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1.
Nature ; 614(7947): 349-357, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36725930

RESUMO

Tissues derive ATP from two pathways-glycolysis and the tricarboxylic acid (TCA) cycle coupled to the electron transport chain. Most energy in mammals is produced via TCA metabolism1. In tumours, however, the absolute rates of these pathways remain unclear. Here we optimize tracer infusion approaches to measure the rates of glycolysis and the TCA cycle in healthy mouse tissues, Kras-mutant solid tumours, metastases and leukaemia. Then, given the rates of these two pathways, we calculate total ATP synthesis rates. We find that TCA cycle flux is suppressed in all five primary solid tumour models examined and is increased in lung metastases of breast cancer relative to primary orthotopic tumours. As expected, glycolysis flux is increased in tumours compared with healthy tissues (the Warburg effect2,3), but this increase is insufficient to compensate for low TCA flux in terms of ATP production. Thus, instead of being hypermetabolic, as commonly assumed, solid tumours generally produce ATP at a slower than normal rate. In mouse pancreatic cancer, this is accommodated by the downregulation of protein synthesis, one of this tissue's major energy costs. We propose that, as solid tumours develop, cancer cells shed energetically expensive tissue-specific functions, enabling uncontrolled growth despite a limited ability to produce ATP.


Assuntos
Trifosfato de Adenosina , Neoplasias da Mama , Ciclo do Ácido Cítrico , Desaceleração , Neoplasias Pulmonares , Metástase Neoplásica , Neoplasias Pancreáticas , Animais , Camundongos , Trifosfato de Adenosina/biossíntese , Trifosfato de Adenosina/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ciclo do Ácido Cítrico/fisiologia , Metabolismo Energético , Glicólise , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Especificidade de Órgãos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Biossíntese de Proteínas
2.
Bioinformatics ; 39(1)2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36495209

RESUMO

MOTIVATION: Large-scale kinetic models are an invaluable tool to understand the dynamic and adaptive responses of biological systems. The development and application of these models have been limited by the availability of computational tools to build and analyze large-scale models efficiently. The toolbox presented here provides the means to implement, parameterize and analyze large-scale kinetic models intuitively and efficiently. RESULTS: We present a Python package (SKiMpy) bridging this gap by implementing an efficient kinetic modeling toolbox for the semiautomatic generation and analysis of large-scale kinetic models for various biological domains such as signaling, gene expression and metabolism. Furthermore, we demonstrate how this toolbox is used to parameterize kinetic models around a steady-state reference efficiently. Finally, we show how SKiMpy can implement multispecies bioreactor simulations to assess biotechnological processes. AVAILABILITY AND IMPLEMENTATION: The software is available as a Python 3 package on GitHub: https://github.com/EPFL-LCSB/SKiMpy, along with adequate documentation. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Modelos Biológicos , Software , Cinética , Documentação
3.
Biophys J ; 117(2): 355-368, 2019 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-31311624

RESUMO

Many computational models for analyzing and predicting cell physiology rely on in vitro data collected in dilute and controlled buffer solutions. However, this can mislead models because up to 40% of the intracellular volume-depending on the organism, the physiology, and the cellular compartment-is occupied by a dense mixture of proteins, lipids, polysaccharides, RNA, and DNA. These intracellular macromolecules interfere with the interactions of enzymes and their reactants and thus affect the kinetics of biochemical reactions, making in vivo reactions considerably more complex than the in vitro data indicates. In this work, we present a new, to our knowledge, type of kinetics that captures and quantifies the effect of volume exclusion and other spatial phenomena on the kinetics of elementary reactions. We further developed a framework that allows for the efficient parameterization of these kinetics using particle simulations. Our formulation, entitled generalized elementary kinetics, can be used to analyze and predict the effect of intracellular crowding on enzymatic reactions and was herein applied to investigate the influence of crowding on phosphoglycerate mutase in Escherichia coli, which exhibits prototypical reversible Michaelis-Menten kinetics. Current research indicates that many enzymes are reaction limited and not diffusion limited, and our results suggest that the influence of fractal diffusion is minimal for these reaction-limited enzymes. Instead, increased association rates and decreased dissociation rates lead to a strong decrease in the effective maximal velocities Vmax and the effective Michaelis-Menten constants KM under physiologically relevant volume occupancies. Finally, the effects of crowding were explored in the context of a linear pathway, with the finding that crowding can have a redistributing effect on the effective flux responses in the case of twofold enzyme overexpression. We suggest that this framework, in combination with detailed kinetics models, will improve our understanding of enzyme reaction networks under nonideal conditions.


Assuntos
Simulação por Computador , Substâncias Macromoleculares/química , Algoritmos , Difusão , Escherichia coli/metabolismo , Cinética , Modelos Lineares , Modelos Moleculares , Tamanho da Partícula
4.
Nucleic Acids Res ; 45(18): 10504-10517, 2017 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-28985346

RESUMO

Chromatin recruitment of effector proteins involved in gene regulation depends on multivalent interaction with histone post-translational modifications (PTMs) and structural features of the chromatin fiber. Due to the complex interactions involved, it is currently not understood how effectors dynamically sample the chromatin landscape. Here, we dissect the dynamic chromatin interactions of a family of multivalent effectors, heterochromatin protein 1 (HP1) proteins, using single-molecule fluorescence imaging and computational modeling. We show that the three human HP1 isoforms are recruited and retained on chromatin by a dynamic exchange between histone PTM and DNA bound states. These interactions depend on local chromatin structure, the HP1 isoforms as well as on PTMs on HP1 itself. Of the HP1 isoforms, HP1α exhibits the longest residence times and fastest binding rates due to DNA interactions in addition to PTM binding. HP1α phosphorylation further increases chromatin retention through strengthening of multivalency while reducing DNA binding. As DNA binding in combination with specific PTM recognition is found in many chromatin effectors, we propose a general dynamic capture mechanism for effector recruitment. Multiple weak protein and DNA interactions result in a multivalent interaction network that targets effectors to a specific chromatin modification state, where their activity is required.


Assuntos
Cromatina/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , DNA/metabolismo , Código das Histonas/fisiologia , Histonas/metabolismo , Processamento de Proteína Pós-Traducional , Animais , Homólogo 5 da Proteína Cromobox , Epigênese Genética , Regulação da Expressão Gênica , Humanos , Técnicas In Vitro , Cinética , Camundongos , Células NIH 3T3 , Fosforilação , Ligação Proteica , Imagem Individual de Molécula
5.
Nat Commun ; 14(1): 2618, 2023 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-37147292

RESUMO

Deciphering the metabolic functions of organisms requires understanding the dynamic responses of living cells upon genetic and environmental perturbations, which in turn can be inferred from enzymatic activity. In this work, we investigate the optimal modes of operation for enzymes in terms of the evolutionary pressure driving them toward increased catalytic efficiency. We develop a framework using a mixed-integer formulation to assess the distribution of thermodynamic forces and enzyme states, providing detailed insights into the enzymatic mode of operation. We use this framework to explore Michaelis-Menten and random-ordered multi-substrate mechanisms. We show that optimal enzyme utilization is achieved by unique or alternative operating modes dependent on reactant concentrations. We find that in a bimolecular enzyme reaction, the random mechanism is optimal over any other ordered mechanism under physiological conditions. Our framework can investigate the optimal catalytic properties of complex enzyme mechanisms. It can further guide the directed evolution of enzymes and fill in the knowledge gaps in enzyme kinetics.


Assuntos
Enzimas , Física , Cinética , Termodinâmica , Fenômenos Químicos , Catálise , Enzimas/metabolismo
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