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1.
Nat Commun ; 11(1): 4496, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901024

RESUMO

Aging is characterized by the loss of homeostasis and the general decline of physiological functions, accompanied by various degenerative diseases and increased rates of mortality. Aging targeting small molecule screens have been performed many times, however, few have focused on endogenous metabolic intermediates-metabolites. Here, using C. elegans lifespan assays, we conducted a worm metabolite screen and identified an eukaryotes conserved metabolite, myo-inositol (MI), to extend lifespan, increase mobility and reduce fat content. Genetic analysis of enzymes in MI metabolic pathway suggest that MI alleviates aging through its derivative PI(4,5)P2. MI and PI(4,5)P2 are precursors of PI(3,4,5)P3, which is negatively related to longevity. The longevity effect of MI is dependent on the tumor suppressor gene, daf-18 (homologous to mouse Pten), independent of its classical pathway downstream genes, akt or daf-16. Furthermore, we found MI effects on aging and lifespan act through mitophagy regulator PTEN induced kinase-1 (pink-1) and mitophagy. MI's anti-aging effect is also conserved in mouse, indicating a conserved mechanism in mammals.


Assuntos
Envelhecimento/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Inositol/metabolismo , Longevidade/fisiologia , PTEN Fosfo-Hidrolase/metabolismo , Envelhecimento/efeitos dos fármacos , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Linhagem Celular Tumoral , Feminino , Fatores de Transcrição Forkhead/genética , Inositol/administração & dosagem , Locomoção/fisiologia , Longevidade/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Metabolômica , Camundongos , Mitofagia/fisiologia , Modelos Animais , Fosfatos de Fosfatidilinositol/metabolismo , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA , RNA-Seq
2.
Adv Exp Med Biol ; 1274: 101-135, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32894509

RESUMO

Intensive research in the field of sphingolipids has revealed diverse roles in cell biological responses and human health and disease. This immense molecular family is primarily represented by the bioactive molecules ceramide, sphingosine, and sphingosine 1-phosphate (S1P). The flux of sphingolipid metabolism at both the subcellular and extracellular levels provides multiple opportunities for pharmacological intervention. The caveat is that perturbation of any single node of this highly regulated flux may have effects that propagate throughout the metabolic network in a dramatic and sometimes unexpected manner. Beginning with S1P, the receptors for which have thus far been the most clinically tractable pharmacological targets, this review will describe recent advances in therapeutic modulators targeting sphingolipids, their chaperones, transporters, and metabolic enzymes.


Assuntos
Redes e Vias Metabólicas/efeitos dos fármacos , Modelos Biológicos , Terapia de Alvo Molecular , Esfingolipídeos/metabolismo , Ceramidas/metabolismo , Humanos , Lisofosfolipídeos/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismo
3.
Nat Commun ; 11(1): 4880, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978375

RESUMO

Through advanced mechanistic modeling and the generation of large high-quality datasets, machine learning is becoming an integral part of understanding and engineering living systems. Here we show that mechanistic and machine learning models can be combined to enable accurate genotype-to-phenotype predictions. We use a genome-scale model to pinpoint engineering targets, efficient library construction of metabolic pathway designs, and high-throughput biosensor-enabled screening for training diverse machine learning algorithms. From a single data-generation cycle, this enables successful forward engineering of complex aromatic amino acid metabolism in yeast, with the best machine learning-guided design recommendations improving tryptophan titer and productivity by up to 74 and 43%, respectively, compared to the best designs used for algorithm training. Thus, this study highlights the power of combining mechanistic and machine learning models to effectively direct metabolic engineering efforts.


Assuntos
Aprendizado de Máquina , Engenharia Metabólica/métodos , Saccharomyces cerevisiae/metabolismo , Triptofano/metabolismo , Algoritmos , Aminoácidos/metabolismo , Fenômenos Bioquímicos , Técnicas Biossensoriais , Genótipo , Redes e Vias Metabólicas , Modelos Biológicos , Fenótipo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento
4.
Nat Commun ; 11(1): 4866, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978391

RESUMO

Mitochondria house evolutionarily conserved pathways of carbon and nitrogen metabolism that drive cellular energy production. Mitochondrial bioenergetics is regulated by calcium uptake through the mitochondrial calcium uniporter (MCU), a multi-protein complex whose assembly in the inner mitochondrial membrane is facilitated by the scaffold factor MCUR1. Intriguingly, many fungi that lack MCU contain MCUR1 homologs, suggesting alternate functions. Herein, we characterize Saccharomyces cerevisiae homologs Put6 and Put7 of MCUR1 as regulators of mitochondrial proline metabolism. Put6 and Put7 are tethered to the inner mitochondrial membrane in a large hetero-oligomeric complex, whose abundance is regulated by proline. Loss of this complex perturbs mitochondrial proline homeostasis and cellular redox balance. Yeast cells lacking either Put6 or Put7 exhibit a pronounced defect in proline utilization, which can be corrected by the heterologous expression of human MCUR1. Our work uncovers an unexpected role of MCUR1 homologs in mitochondrial proline metabolism.


Assuntos
Proteínas de Membrana/metabolismo , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Prolina/metabolismo , Saccharomyces cerevisiae/metabolismo , Canais de Cálcio , Regulação Fúngica da Expressão Gênica , Genes Fúngicos/genética , Homeostase , Humanos , Proteínas de Membrana/genética , Redes e Vias Metabólicas/genética , Membranas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento , Transcriptoma
5.
Nat Commun ; 11(1): 4865, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978396

RESUMO

The metabolic state of an organism instructs gene expression modalities, leading to changes in complex life history traits, such as longevity. Dietary restriction (DR), which positively affects health and life span across species, leads to metabolic reprogramming that enhances utilisation of fatty acids for energy generation. One direct consequence of this metabolic shift is the upregulation of cytoprotective (CyTP) genes categorized in the Gene Ontology (GO) term of "Xenobiotic Detoxification Program" (XDP). How an organism senses metabolic changes during nutritional stress to alter gene expression programs is less known. Here, using a genetic model of DR, we show that the levels of polyunsaturated fatty acids (PUFAs), especially linoleic acid (LA) and eicosapentaenoic acid (EPA), are increased following DR and these PUFAs are able to activate the CyTP genes. This activation of CyTP genes is mediated by the conserved p38 mitogen-activated protein kinase (p38-MAPK) pathway. Consequently, genes of the PUFA biosynthesis and p38-MAPK pathway are required for multiple paradigms of DR-mediated longevity, suggesting conservation of mechanism. Thus, our study shows that PUFAs and p38-MAPK pathway function downstream of DR to help communicate the metabolic state of an organism to regulate expression of CyTP genes, ensuring extended life span.


Assuntos
Ácidos Graxos Insaturados/genética , Ácidos Graxos Insaturados/metabolismo , Regulação da Expressão Gênica , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Fenômenos Bioquímicos , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Ácido Eicosapentaenoico/análogos & derivados , Regulação da Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Ácido Linoleico/metabolismo , Longevidade , Redes e Vias Metabólicas/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo
7.
PLoS Comput Biol ; 16(9): e1007646, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32925899

RESUMO

In this study we analyze the growth-phase dependent metabolic states of Bdellovibrio bacteriovorus by constructing a fully compartmented, mass and charge-balanced genome-scale metabolic model of this predatory bacterium (iCH457). Considering the differences between life cycle phases driving the growth of this predator, growth-phase condition-specific models have been generated allowing the systematic study of its metabolic capabilities. Using these computational tools, we have been able to analyze, from a system level, the dynamic metabolism of the predatory bacteria as the life cycle progresses. We provide computational evidences supporting potential axenic growth of B. bacteriovorus's in a rich medium based on its encoded metabolic capabilities. Our systems-level analysis confirms the presence of "energy-saving" mechanisms in this predator as well as an abrupt metabolic shift between the attack and intraperiplasmic growth phases. Our results strongly suggest that predatory bacteria's metabolic networks have low robustness, likely hampering their ability to tackle drastic environmental fluctuations, thus being confined to stable and predictable habitats. Overall, we present here a valuable computational testbed based on predatory bacteria activity for rational design of novel and controlled biocatalysts in biotechnological/clinical applications.


Assuntos
Bdellovibrio bacteriovorus/genética , Bdellovibrio bacteriovorus/metabolismo , Genoma Bacteriano/genética , Redes e Vias Metabólicas , Modelos Biológicos , Redes e Vias Metabólicas/genética , Redes e Vias Metabólicas/fisiologia , Biologia de Sistemas/métodos
8.
PLoS Comput Biol ; 16(9): e1008185, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32925942

RESUMO

Cells adjust their metabolism in response to mutations, but how this reprogramming depends on the genetic context is not well known. Specifically, the absence of individual enzymes can affect reprogramming, and thus the impact of mutations in cell growth. Here, we examine this issue with an in silico model of Saccharomyces cerevisiae's metabolism. By quantifying the variability in the growth rate of 10000 different mutant metabolisms that accumulated changes in their reaction fluxes, in the presence, or absence, of a specific enzyme, we distinguish a subset of modifier genes serving as buffers or potentiators of variability. We notice that the most potent modifiers refer to the glycolysis pathway and that, more broadly, they show strong pleiotropy and epistasis. Moreover, the evidence that this subset depends on the specific growing condition strengthens its systemic underpinning, a feature only observed before in a toy model of a gene-regulatory network. Some of these enzymes also modulate the effect that biochemical noise and environmental fluctuations produce in growth. Thus, the reorganization of metabolism induced by mutations has not only direct physiological implications but also transforms the influence that other mutations have on growth. This is a general result with implications in the development of cancer therapies based on metabolic inhibitors.


Assuntos
Redes Reguladoras de Genes/genética , Redes e Vias Metabólicas , Mutação , Redes e Vias Metabólicas/genética , Redes e Vias Metabólicas/fisiologia , Mutação/genética , Mutação/fisiologia , Fenótipo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Biologia de Sistemas
9.
PLoS One ; 15(8): e0236249, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32804964

RESUMO

BACKGROUND: The insect predator Coccinella septempunctata can effectively control many types of pests, such as aphids, whiteflies, and small lepidopteran larvae. We previously found that C. septempunctata fed an artificial diet showed diminished biological properties(e.g. fecundity, egg hatching rate, survival rate, etc.) compared with those fed natural prey (Aphis craccivora), likely due to different nutritional characteristics of the diet. In this study, we used transcriptome sequencing analysis to identify nutrition- and metabolism-related genes of C. septempunctata that were differentially expressed depending on diet. METHODOLOGY/PRINCIPAL FINDINGS: The Illumina HiSeq2000 was used to sequence 691,942,058 total clean reads from artificial diet-fed and A. craccivora-fed C. septempunctata libraries, and the clean reads were assembled using Trinity de novo software (Tabel 2). Comparison of transcriptome sequences revealed that expression of 38,315 genes was affected by the artificial diet, and 1,182 of these genes showed a significant change in expression levels (FDR ≤ 0.05,|log2FC|≥1, "FC" stands for "fold change"). These differentially expressed genes (DEGs) were likely associated with the decreased egg laying capacity, hatching rate, longevity, and increased sex ratio (♀:♂) of adult C. septempunctata observed in the group fed the artificial diet. Furthermore, in the most DEGs metabolic pathways for C. septempunctata feeding on the artificial diet accumulated amino acid metabolic pathways, lipid metabolic pathways, and starch and glucose metabolism were down-regulated. CONCLUSIONS/SIGNIFICANCE: We found some differentially expressed genes and metabolic pathways are related to nutrition, from which a more informative feedback for diet formulation was obtained and the artificial diet could be more efficiently optimized.


Assuntos
Fenômenos Fisiológicos da Nutrição Animal/genética , Afídeos , Besouros/fisiologia , Genes de Insetos , Comportamento Predatório/fisiologia , Aminoácidos/metabolismo , Animais , Regulação para Baixo , Fertilidade/fisiologia , Perfilação da Expressão Gênica , Glucose/metabolismo , Metabolismo dos Lipídeos/genética , Longevidade/fisiologia , Redes e Vias Metabólicas/genética , Controle Biológico de Vetores/métodos , Razão de Masculinidade , Amido/metabolismo , Sequenciamento Completo do Exoma
10.
J Cell Biol ; 219(10)2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-32785687

RESUMO

With the rapid global spread of SARS-CoV-2, we have become acutely aware of the inadequacies of our ability to respond to viral epidemics. Although disrupting the viral life cycle is critical for limiting viral spread and disease, it has proven challenging to develop targeted and selective therapeutics. Synthetic lethality offers a promising but largely unexploited strategy against infectious viral disease; as viruses infect cells, they abnormally alter the cell state, unwittingly exposing new vulnerabilities in the infected cell. Therefore, we propose that effective therapies can be developed to selectively target the virally reconfigured host cell networks that accompany altered cellular states to cripple the host cell that has been converted into a virus factory, thus disrupting the viral life cycle.


Assuntos
Antivirais/farmacologia , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Viroses/tratamento farmacológico , Replicação Viral/efeitos dos fármacos , Descoberta de Drogas , Humanos , Fatores Imunológicos/farmacologia , Redes e Vias Metabólicas/efeitos dos fármacos , Mapas de Interação de Proteínas , Proteólise , Vírus de RNA/efeitos dos fármacos , Vírus de RNA/fisiologia , Viroses/genética
11.
Commun Biol ; 3(1): 466, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32811894

RESUMO

Chinese herbal formulas including the lung-cleaning and toxicity-excluding (LCTE) soup have played an important role in treating the ongoing COVID-19 pandemic (caused by SARS-CoV-2) in China. Applying LCTE outside of China may prove challenging due to the unfamiliar rationale behind its application in terms of Traditional Chinese Medicine. To overcome this barrier, a biochemical understanding of the clinical effects of LCTE is needed. Here, we explore the chemical compounds present in the reported LCTE ingredients and the proteins targeted by these compounds via a network pharmacology analysis. Our results indicate that LCTE contains compounds with the potential to directly inhibit SARS-CoV-2 and inflammation, and that the compound targets proteins highly related to COVID-19's main symptoms. We predict the general effect of LCTE is to affect the pathways involved in viral and other microbial infections, inflammation/cytokine response, and lung diseases. Our work provides a biochemical basis for using LCTE to treat COVID-19 and its main symptoms.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Medicina Tradicional Chinesa , Pandemias , Pneumonia Viral/tratamento farmacológico , Anti-Inflamatórios/análise , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antivirais/química , Antivirais/uso terapêutico , Sulfato de Cálcio , China/epidemiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Sistemas de Liberação de Medicamentos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/uso terapêutico , Trato Gastrointestinal/efeitos dos fármacos , Humanos , Redes e Vias Metabólicas/efeitos dos fármacos , Fitoterapia , Plantas Medicinais/química , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Sistema Respiratório/efeitos dos fármacos , Proteínas Virais/antagonistas & inibidores
12.
Nat Commun ; 11(1): 3978, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32770044

RESUMO

Methionine restriction, a dietary regimen that protects against metabolic diseases and aging, represses cancer growth and improves cancer therapy. However, the response of different cancer cells to this nutritional manipulation is highly variable, and the molecular determinants of this heterogeneity remain poorly understood. Here we report that hepatocyte nuclear factor 4α (HNF4α) dictates the sensitivity of liver cancer to methionine restriction. We show that hepatic sulfur amino acid (SAA) metabolism is under transcriptional control of HNF4α. Knocking down HNF4α or SAA enzymes in HNF4α-positive epithelial liver cancer lines impairs SAA metabolism, increases resistance to methionine restriction or sorafenib, promotes epithelial-mesenchymal transition, and induces cell migration. Conversely, genetic or metabolic restoration of the transsulfuration pathway in SAA metabolism significantly alleviates the outcomes induced by HNF4α deficiency in liver cancer cells. Our study identifies HNF4α as a regulator of hepatic SAA metabolism that regulates the sensitivity of liver cancer to methionine restriction.


Assuntos
Fator 4 Nuclear de Hepatócito/metabolismo , Neoplasias Hepáticas/metabolismo , Metionina/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Cisteína/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fator 4 Nuclear de Hepatócito/genética , Fígado/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Mesoderma/efeitos dos fármacos , Mesoderma/patologia , Redes e Vias Metabólicas/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Camundongos , Sorafenibe/farmacologia , Transcrição Genética/efeitos dos fármacos
13.
PLoS Comput Biol ; 16(8): e1008125, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32776925

RESUMO

In the growing field of metabolic engineering, where cells are treated as 'factories' that synthesize industrial compounds, it is essential to consider the ability of the cells' native metabolism to accommodate the demands of synthetic pathways, as these pathways will alter the homeostasis of cellular energy and electron metabolism. From the breakdown of substrate, microorganisms activate and reduce key co-factors such as ATP and NAD(P)H, which subsequently need to be hydrolysed and oxidized, respectively, in order to restore cellular balance. A balanced supply and consumption of such co-factors, here termed co-factor balance, will influence biotechnological performance. To aid the strain selection and design process, we used stoichiometric modelling (FBA, pFBA, FVA and MOMA) and the Escherichia coli (E.coli) core stoichiometric model to investigate the network-wide effect of butanol and butanol precursor production pathways differing in energy and electron demand on product yield. An FBA-based co-factor balance assessment (CBA) algorithm was developed to track and categorise how ATP and NAD(P)H pools are affected in the presence of a new pathway. CBA was compared to the balance calculations proposed by Dugar et al. (Nature Biotechnol. 29 (12), 1074-1078). Predicted solutions were compromised by excessively underdetermined systems, displaying greater flexibility in the range of reaction fluxes than experimentally measured by 13C-metabolic flux analysis (MFA) and the appearance of unrealistic futile co-factor cycles. With the assumption that futile cycles are tightly regulated in reality, the FBA models were manually constrained in a step-wise manner. Solutions with minimal futile cycling diverted surplus energy and electrons towards biomass formation. As an alternative, the use of loopless FBA or constraining the models with measured flux ranges were tried but did not prevent futile co-factor cycles. The results highlight the need to account for co-factor imbalance and confirm that better-balanced pathways with minimal diversion of surplus towards biomass formation present the highest theoretical yield. The analysis also suggests that ATP and NAD(P)H balancing cannot be assessed in isolation from each other, or even from the balance of additional co-factors such as AMP and ADP. We conclude that, through revealing the source of co-factor imbalance CBA can facilitate pathway and host selection when designing new biocatalysts for implementation by metabolic engineering.


Assuntos
Simulação por Computador , Escherichia coli , Engenharia Metabólica/métodos , Algoritmos , Biomassa , Butanóis/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Análise do Fluxo Metabólico , Redes e Vias Metabólicas , Modelos Biológicos
14.
Phytochemistry ; 178: 112467, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32771675

RESUMO

Mucuna pruriens L., commonly known as velvetbean or cow-itch, is a self-pollinated tropical legume of the family Fabaceae, known for its medicinal properties. The active principle L-DOPA extracted from the plant is a potent drug used in the treatment of Parkinson's disease. Although, it is hypothesized that a single step reaction can produce L-DOPA, the presence of optional routes makes the pathway more intricate. For instance, the catecholamine biosynthetic pathway, which leads to L-DOPA production, could occur by hydroxylation of tyrosine to L-DOPA either by polyphenol oxidase (PPO) or tyrosine hydroxylase (TH). Furthermore, Cytochrome P450 (CYP) enzymes can also cause hydroxylation of tyrosine, resulting in L-DOPA synthesis. Therefore, the present investigation was focused on validating the step, which catalyzes the synthesis of L-DOPA, at the biochemical and molecular levels. Enzyme inhibitor studies showed significant inhibition of PPO enzyme with corresponding decrease in L-DOPA synthesis while TH and CYP inhibition had no effect on L-DOPA synthesis. Activity staining of non-denaturing PAGE gel for PPO and TH showed activity only to PPO enzyme. Following in-gel assay and tryptic digestion of the excised stained gel portion, peptide recovery and LC-MS/MS analysis were performed. Degenerate primers based on peptide sequence resulted in an 800bp amplicon. The subsequent sub-cloning, RACE analysis and BLAST search resulted in the isolation of full-length PPO coding sequence of 1800 bp. Structure prediction and phylogenetic analysis of the obtained sequence revealed strong similarity to other plant PPO's like Glycine max, Vigna radiata and Vicia faba of the same family.


Assuntos
Mucuna , Animais , Catecol Oxidase , Bovinos , Cromatografia Líquida , Sistema Enzimático do Citocromo P-450 , Feminino , Levodopa , Redes e Vias Metabólicas , Filogenia , Espectrometria de Massas em Tandem , Tirosina , Tirosina 3-Mono-Oxigenase
15.
Nat Commun ; 11(1): 3941, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32770005

RESUMO

Anaerobic oxidation of methane (AOM) mediated by anaerobic methanotrophic archaea (ANME) is the primary process that provides energy to cold seep ecosystems by converting methane into inorganic carbon. Notably, cold seep ecosystems are dominated by highly divergent heterotrophic microorganisms. The role of the AOM process in supporting heterotrophic population remains unknown. We investigate the acetogenic capacity of ANME-2a in a simulated cold seep ecosystem using high-pressure biotechnology, where both AOM activity and acetate production are detected. The production of acetate from methane is confirmed by isotope-labeling experiments. A complete archaeal acetogenesis pathway is identified in the ANME-2a genome, and apparent acetogenic activity of the key enzymes ADP-forming acetate-CoA ligase and acetyl-CoA synthetase is demonstrated. Here, we propose a modified model of carbon cycling in cold seeps: during AOM process, methane can be converted into organic carbon, such as acetate, which further fuels the heterotrophic community in the ecosystem.


Assuntos
Acetatos/metabolismo , Archaea/enzimologia , Proteínas de Bactérias/metabolismo , Coenzima A Ligases/metabolismo , Metano/metabolismo , Anaerobiose , Archaea/genética , Proteínas de Bactérias/genética , Ciclo do Carbono/fisiologia , Coenzima A Ligases/genética , Genoma Arqueal , Sedimentos Geológicos/microbiologia , Redes e Vias Metabólicas/genética , Oxirredução , Água do Mar/microbiologia
16.
PLoS One ; 15(8): e0236954, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760106

RESUMO

To infer the parameters of mechanistic models with intractable likelihoods, techniques such as approximate Bayesian computation (ABC) are increasingly being adopted. One of the main disadvantages of ABC in practical situations, however, is that parameter inference must generally rely on summary statistics of the data. This is particularly the case for problems involving high-dimensional data, such as biological imaging experiments. However, some summary statistics contain more information about parameters of interest than others, and it is not always clear how to weight their contributions within the ABC framework. We address this problem by developing an automatic, adaptive algorithm that chooses weights for each summary statistic. Our algorithm aims to maximize the distance between the prior and the approximate posterior by automatically adapting the weights within the ABC distance function. Computationally, we use a nearest neighbour estimator of the distance between distributions. We justify the algorithm theoretically based on properties of the nearest neighbour distance estimator. To demonstrate the effectiveness of our algorithm, we apply it to a variety of test problems, including several stochastic models of biochemical reaction networks, and a spatial model of diffusion, and compare our results with existing algorithms.


Assuntos
Algoritmos , Teorema de Bayes , Biometria/métodos , Fenômenos Bioquímicos , Simulação por Computador , Funções Verossimilhança , Cadeias de Markov , Redes e Vias Metabólicas , Modelos Biológicos , Modelos Estatísticos , Método de Monte Carlo , Análise de Regressão , Processos Estocásticos
17.
BMC Bioinformatics ; 21(Suppl 10): 349, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32838750

RESUMO

BACKGROUND: Biological networks are representative of the diverse molecular interactions that occur within cells. Some of the commonly studied biological networks are modeled through protein-protein interactions, gene regulatory, and metabolic pathways. Among these, metabolic networks are probably the most studied, as they directly influence all physiological processes. Exploration of biochemical pathways using multigraph representation is important in understanding complex regulatory mechanisms. Feature extraction and clustering of these networks enable grouping of samples obtained from different biological specimens. Clustering techniques separate networks depending on their mutual similarity. RESULTS: We present a clustering analysis on tissue-specific metabolic networks for single samples from three primary tumor sites: breast, lung, and kidney cancer. The metabolic networks were obtained by integrating genome scale metabolic models with gene expression data. We performed network simplification to reduce the computational time needed for the computation of network distances. We empirically proved that networks clustering can characterize groups of patients in multiple conditions. CONCLUSIONS: We provide a computational methodology to explore and characterize the metabolic landscape of tumors, thus providing a general methodology to integrate analytic metabolic models with gene expression data. This method represents a first attempt in clustering large scale metabolic networks. Moreover, this approach gives the possibility to get valuable information on what are the effects of different conditions on the overall metabolism.


Assuntos
Redes e Vias Metabólicas , Neoplasias/metabolismo , Algoritmos , Análise por Conglomerados , Bases de Dados como Assunto , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Rim/metabolismo , Neoplasias/genética
18.
Nat Commun ; 11(1): 4018, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32782301

RESUMO

The gut microbiome is an ecosystem that involves complex interactions. Currently, our knowledge about the role of the gut microbiome in health and disease relies mainly on differential microbial abundance, and little is known about the role of microbial interactions in the context of human disease. Here, we construct and compare microbial co-abundance networks using 2,379 metagenomes from four human cohorts: an inflammatory bowel disease (IBD) cohort, an obese cohort and two population-based cohorts. We find that the strengths of 38.6% of species co-abundances and 64.3% of pathway co-abundances vary significantly between cohorts, with 113 species and 1,050 pathway co-abundances showing IBD-specific effects and 281 pathway co-abundances showing obesity-specific effects. We can also replicate these IBD microbial co-abundances in longitudinal data from the IBD cohort of the integrative human microbiome (iHMP-IBD) project. Our study identifies several key species and pathways in IBD and obesity and provides evidence that altered microbial abundances in disease can influence their co-abundance relationship, which expands our current knowledge regarding microbial dysbiosis in disease.


Assuntos
Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais/microbiologia , Consórcios Microbianos , Obesidade/microbiologia , Adulto , Bactérias/crescimento & desenvolvimento , Bactérias/isolamento & purificação , Bactérias/metabolismo , Estudos de Coortes , Disbiose/metabolismo , Disbiose/microbiologia , Feminino , Microbioma Gastrointestinal/genética , Especificidade de Hospedeiro , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Masculino , Redes e Vias Metabólicas , Pessoa de Meia-Idade , Obesidade/metabolismo
19.
Nat Commun ; 11(1): 4236, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32843654

RESUMO

The impact of commensal bacteria on the host arises from complex microbial-diet-host interactions. Mapping metabolic interactions in gut microbial communities is therefore key to understand how the microbiome influences the host. Here we use an interdisciplinary approach including isotope-resolved metabolomics to show that in Drosophila melanogaster, Acetobacter pomorum (Ap) and Lactobacillus plantarum (Lp) a syntrophic relationship is established to overcome detrimental host diets and identify Ap as the bacterium altering the host's feeding decisions. Specifically, we show that Ap uses the lactate produced by Lp to supply amino acids that are essential to Lp, allowing it to grow in imbalanced diets. Lactate is also necessary and sufficient for Ap to alter the fly's protein appetite. Our data show that gut bacterial communities use metabolic interactions to become resilient to detrimental host diets. These interactions also ensure the constant flow of metabolites used by the microbiome to alter reproduction and host behaviour.


Assuntos
Dieta , Drosophila melanogaster/microbiologia , Drosophila melanogaster/fisiologia , Microbioma Gastrointestinal/fisiologia , Acetobacter/crescimento & desenvolvimento , Acetobacter/metabolismo , Aminoácidos/deficiência , Aminoácidos/metabolismo , Animais , Apetite , Feminino , Preferências Alimentares , Interações entre Hospedeiro e Microrganismos , Ácido Láctico/metabolismo , Lactobacillus plantarum/crescimento & desenvolvimento , Lactobacillus plantarum/metabolismo , Redes e Vias Metabólicas , Metabolômica , Consórcios Microbianos , Reprodução
20.
PLoS Biol ; 18(8): e3000757, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32833957

RESUMO

In eukaryotes, conserved mechanisms ensure that cell growth is coordinated with nutrient availability. Overactive growth during nutrient limitation ("nutrient-growth dysregulation") can lead to rapid cell death. Here, we demonstrate that cells can adapt to nutrient-growth dysregulation by evolving major metabolic defects. Specifically, when yeast lysine-auxotrophic mutant lys- encountered lysine limitation, an evolutionarily novel stress, cells suffered nutrient-growth dysregulation. A subpopulation repeatedly evolved to lose the ability to synthesize organosulfurs (lys-orgS-). Organosulfurs, mainly reduced glutathione (GSH) and GSH conjugates, were released by lys- cells during lysine limitation when growth was dysregulated, but not during glucose limitation when growth was regulated. Limiting organosulfurs conferred a frequency-dependent fitness advantage to lys-orgS- by eliciting a proper slow growth program, including autophagy. Thus, nutrient-growth dysregulation is associated with rapid organosulfur release, which enables the selection of organosulfur auxotrophy to better tune cell growth to the metabolic environment. We speculate that evolutionarily novel stresses can trigger atypical release of certain metabolites, setting the stage for the evolution of new ecological interactions.


Assuntos
Adaptação Fisiológica/genética , Lisina/farmacologia , Redes e Vias Metabólicas/efeitos dos fármacos , Nutrientes/farmacologia , Saccharomyces cerevisiae/metabolismo , Autofagia/efeitos dos fármacos , Autofagia/genética , Evolução Biológica , Glucose/metabolismo , Glucose/farmacologia , Lisina/deficiência , Redes e Vias Metabólicas/genética , Nitrogênio/metabolismo , Nitrogênio/farmacologia , Nutrientes/metabolismo , Ribossomos/efeitos dos fármacos , Ribossomos/metabolismo , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento , Sirolimo/farmacologia , Estresse Fisiológico
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