature-curated, interspecies network of the mammalian gut microbiota for mouse and human hosts, called NJC19. This network is an extensive data resource, encompassing 838 microbial species (766 bacteria, 53 archaea, and 19 eukaryotes) and 6 host cell types, interacting through 8,224 small-molecule transport and macromolecule degradation events. Moreover, we compiled 912 negative associations between organisms and metabolic compounds that are not transportable or degradable by those organisms. Our network may facilitate experimental and computational endeavors for the mechanistic investigations of host-associated microbial communities.


Assuntos
Microbioma Gastrointestinal , Redes e Vias Metabólicas , Animais , Humanos , Camundongos
6.
Commun Biol ; 1: 207, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30511021

RESUMO

Circadian clocks play a pivotal role in orchestrating numerous physiological and developmental events. Waveform shapes of the oscillations of protein abundances can be informative about the underlying biochemical processes of circadian clocks. We derive a mathematical framework where waveforms do reveal hidden biochemical mechanisms of circadian timekeeping. We find that the cost of synthesizing proteins with particular waveforms can be substantially reduced by rhythmic protein half-lives over time, as supported by previous plant and mammalian data, as well as our own seedling experiment. We also find that previously enigmatic, cyclic expression of positive arm components within the mammalian and insect clocks allows both a broad range of peak time differences between protein waveforms and the symmetries of the waveforms about the peak times. Such various peak-time differences may facilitate tissue-specific or developmental stage-specific multicellular processes. Our waveform-guided approach can be extended to various biological oscillators, including cell-cycle and synthetic genetic oscillators.

7.
Sci Rep ; 8(1): 4344, 2018 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-29531252

RESUMO

Diet design for vegetarian health is challenging due to the limited food repertoire of vegetarians. This challenge can be partially overcome by quantitative, data-driven approaches that utilise massive nutritional information collected for many different foods. Based on large-scale data of foods' nutrient compositions, the recent concept of nutritional fitness helps quantify a nutrient balance within each food with regard to satisfying daily nutritional requirements. Nutritional fitness offers prioritisation of recommended foods using the foods' occurrence in nutritionally adequate food combinations. Here, we systematically identify nutritionally recommendable foods for semi- to strict vegetarian diets through the computation of nutritional fitness. Along with commonly recommendable foods across different diets, our analysis reveals favourable foods specific to each diet, such as immature lima beans for a vegan diet as an amino acid and choline source, and mushrooms for ovo-lacto vegetarian and vegan diets as a vitamin D source. Furthermore, we find that selenium and other essential micronutrients can be subject to deficiency in plant-based diets, and suggest nutritionally-desirable dietary patterns. We extend our analysis to two hypothetical scenarios of highly personalised, plant-based methionine-restricted diets. Our nutrient-profiling approach may provide a useful guide for designing different types of personalised vegetarian diets.


Assuntos
Dieta Vegana/normas , Necessidades Nutricionais , Proteínas de Vegetais Comestíveis/normas , Oligoelementos/normas , Vegetarianos , Vitaminas/normas , Bases de Dados Factuais , Humanos
8.
Nat Commun ; 8: 15393, 2017 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-28585563

RESUMO

A system-level framework of complex microbe-microbe and host-microbe chemical cross-talk would help elucidate the role of our gut microbiota in health and disease. Here we report a literature-curated interspecies network of the human gut microbiota, called NJS16. This is an extensive data resource composed of ∼570 microbial species and 3 human cell types metabolically interacting through >4,400 small-molecule transport and macromolecule degradation events. Based on the contents of our network, we develop a mathematical approach to elucidate representative microbial and metabolic features of the gut microbial community in a given population, such as a disease cohort. Applying this strategy to microbiome data from type 2 diabetes patients reveals a context-specific infrastructure of the gut microbial ecosystem, core microbial entities with large metabolic influence, and frequently produced metabolic compounds that might indicate relevant community metabolic processes. Our network presents a foundation towards integrative investigations of community-scale microbial activities within the human gut.


Assuntos
Microbioma Gastrointestinal , Redes e Vias Metabólicas , Bactérias/metabolismo , Transporte Biológico , Bases de Dados como Assunto , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/microbiologia , Humanos , Masculino
9.
Appl Transl Genom ; 10: 10-5, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27668170

RESUMO

The recent advances in high-throughput omics technologies have enabled researchers to explore the intricacies of the human microbiome. On the clinical front, the gut microbial community has been the focus of many biomarker-discovery studies. While the recent deluge of high-throughput data in microbiome research has been vastly informative and groundbreaking, we have yet to capture the full potential of omics-based approaches. Realizing the promise of multi-omics data will require integration of disparate omics data, as well as a biologically relevant, mechanistic framework - or metabolic model - on which to overlay these data. Also, a new paradigm for metabolic model evaluation is necessary. Herein, we outline the need for multi-omics data integration, as well as the accompanying challenges. Furthermore, we present a framework for characterizing the ecology of the gut microbiome based on metabolic network modeling.

10.
Aging (Albany NY) ; 8(5): 986-99, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27193830

RESUMO

Genetic studies using model organisms have shown that many long-lived mutants display impaired fitness, such as reduced fecundity and delayed development. However, in several wild animals, the association between longevity and fitness does not seem to be inevitable. Thus, the relationship between longevity and fitness in wild organisms remains inconclusive. Here, we determined the correlation between lifespan and fitness, developmental rate and brood size, by using 16 wild-derived C. elegans strains originated from various geographic areas. We found a negative correlation between lifespan and developmental rate. In contrast, we did not find such negative correlation between longevity and developmental rate among the individuals of C. elegans strains. These data imply that polymorphic genetic variants among wild isolates determine resource allocation to longevity and developmental rate.


Assuntos
Envelhecimento/genética , Caenorhabditis elegans/genética , Longevidade/genética , Animais , Especificidade da Espécie
11.
PLoS Comput Biol ; 12(2): e1004748, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26828650

RESUMO

A wide range of organisms features molecular machines, circadian clocks, which generate endogenous oscillations with ~24 h periodicity and thereby synchronize biological processes to diurnal environmental fluctuations. Recently, it has become clear that plants harbor more complex gene regulatory circuits within the core circadian clocks than other organisms, inspiring a fundamental question: are all these regulatory interactions between clock genes equally crucial for the establishment and maintenance of circadian rhythms? Our mechanistic simulation for Arabidopsis thaliana demonstrates that at least half of the total regulatory interactions must be present to express the circadian molecular profiles observed in wild-type plants. A set of those essential interactions is called herein a kernel of the circadian system. The kernel structure unbiasedly reveals four interlocked negative feedback loops contributing to circadian rhythms, and three feedback loops among them drive the autonomous oscillation itself. Strikingly, the kernel structure, as well as the whole clock circuitry, is overwhelmingly composed of inhibitory, rather than activating, interactions between genes. We found that this tendency underlies plant circadian molecular profiles which often exhibit sharply-shaped, cuspidate waveforms. Through the generation of these cuspidate profiles, inhibitory interactions may facilitate the global coordination of temporally-distant clock events that are markedly peaked at very specific times of day. Our systematic approach resulting in experimentally-testable predictions provides insights into a design principle of biological clockwork, with implications for synthetic biology.


Assuntos
Arabidopsis/genética , Relógios Circadianos/genética , Redes Reguladoras de Genes/genética , Genes de Plantas/genética , Algoritmos , Arabidopsis/fisiologia , Relógios Circadianos/fisiologia , Biologia Computacional , Modelos Genéticos
12.
Antimicrob Agents Chemother ; 60(4): 2232-40, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26810657

RESUMO

Bacterial persisters are a small fraction of quiescent cells that survive in the presence of lethal concentrations of antibiotics. They can regrow to give rise to a new population that has the same vulnerability to the antibiotics as did the parental population. Although formation of bacterial persisters in the presence of various antibiotics has been documented, the molecular mechanisms by which these persisters tolerate the antibiotics are still controversial. We found that amplification of the fumarate reductase operon (FRD) inEscherichia coliled to a higher frequency of persister formation. The persister frequency ofE. coliwas increased when the cells contained elevated levels of intracellular fumarate. Genetic perturbations of the electron transport chain (ETC), a metabolite supplementation assay, and even the toxin-antitoxin-relatedhipA7mutation indicated that surplus fumarate markedly elevated theE. colipersister frequency. AnE. colistrain lacking succinate dehydrogenase (SDH), thereby showing a lower intracellular fumarate concentration, was killed ∼1,000-fold more effectively than the wild-type strain in the stationary phase. It appears thatSDHandFRDrepresent a paired system that gives rise to and maintainsE. colipersisters by producing and utilizing fumarate, respectively.


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Farmacorresistência Bacteriana Múltipla/genética , Escherichia coli/efeitos dos fármacos , Regulação Bacteriana da Expressão Gênica , Succinato Desidrogenase/genética , Ampicilina/farmacologia , Proteínas de Bactérias/metabolismo , Ciclo do Ácido Cítrico/efeitos dos fármacos , Ciclo do Ácido Cítrico/genética , Transporte de Elétrons/efeitos dos fármacos , Transporte de Elétrons/genética , Escherichia coli/enzimologia , Escherichia coli/genética , Fumaratos/metabolismo , Perfilação da Expressão Gênica , Biblioteca Gênica , Canamicina/farmacologia , Testes de Sensibilidade Microbiana , Norfloxacino/farmacologia , Óperon , Succinato Desidrogenase/deficiência
13.
PLoS One ; 10(3): e0118697, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25768022

RESUMO

Recent progresses in data-driven analysis methods, including network-based approaches, are revolutionizing many classical disciplines. These techniques can also be applied to food and nutrition, which must be studied to design healthy diets. Using nutritional information from over 1,000 raw foods, we systematically evaluated the nutrient composition of each food in regards to satisfying daily nutritional requirements. The nutrient balance of a food was quantified and termed nutritional fitness; this measure was based on the food's frequency of occurrence in nutritionally adequate food combinations. Nutritional fitness offers a way to prioritize recommendable foods within a global network of foods, in which foods are connected based on the similarities of their nutrient compositions. We identified a number of key nutrients, such as choline and α-linolenic acid, whose levels in foods can critically affect the nutritional fitness of the foods. Analogously, pairs of nutrients can have the same effect. In fact, two nutrients can synergistically affect the nutritional fitness, although the individual nutrients alone may not have an impact. This result, involving the tendency among nutrients to exhibit correlations in their abundances across foods, implies a hidden layer of complexity when exploring for foods whose balance of nutrients within pairs holistically helps meet nutritional requirements. Interestingly, foods with high nutritional fitness successfully maintain this nutrient balance. This effect expands our scope to a diverse repertoire of nutrient-nutrient correlations, which are integrated under a common network framework that yields unexpected yet coherent associations between nutrients. Our nutrient-profiling approach combined with a network-based analysis provides a more unbiased, global view of the relationships between foods and nutrients, and can be extended towards nutritional policies, food marketing, and personalized nutrition.


Assuntos
Alimentos , Valor Nutritivo , Interpretação Estatística de Dados , Dieta , Humanos , Necessidades Nutricionais
14.
PLoS One ; 10(2): e0117388, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25671617

RESUMO

The quest for historically impactful science and technology provides invaluable insight into the innovation dynamics of human society, yet many studies are limited to qualitative and small-scale approaches. Here, we investigate scientific evolution through systematic analysis of a massive corpus of digitized English texts between 1800 and 2008. Our analysis reveals great predictability for long-prevailing scientific concepts based on the levels of their prior usage. Interestingly, once a threshold of early adoption rates is passed even slightly, scientific concepts can exhibit sudden leaps in their eventual lifetimes. We developed a mechanistic model to account for such results, indicating that slowly-but-commonly adopted science and technology surprisingly tend to have higher innate strength than fast-and-commonly adopted ones. The model prediction for disciplines other than science was also well verified. Our approach sheds light on unbiased and quantitative analysis of scientific evolution in society, and may provide a useful basis for policy-making.


Assuntos
Ciência/história , Evolução Cultural , História do Século XIX , História do Século XX , História do Século XXI , Filosofia , Tecnologia/história , Redação
15.
J Biotechnol ; 194: 48-57, 2015 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-25435378

RESUMO

In order to determine beneficial gene deletions for ethanol production by the yeast Saccharomyces cerevisiae, we performed an in silico gene deletion experiment based on a genome-scale metabolic model. Genes coding for two oxidative phosphorylation reactions (cytochrome c oxidase and ubiquinol cytochrome c reductase) were identified by the model-based simulation as potential deletion targets for enhancing ethanol production and maintaining acceptable overall growth rate in oxygen-limited conditions. Since the two target enzymes are composed of multiple subunits, we conducted a genetic screening study to evaluate the in silico results and compare the effect of deleting various portions of the respiratory enzyme complexes. Over two-thirds of the knockout mutants identified by the in silico study did exhibit experimental behavior in qualitative agreement with model predictions, but the exceptions illustrate the limitation of using a purely stoichiometric model-based approach. Furthermore, there was a substantial quantitative variation in phenotype among the various respiration-deficient mutants that were screened in this study, and three genes encoding respiratory enzyme subunits were identified as the best knockout targets for improving hexose fermentation in microaerobic conditions. Specifically, deletion of either COX9 or QCR9 resulted in higher ethanol production rates than the parental strain by 37% and 27%, respectively, with slight growth disadvantages. Also, deletion of QCR6 led to improved ethanol production rate by 24% with no growth disadvantage. The beneficial effects of these gene deletions were consistently demonstrated in different strain backgrounds and with four common hexoses. The combination of stoichiometric modeling and genetic screening using a systematic knockout collection was useful for narrowing a large set of gene targets and identifying targets of interest.


Assuntos
Fermentação/fisiologia , Hexoses/metabolismo , Saccharomyces cerevisiae/metabolismo
16.
Environ Microbiol ; 16(6): 1695-708, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24238218

RESUMO

A low-diversity microbial community, dominated by the γ-proteobacterium Halomonas sulfidaeris, was detected in samples of warm saline formation porewater collected from the Cambrian Mt. Simon Sandstone in the Illinois Basin of the North American Midcontinent (1.8 km/5872 ft burial depth, 50°C, pH 8, 181 bars pressure). These highly porous and permeable quartz arenite sandstones are directly analogous to reservoirs around the world targeted for large-scale hydrocarbon extraction, as well as subsurface gas and carbon storage. A new downhole low-contamination subsurface sampling probe was used to collect in situ formation water samples for microbial environmental metagenomic analyses. Multiple lines of evidence suggest that this H. sulfidaeris-dominated subsurface microbial community is indigenous and not derived from drilling mud microbial contamination. Data to support this includes V1-V3 pyrosequencing of formation water and drilling mud, as well as comparison with previously published microbial analyses of drilling muds in other sites. Metabolic pathway reconstruction, constrained by the geology, geochemistry and present-day environmental conditions of the Mt. Simon Sandstone, implies that H. sulfidaeris-dominated subsurface microbial community may utilize iron and nitrogen metabolisms and extensively recycle indigenous nutrients and substrates. The presence of aromatic compound metabolic pathways suggests this microbial community can readily adapt to and survive subsurface hydrocarbon migration.


Assuntos
Halomonas/genética , Microbiologia da Água , Genes Bacterianos , Illinois , Redes e Vias Metabólicas/genética , Metagenoma , Microbiota/genética , Anotação de Sequência Molecular , Dados de Sequência Molecular , Filogenia , Quartzo , RNA Ribossômico 16S/genética , Análise de Sequência de DNA
17.
PLoS Comput Biol ; 9(7): e1003148, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23935471

RESUMO

We utilized abundant transcriptomic data for the primary classes of brain cancers to study the feasibility of separating all of these diseases simultaneously based on molecular data alone. These signatures were based on a new method reported herein--Identification of Structured Signatures and Classifiers (ISSAC)--that resulted in a brain cancer marker panel of 44 unique genes. Many of these genes have established relevance to the brain cancers examined herein, with others having known roles in cancer biology. Analyses on large-scale data from multiple sources must deal with significant challenges associated with heterogeneity between different published studies, for it was observed that the variation among individual studies often had a larger effect on the transcriptome than did phenotype differences, as is typical. For this reason, we restricted ourselves to studying only cases where we had at least two independent studies performed for each phenotype, and also reprocessed all the raw data from the studies using a unified pre-processing pipeline. We found that learning signatures across multiple datasets greatly enhanced reproducibility and accuracy in predictive performance on truly independent validation sets, even when keeping the size of the training set the same. This was most likely due to the meta-signature encompassing more of the heterogeneity across different sources and conditions, while amplifying signal from the repeated global characteristics of the phenotype. When molecular signatures of brain cancers were constructed from all currently available microarray data, 90% phenotype prediction accuracy, or the accuracy of identifying a particular brain cancer from the background of all phenotypes, was found. Looking forward, we discuss our approach in the context of the eventual development of organ-specific molecular signatures from peripheral fluids such as the blood.


Assuntos
Neoplasias Encefálicas/genética , Transcriptoma , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/metabolismo , Biologia Computacional , Humanos , Reprodutibilidade dos Testes
18.
BMC Syst Biol ; 5: 126, 2011 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-21843333

RESUMO

BACKGROUND: Proteins in organisms, rather than act alone, usually form protein complexes to perform cellular functions. We analyze the topological network structure of protein complexes and their component proteins in the budding yeast in terms of the bipartite network and its projections, where the complexes and proteins are its two distinct components. Compared to conventional protein-protein interaction networks, the networks from the protein complexes show more homogeneous structures than those of the binary protein interactions, implying the formation of complexes that cause a relatively more uniform number of interaction partners. In addition, we suggest a new optimization method to determine the abundance and function of protein complexes, based on the information of their global organization. Estimating abundance and biological functions is of great importance for many researches, by providing a quantitative description of cell behaviors, instead of just a "catalogues" of the lists of protein interactions. RESULTS: With our new optimization method, we present genome-wide assignments of abundance and biological functions for complexes, as well as previously unknown abundance and functions of proteins, which can provide significant information for further investigations in proteomics. It is strongly supported by a number of biologically relevant examples, such as the relationship between the cytoskeleton proteins and signal transduction and the metabolic enzyme Eno2's involvement in the cell division process. CONCLUSIONS: We believe that our methods and findings are applicable not only to the specific area of proteomics, but also to much broader areas of systems biology with the concept of optimization principle.


Assuntos
Proteínas Fúngicas/genética , Modelos Biológicos , Complexos Multiproteicos/genética , Mapas de Interação de Proteínas/genética , Proteômica/métodos , Saccharomyces cerevisiae/genética , Biologia de Sistemas/métodos
19.
BMC Syst Biol ; 5: 130, 2011 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-21846360

RESUMO

BACKGROUND: Solventogenic clostridia offer a sustainable alternative to petroleum-based production of butanol--an important chemical feedstock and potential fuel additive or replacement. C. beijerinckii is an attractive microorganism for strain design to improve butanol production because it (i) naturally produces the highest recorded butanol concentrations as a byproduct of fermentation; and (ii) can co-ferment pentose and hexose sugars (the primary products from lignocellulosic hydrolysis). Interrogating C. beijerinckii metabolism from a systems viewpoint using constraint-based modeling allows for simulation of the global effect of genetic modifications. RESULTS: We present the first genome-scale metabolic model (iCM925) for C. beijerinckii, containing 925 genes, 938 reactions, and 881 metabolites. To build the model we employed a semi-automated procedure that integrated genome annotation information from KEGG, BioCyc, and The SEED, and utilized computational algorithms with manual curation to improve model completeness. Interestingly, we found only a 34% overlap in reactions collected from the three databases--highlighting the importance of evaluating the predictive accuracy of the resulting genome-scale model. To validate iCM925, we conducted fermentation experiments using the NCIMB 8052 strain, and evaluated the ability of the model to simulate measured substrate uptake and product production rates. Experimentally observed fermentation profiles were found to lie within the solution space of the model; however, under an optimal growth objective, additional constraints were needed to reproduce the observed profiles--suggesting the existence of selective pressures other than optimal growth. Notably, a significantly enriched fraction of actively utilized reactions in simulations--constrained to reflect experimental rates--originated from the set of reactions that overlapped between all three databases (P = 3.52 × 10-9, Fisher's exact test). Inhibition of the hydrogenase reaction was found to have a strong effect on butanol formation--as experimentally observed. CONCLUSIONS: Microbial production of butanol by C. beijerinckii offers a promising, sustainable, method for generation of this important chemical and potential biofuel. iCM925 is a predictive model that can accurately reproduce physiological behavior and provide insight into the underlying mechanisms of microbial butanol production. As such, the model will be instrumental in efforts to better understand, and metabolically engineer, this microorganism for improved butanol production.


Assuntos
Reatores Biológicos , Clostridium beijerinckii/metabolismo , Genoma Bacteriano/genética , Microbiologia Industrial/métodos , Redes e Vias Metabólicas/fisiologia , Modelos Biológicos , Biologia de Sistemas/métodos , Butanóis/metabolismo , Clostridium beijerinckii/genética , Simulação por Computador , Fermentação , Hexoses/metabolismo , Pentoses/metabolismo
20.
PLoS Comput Biol ; 7(12): e1002340, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22219725

RESUMO

The phenotype of any organism on earth is, in large part, the consequence of interplay between numerous gene products encoded in the genome, and such interplay between gene products affects the evolutionary fate of the genome itself through the resulting phenotype. In this regard, contemporary genomes can be used as molecular records that reveal associations of various genes working in their natural lifestyles. By analyzing thousands of orthologs across ∼600 bacterial species, we constructed a map of gene-gene co-occurrence across much of the sequenced biome. If genes preferentially co-occur in the same organisms, they were called herein correlogs; in the opposite case, called anti-correlogs. To quantify correlogy and anti-correlogy, we alleviated the contribution of indirect correlations between genes by adapting ideas developed for reverse engineering of transcriptional regulatory networks. Resultant correlogous associations are highly enriched for physically interacting proteins and for co-expressed transcripts, clearly differentiating a subgroup of functionally-obligatory protein interactions from conditional or transient interactions. Other biochemical and phylogenetic properties were also found to be reflected in correlogous and anti-correlogous relationships. Additionally, our study elucidates the global organization of the gene association map, in which various modules of correlogous genes are strikingly interconnected by anti-correlogous crosstalk between the modules. We then demonstrate the effectiveness of such associations along different domains of life and environmental microbial communities. These phylogenetic profiling approaches infer functional coupling of genes regardless of mechanistic details, and may be useful to guide exogenous gene import in synthetic biology.


Assuntos
Bactérias/genética , Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , Meio Ambiente , Evolução Molecular , Trato Gastrointestinal/microbiologia , Redes Reguladoras de Genes , Genes Bacterianos , Genoma Bacteriano , Humanos , Modelos Biológicos , Fenótipo , Filogenia , Análise de Sequência de DNA , Especificidade da Espécie
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