scholarly journals In silico study of peculiarities of metabolism of erythrocytes with glucosephosphate isomerase deficiency

2019 ◽  
Vol 10 (3) ◽  
pp. 306-313
Author(s):  
O. I. Dotsenko
Keyword(s):  
Alternative Energy ◽  
Metabolic Networks ◽  
Experimental Studies ◽  
Supportive Therapy ◽  
Pentose Phosphate ◽  
Premature Aging ◽  
Enzymatic Reactions ◽  
Theoretical Substantiation ◽  
Evaluation Approach ◽  
Balance Analysis

Glucose phosphate isomerase (GPI) deficiency, the third most common cause of hereditary nonspherocytic hemolytic anemia, is associated with the mutation of the GPI gene. The results of the GPI deficiency are premature aging of erythrocytes, macrocytosis, reticulocytosis, minor splenomegaly, hyperbilirubinemia and hyperferritinemia, and hemolytic crisis under the influence of exogenous oxidants such as infections or drugs. Regarding the the lack of GPI correction drugs, the theoretical substantiation of supportive therapy based on system biology approaches that would allow the analysis of the relationships between numerical metabolic processes in a cell would be beneficial. The stoichiometric model of erythrocytes’ steady state metabolism, including the pathways of Embden-Meyerhof and pentose phosphate (PPP), purine metabolism cycles and glutathione synthesis, has been developed. To predict the redistribution of metabolic flows in erythrocytes under conditions of GPI deficiency, we used the flux balance analysis (FBA). In this approach, calculations of the elementary flux modes (EFMs) and the control-effective flux (CEF) have been performed. Using the CEF evaluation approach, effective profiles of enzymatic reactions depending on the degree of enzyme deficiency were obtained. It has been shown that these relationships can be the basis for future experimental studies. Analysis of the profiles of enzymatic reactions of metabolic networks suggests that erythrocytes are capable of metabolizing other substrates that contribute to overcoming the effects of energy stress in the case of enzymopathies. So, it is shown that erythrocytes can effectively use SAM and adenosine as alternative energy sources. It has been established that the GPI enzymopathy results in a decrease in the flow through the glycolysis and pentose phosphate pathway, resulting in a decrease in the content of such reducing agents as NADPH and GSH, ATP. The processes of the GSH synthesis from amino acids in the cell are shown to be suppressed. Decreased content of NADPH and GSH cause the premature aging of erythrocytes. The target therapeutic approaches that influence the behaviour of the metabolic network of erythrocytes are discussed.

scholarly journals Conditional iron and pH-dependent activity of a non-enzymatic glycolysis and pentose phosphate pathway

2016 ◽  
Vol 2 (1) ◽  
pp. e1501235 ◽  
Author(s):  
Markus A. Keller ◽  
Andre Zylstra ◽  
Cecilia Castro ◽  
Alexandra V. Turchyn ◽  
Julian L. Griffin ◽  
...  
Keyword(s):  
Pentose Phosphate Pathway ◽  
Metabolic Networks ◽  
Reaction Rates ◽  
Structural Features ◽  
Pentose Phosphate ◽  
Resonance Spectroscopy ◽  
Enzymatic Reactions ◽  
Evolutionary Origins ◽  
Sugar Phosphates ◽  
Neutral Conditions

Little is known about the evolutionary origins of metabolism. However, key biochemical reactions of glycolysis and the pentose phosphate pathway (PPP), ancient metabolic pathways central to the metabolic network, have non-enzymatic pendants that occur in a prebiotically plausible reaction milieu reconstituted to contain Archean sediment metal components. These non-enzymatic reactions could have given rise to the origin of glycolysis and the PPP during early evolution. Using nuclear magnetic resonance spectroscopy and high-content metabolomics that allowed us to measure several thousand reaction mixtures, we experimentally address the chemical logic of a metabolism-like network constituted from these non-enzymatic reactions. Fe(II), the dominant transition metal component of Archean oceanic sediments, has binding affinity toward metabolic sugar phosphates and drives metabolism-like reactivity acting as both catalyst and cosubstrate. Iron and pH dependencies determine a metabolism-like network topology and comediate reaction rates over several orders of magnitude so that the network adopts conditional activity. Alkaline pH triggered the activity of the non-enzymatic PPP pendant, whereas gentle acidic or neutral conditions favored non-enzymatic glycolytic reactions. Fe(II)-sensitive glycolytic and PPP-like reactions thus form a chemical network mimicking structural features of extant carbon metabolism, including topology, pH dependency, and conditional reactivity. Chemical networks that obtain structure and catalysis on the basis of transition metals found in Archean sediments are hence plausible direct precursors of cellular metabolic networks.

scholarly journals The Metano Modeling Toolbox MMTB: An Intuitive, Web-Based Toolbox Introduced by Two Use Cases

Metabolites ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 113
Author(s):  
Julia Koblitz ◽  
Sabine Will ◽  
S. Riemer ◽  
Thomas Ulas ◽  
Meina Neumann-Schaal ◽  
...  
Keyword(s):  
Metabolic Networks ◽  
Point Of View ◽  
Use Cases ◽  
Mathematical Methods ◽  
State Behavior ◽  
Web Based ◽  
Research Fields ◽  
Balance Analysis ◽  
Metabolic Models ◽  
User Friendly

Genome-scale metabolic models are of high interest in a number of different research fields. Flux balance analysis (FBA) and other mathematical methods allow the prediction of the steady-state behavior of metabolic networks under different environmental conditions. However, many existing applications for flux optimizations do not provide a metabolite-centric view on fluxes. Metano is a standalone, open-source toolbox for the analysis and refinement of metabolic models. While flux distributions in metabolic networks are predominantly analyzed from a reaction-centric point of view, the Metano methods of split-ratio analysis and metabolite flux minimization also allow a metabolite-centric view on flux distributions. In addition, we present MMTB (Metano Modeling Toolbox), a web-based toolbox for metabolic modeling including a user-friendly interface to Metano methods. MMTB assists during bottom-up construction of metabolic models by integrating reaction and enzymatic annotation data from different databases. Furthermore, MMTB is especially designed for non-experienced users by providing an intuitive interface to the most commonly used modeling methods and offering novel visualizations. Additionally, MMTB allows users to upload their models, which can in turn be explored and analyzed by the community. We introduce MMTB by two use cases, involving a published model of Corynebacterium glutamicum and a newly created model of Phaeobacter inhibens.

scholarly journals Cardiometabolism as an Interlocking Puzzle between the Healthy and Diseased Heart: New Frontiers in Therapeutic Applications

2021 ◽  
Vol 10 (4) ◽  
pp. 721
Author(s):  
Teresa Pasqua ◽  
Carmine Rocca ◽  
Anita Giglio ◽  
Tommaso Angelone
Keyword(s):  
Cardiac Muscle ◽  
Metabolic Networks ◽  
Mechanical Energy ◽  
Cardiac Metabolism ◽  
Protective Mechanism ◽  
Enzymatic Reactions ◽  
Carbohydrate Utilization ◽  
Pharmacological Agents ◽  
Physiological Structure ◽  
And Function

Cardiac metabolism represents a crucial and essential connecting bridge between the healthy and diseased heart. The cardiac muscle, which may be considered an omnivore organ with regard to the energy substrate utilization, under physiological conditions mainly draws energy by fatty acids oxidation. Within cardiomyocytes and their mitochondria, through well-concerted enzymatic reactions, substrates converge on the production of ATP, the basic chemical energy that cardiac muscle converts into mechanical energy, i.e., contraction. When a perturbation of homeostasis occurs, such as an ischemic event, the heart is forced to switch its fatty acid-based metabolism to the carbohydrate utilization as a protective mechanism that allows the maintenance of its key role within the whole organism. Consequently, the flexibility of the cardiac metabolic networks deeply influences the ability of the heart to respond, by adapting to pathophysiological changes. The aim of the present review is to summarize the main metabolic changes detectable in the heart under acute and chronic cardiac pathologies, analyzing possible therapeutic targets to be used. On this basis, cardiometabolism can be described as a crucial mechanism in keeping the physiological structure and function of the heart; furthermore, it can be considered a promising goal for future pharmacological agents able to appropriately modulate the rate-limiting steps of heart metabolic pathways.

scholarly journals Elaboration of the corticosteroid synthesis pathway in primates through a multi-step enzyme

2019 ◽  
Author(s):  
Carrie F. Olson-Manning
Keyword(s):  
Cytochrome P450 ◽  
Gene Duplication ◽  
Metabolic Networks ◽  
Cellular Systems ◽  
Potential Outcomes ◽  
Enzymatic Reactions ◽  
Ancestral State ◽  
State Reconstruction ◽  
Specific Regulation

AbstractMetabolic networks are complex cellular systems dependent on the interactions among, and regulation of, the enzymes in the network. However, the mechanisms that lead to the expansion of networks are not well understood. While gene duplication is a major driver of the expansion and functional evolution of metabolic networks, the effect and fate of retained duplicates in a network is poorly understood. Here, I study the evolution of an enzyme family that performs multiple subsequent enzymatic reactions in the corticosteroid pathway in primates to illuminate the mechanisms that shape network components following duplication. The products of the pathway (aldosterone, corticosterone, and cortisol) are steroid hormones that regulate metabolism and stress in tetrapods. These steroids are synthesized by a multi-step enzyme Cytochrome P450 11B (CYP11B) that performs subsequent steps on different carbon atoms of the steroid derivatives. Through ancestral state reconstruction and in vitro characterization, I find the ancestor of the CYP11B1 and CYP11B2 paralogs (in primates) had moderate ability to synthesize cortisol and aldosterone. Following duplication in the primate lineage the CYP11B1 homolog specialized on the production of cortisol while its paralog, CYP11B2, maintained its ability to perform multiple subsequent steps as in the ancestral pathway. Unlike CYP11B1, CYP11B2 could not specialize on the production of aldosterone because it is constrained to perform earlier steps in the corticosteroid synthesis pathway to achieve the final product aldosterone. These results suggest that pathway context, along with tissue-specific regulation, both play a role in shaping potential outcomes of metabolic network elaboration.

Finding Minimum Reaction Cuts of Metabolic Networks Under a Boolean Model Using Integer Programming and Feedback Vertex Sets

2012 ◽  
pp. 774-791
Author(s):  
Takeyuki Tamura ◽  
Kazuhiro Takemoto ◽  
Tatsuya Akutsu
Keyword(s):  
Integer Programming ◽  
Metabolic Network ◽  
Drug Targets ◽  
Metabolic Networks ◽  
Boolean Model ◽  
Pentose Phosphate ◽  
Minimum Size ◽  
E Coli ◽  
Potential Applications ◽  
Vertex Set

In this paper, the authors consider the problem of, given a metabolic network, a set of source compounds and a set of target compounds, finding a minimum size reaction cut, where a Boolean model is used as a model of metabolic networks. The problem has potential applications to measurement of structural robustness of metabolic networks and detection of drug targets. They develop an integer programming-based method for this optimization problem. In order to cope with cycles and reversible reactions, they further develop a novel integer programming (IP) formalization method using a feedback vertex set (FVS). When applied to an E. coli metabolic network consisting of Glycolysis/Glyconeogenesis, Citrate cycle and Pentose phosphate pathway obtained from KEGG database, the FVS-based method can find an optimal set of reactions to be inactivated much faster than a naive IP-based method and several times faster than a flux balance-based method. The authors also confirm that our proposed method works even for large networks and discuss the biological meaning of our results.

Experimental Studies on Loads Acting on Two Piles of Side-by-Side Arrangements in the Uniform Flow

2012 ◽  
Vol 226-228 ◽  
pp. 1785-1788
Author(s):  
Zhao Qing Zhu ◽  
Guo Liang Dai
Keyword(s):  
Drag Coefficient ◽  
Flow Velocity ◽  
Experimental Studies ◽  
Reynolds Numbers ◽  
Uniform Flow ◽  
Drag Forces ◽  
Pile Diameter ◽  
Two Component ◽  
Balance Analysis ◽  
Different Diameters

Indoor model experiments were made to study drag loads on two piles of side-by-side arrangements in the uniform flow. Take three different velocities of the flow, three different diameters of piles and five different distances of two piles in the experiments to get the variations of loads. Drag forces were measured by a two-component balance. Analysis on experiment results shows that drag forces increase with the increase of the pile diameter, the increase of the flow velocity and the decrease of the distance of two piles. The drag coefficient CDunder different Reynolds numbers shows the same change law. The drag coefficient CDdecreases with the increase of the distance of two piles and has good coherence to the ratio of the distance of two piles to the pile diameter.

scholarly journals Regulatory Tasks of the Phosphoenolpyruvate-Phosphotransferase System of Pseudomonas putida in Central Carbon Metabolism

mBio ◽  
2012 ◽  
Vol 3 (2) ◽  
Author(s):  
Max Chavarría ◽  
Roelco J. Kleijn ◽  
Uwe Sauer ◽  
Katharina Pflüger-Grau ◽  
Víctor de Lorenzo
Keyword(s):  
Pseudomonas Putida ◽  
Metabolic Networks ◽  
Tca Cycle ◽  
High Energy ◽  
Pentose Phosphate ◽  
Cell Physiology ◽  
Phosphotransferase System ◽  
Content Type ◽  
Metabolic Fluxes ◽  
Central Carbon

ABSTRACTTwo branches of the phosphoenolpyruvate-phosphotransferase system (PTS) operate in the soil bacteriumPseudomonas putidaKT2440. One branch encompasses a complete set of enzymes for fructose intake (PTSFru), while the other (N-related PTS, or PTSNtr) controls various cellular functions unrelated to the transport of carbohydrates. The potential of these two systems for regulating central carbon catabolism has been investigated by measuring the metabolic fluxes of isogenic strains bearing nonpolar mutations in PTSFruor PTSNtrgenes and grown on either fructose (a PTS substrate) or glucose, the transport of which is not governed by the PTS in this bacterium. The flow of carbon from each sugar was distinctly split between the Entner-Doudoroff, pentose phosphate, and Embden-Meyerhof-Parnas pathways in a ratio that was maintained in each of the PTS mutants examined. However, strains lacking PtsN (EIIANtr) displayed significantly higher fluxes in the reactions of the pyruvate shunt, which bypasses malate dehydrogenase in the TCA cycle. This was consistent with the increased activity of the malic enzyme and the pyruvate carboxylase found in the corresponding PTS mutants. Genetic evidence suggested that such a metabolic effect of PtsN required the transfer of high-energy phosphate through the system. The EIIANtrprotein of the PTSNtrthus helps adjust central metabolic fluxes to satisfy the anabolic and energetic demands of the overall cell physiology.IMPORTANCEThis study demonstrates that EIIANtrinfluences the biochemical reactions that deliver carbon between the upper and lower central metabolic domains for the consumption of sugars byP. putida. These findings indicate that the EIIANtrprotein is a key player for orchestrating the fate of carbon in various physiological destinations in this bacterium. Additionally, these results highlight the importance of the posttranslational regulation of extant enzymatic complexes for increasing the robustness of the corresponding metabolic networks.

scholarly journals Experimental Studies on Oscillation Modes of Vibration Separation Devices

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
M. Demianenko ◽  
M. Volf ◽  
I. Pavlenko ◽  
O. Liaposhchenko
Keyword(s):  
Alternative Energy ◽  
Gas Flow ◽  
Separation Efficiency ◽  
Rapid Development ◽  
Specific Energy Consumption ◽  
Experimental Studies ◽  
Operating Modes ◽  
Physical Experiments ◽  
Modes Of Vibration ◽  
Separation Devices

Despite the rapid development of alternative energy sources, the role of hydrocarbons in the global fuel and energy balance remains significant. For their transportation and further processing, pre-processing is carried out using a set of equipment. In this case, the mandatory devices are separators. In terms of specific energy consumption and separation efficiency, methods based on the action of inertia forces are optimal. However, standard designs have common disadvantages. A method of dynamic separation is proposed to eliminate them. The proposed devices are automatic control systems. The object of regulation is hydraulic resistance, and elastic forces are the regulating actions. Aerohydroelastic phenomena accompany the operation of dynamic separation devices. Among them, the most interesting are flutter and buffeting. Oscillations of adjustable baffles accompany them. It is necessary to conduct a number of multifactorial experiments to determine the operating parameters of dynamic separation devices. In turn, physical experiments aim to identify patterns and features of processes occurring during vibration-inertial separation (i.e., the dependence of various parameters on velocity). Therefore, the article proposes a methodology for carrying our physical experiments on dynamic separation and a designed experimental setup for these studies. As a result, the operating modes of separation devices for different thicknesses of baffle elements were evaluated. Additionally, the dependences of the adjustable element’s deflections and oscillation amplitudes on the gas flow velocity were determined for different operating modes of vibration separation devices.

scholarly journals The pentose phosphate pathway constitutes a major metabolic hub in pathogenic Francisella

2021 ◽  
Vol 17 (8) ◽  
pp. e1009326
Author(s):  
Héloise Rytter ◽  
Anne Jamet ◽  
Jason Ziveri ◽  
Elodie Ramond ◽  
Mathieu Coureuil ◽  
...  
Keyword(s):  
Pentose Phosphate Pathway ◽  
Metabolic Pathways ◽  
Pathogenic Bacteria ◽  
Metabolic Networks ◽  
Tricarboxylic Acid Cycle ◽  
Sulfur Metabolism ◽  
Time Lapse ◽  
Pentose Phosphate ◽  
Francisella Novicida

Metabolic pathways are now considered as intrinsic virulence attributes of pathogenic bacteria and thus represent potential targets for antibacterial strategies. Here we focused on the role of the pentose phosphate pathway (PPP) and its connections with other metabolic pathways in the pathophysiology of Francisella novicida. The involvement of the PPP in the intracellular life cycle of Francisella was first demonstrated by studying PPP inactivating mutants. Indeed, we observed that inactivation of the tktA, rpiA or rpe genes severely impaired intramacrophage multiplication during the first 24 hours. However, time-lapse video microscopy demonstrated that rpiA and rpe mutants were able to resume late intracellular multiplication. To better understand the links between PPP and other metabolic networks in the bacterium, we also performed an extensive proteo-metabolomic analysis of these mutants. We show that the PPP constitutes a major bacterial metabolic hub with multiple connections to glycolysis, the tricarboxylic acid cycle and other pathways, such as fatty acid degradation and sulfur metabolism. Altogether our study highlights how PPP plays a key role in the pathogenesis and growth of Francisella in its intracellular niche.

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