Dataset Information

Glutathione synthesis and turnover in the human erythrocyte: alignment of a model based on detailed enzyme kinetics with experimental data.

ABSTRACT: The erythrocyte is exposed to reactive oxygen species in the circulation and also to those produced by autoxidation of hemoglobin. Consequently, erythrocytes depend on protection by the antioxidant glutathione. Mathematical models based on realistic kinetic data have provided valuable insights into the regulation of biochemical pathways within the erythrocyte but none have satisfactorily accounted for glutathione metabolism. In the current model, rate equations were derived for the enzyme-catalyzed reactions, and for each equation the nonlinear algebraic relationship between the steady-state kinetic parameters and the unitary rate constants was derived. The model also includes the transport processes that supply the amino acid constituents of glutathione and the export of oxidized glutathione. Values of the kinetic parameters for the individual reactions were measured predominately using isolated enzymes under conditions that differed from the intracellular environment. By comparing the experimental and simulated results, the values of the enzyme-kinetic parameters of the model were refined to yield conformity between model simulations and experimental data. Model output accurately represented the steady-state concentrations of metabolites in erythrocytes suspended in plasma and the changing glutathione concentrations in whole and hemolyzed erythrocytes under specific experimental conditions. Analysis indicated that feedback inhibition of gamma-glutamate-cysteine ligase by glutathione had a limited effect on steady-state glutathione concentrations and was not sufficiently potent to return glutathione concentrations to normal levels in erythrocytes exposed to sustained increases in oxidative load.

SUBMITTER: Raftos JE

PROVIDER: S-EPMC2911318 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Glutathione synthesis and turnover in the human erythrocyte: alignment of a model based on detailed enzyme kinetics with experimental data.

Raftos Julia E JE Whillier Stephney S Kuchel Philip W PW

The Journal of biological chemistry 20100524 31

The erythrocyte is exposed to reactive oxygen species in the circulation and also to those produced by autoxidation of hemoglobin. Consequently, erythrocytes depend on protection by the antioxidant glutathione. Mathematical models based on realistic kinetic data have provided valuable insights into the regulation of biochemical pathways within the erythrocyte but none have satisfactorily accounted for glutathione metabolism. In the current model, rate equations were derived for the enzyme-cataly ...[more]

PMID: 20498365

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Project description:BACKGROUND: The chemical property and biological function of a protein is a direct consequence of its primary structure. Several algorithms have been developed which determine alignment and similarity of primary protein sequences. However, character based similarity cannot provide insight into the structural aspects of a protein. We present a method based on spectral similarity to compare subsequences of amino acids that behave similarly but are not aligned well by considering amino acids as mere characters. This approach finds a similarity score between sequences based on any given attribute, like hydrophobicity of amino acids, on the basis of spectral information after partial conversion to the frequency domain. RESULTS: Distance matrices of various branches of the human kinome, that is the full complement of human kinases, were developed that matched the phylogenetic tree of the human kinome establishing the efficacy of the global alignment of the algorithm. PKCd and PKCe kinases share close biological properties and structural similarities but do not give high scores with character based alignments. Detailed comparison established close similarities between subsequences that do not have any significant character identity. We compared their known 3D structures to establish that the algorithm is able to pick subsequences that are not considered similar by character based matching algorithms but share structural similarities. Similarly many subsequences with low character identity were picked between xyna-theau and xyna-clotm F/10 xylanases. Comparison of 3D structures of the subsequences confirmed the claim of similarity in structure. CONCLUSION: An algorithm is developed which is inspired by successful application of spectral similarity applied to music sequences. The method captures subsequences that do not align by traditional character based alignment tools but give rise to similar secondary and tertiary structures. The Spectral Similarity Score (SSS) is an extension to the conventional similarity methods and results indicate that it holds a strong potential for analysis of various biological sequences and structural variations in proteins.

Dataset Information

Glutathione synthesis and turnover in the human erythrocyte: alignment of a model based on detailed enzyme kinetics with experimental data.

Publications

Glutathione synthesis and turnover in the human erythrocyte: alignment of a model based on detailed enzyme kinetics with experimental data.

Similar Datasets

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