A Macintosh software package for simulation of human red blood cell metabolism

Lee, I-Der; Palsson, Bernhard Ø.

doi:10.1016/0169-2607(92)90102-d

Cited by 12 publications

(6 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These data have formed the basis for a number of kinetic models dealing with various aspects of the human erythrocyte (e.g. [3][4][5][6][7][8][9][10][11][12][13][14][15][16].…”

Section: Human Erythrocytes Are Among the Simplest Of Cells Many Of mentioning

confidence: 99%

Application of Biochemical Systems Theory to Metabolism in Human Red Blood Cells

Ni¹,

Savageau

1996

Journal of Biological Chemistry

View full text Add to dashboard Cite

Human erythrocytes are among the simplest of cells. Many of their enzymes have been characterized kinetically using steady-state methods in vitro, and several investigators have assembled this kinetic information into mathematical models of the integrated system. However, despite its relative simplicity, the integrated behavior of erythrocyte metabolism is still complex and not well understood. Errors will inevitably be encountered in any such model because of this complexity; thus, the construction of an integrative model must be considered an iterative process of assessment and refinement. In a previous study, we selected a recent model of erythrocyte metabolism as our starting point and took it through three stages of model assessment and refinement using systematic strategies provided by biochemical systems theory. At each stage deficiencies were diagnosed, putative remedies were identified, and modifications consistent with existing experimental evidence were incorporated into the working model. In this paper we address two issues: the propagation of biochemical signals within the metabolic network, and the accuracy of kinetic representation. The analysis of signal propagation reveals the importance of glutathione peroxidase, transaldolase, and the concentration of total glutathione in determining systemic behavior. It also reveals a highly amplified diversion of flux between the pathways of pentose phosphate and nucleotide metabolism. In determining the range of accurate representation based on alternative kinetic formalisms we discovered large discrepancies. These were identified with the behavior of the model represented within the Michaelis-Menten formalism. This model fails to exhibit a nominal steady state when the activity of glutathione peroxidase is decreased by as little as 9%. Our current understanding, as embodied in this working model, is in need of further refinement, and the results presented in this paper suggest areas of the model where such effort might profitably be concentrated.

show abstract

“…These data have formed the basis for a number of kinetic models dealing with various aspects of the human erythrocyte (e.g. [3][4][5][6][7][8][9][10][11][12][13][14][15][16].…”

Section: Human Erythrocytes Are Among the Simplest Of Cells Many Of mentioning

confidence: 99%

Application of Biochemical Systems Theory to Metabolism in Human Red Blood Cells

Ni¹,

Savageau

1996

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Because of its simplicity, the human red blood cell represented the best opportunity to achieve this goal. Early metabolic models of human red blood cell metabolism appeared in the 1970s (11) and continued throughout the 1980s and 1990s (14–16). Insights into the functioning of this cell have resulted from these analyses (11, 17, 18).…”

Section: Introductionmentioning

confidence: 99%

Robustness Analysis of the Escherichia coli Metabolic Network

2000

View full text Add to dashboard Cite

Genomic, biochemical, and strain-specific data can be assembled to define an in silico representation of the metabolic network for a select group of single cellular organisms. Flux-balance analysis and phenotypic phase planes derived therefrom have been developed and applied to analyze the metabolic capabilities and characteristics of Escherichia coli K-12. These analyses have shown the existence of seven essential reactions in the central metabolic pathways (glycolysis, pentose phosphate pathway, tricarboxylic acid cycle) for the growth in glucose minimal media. The corresponding seven gene products can be grouped into three categories: (1) pentose phosphate pathway genes, (2) three-carbon glycolytic genes, and (3) tricarboxylic acid cycle genes. Here we develop a procedure that calculates the sensitivity of optimal cellular growth to altered flux levels of these essential gene products. The results indicate that the E. coli metabolic network is robust with respect to the flux levels of these enzymes. The metabolic flux in the transketolase and the tricarboxylic acid cycle reactions can be reduced to 15% and 19%, respectively, of the optimal value without significantly influencing the optimal growth flux. The metabolic network also exhibited robustness with respect to the ribose-5-phosphate isomerase, and the ribose-5-phosephate isomerase flux was reduced to 28% of the optimal value without significantly effecting the optimal growth flux. The metabolic network exhibited limited robustness to the three-carbon glycolytic fluxes both increased and decreased. The development presented another dimension to the use of FBA to study the capabilities of metabolic networks.

show abstract

“…MCA studies use linear and polynomial models to predict which enzymes to change (40,48,81,85,86). Detailed enzymological models have been used to analyze pancreatic glycolysis (1, 2), red blood-cell metabolism (55), and glycolytic/gluconeogenic switching (3). Linear and polynomial models are commonly used for deriving local dynamical models to predict changes in flux within a pathway that reflect changes in experimental conditions.…”

Section: Metabolic Regulationmentioning

confidence: 99%

Simulation of Prokaryotic Genetic Circuits

McAdams

Arkin

1998

Annu. Rev. Biophys. Biomol. Struct.

235

107

View full text Add to dashboard Cite

Biochemical and genetic approaches have identified the molecular mechanisms of many genetic reactions, particularly in bacteria. Now a comparably detailed understanding is needed of how groupings of genes and related protein reactions interact to orchestrate cellular functions over the cell cycle, to implement preprogrammed cellular development, or to dynamically change a cell's processes and structures in response to environmental signals. Simulations using realistic, molecular-level models of genetic mechanisms and of signal transduction networks are needed to analyze dynamic behavior of multigene systems, to predict behavior of mutant circuits, and to identify the design principles applicable to design of genetic regulatory circuits. When the underlying design rules for regulatory circuits are understood, it will be far easier to recognize common circuit motifs, to identify functions of individual proteins in regulation, and to redesign circuits for altered functions.

show abstract

A Macintosh software package for simulation of human red blood cell metabolism

Cited by 12 publications

References 21 publications

Application of Biochemical Systems Theory to Metabolism in Human Red Blood Cells

Application of Biochemical Systems Theory to Metabolism in Human Red Blood Cells

Robustness Analysis of the Escherichia coli Metabolic Network

Simulation of Prokaryotic Genetic Circuits

Contact Info

Product

Resources

About