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Lecture 8 in Powerpoint format

It then sets out to quantify the distribution of

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Unformatted text preview: s out to quantify the distribution of control within a pathway. The degree of control by an enzyme (or group of enzymes) is described quantitatively in the form of flux control coefficients (see next slide). 1 It also can be used to assess the control over the concentrations of the metabolites in a pathway. The distribution of control over metabolite concentrations is described quantitatively in the form of concentration control coefficients. 2 What is a flux control coefficient? A flux control coefficient describes quantitatively how much control a step (or block of steps) has over the flux through a pathway. Flux control coefficients range from -1 to +1 If some perturbation of an enzyme increases its rate by 5%, and the whole pathway by 2%, the enzyme is said to have a flux control coefficient of 2/5, or 0.4. If another perturbation of another enzyme causes its rate to increase by 5%, but the activity of the whole pathway decreases by 2%, the enzyme is said to have a flux control coefficient of -2/5 = -0.4. The sum of all coefficients for a pathway equals 1 (This is called the summation theorem) 0.40 A 0.25 B 0.15 C 0.20 D E Flux Control Coefficients in a Branched Metabolic Pathway Branched For flux A to D For Note that the Summation Theorem holds for branched pathways too Note Applications of Metabolic Control Analysis Control Medical research Medical What What enzymes in a given pathway become disordered in a given disease? • E.g., Altered activity of glycolytic enzymes – implications for pathologies associated with diabetes (retinopathy, neuropathy) pathologies • E.g., hyperthyroidism and impaired oxidative phosphorylation Can Can pharmaceuticals be better designed to normalize metabolic fluxes in disease? metabolic Metabolomics Metabolomics Number of publications per year The field of metabolomics is growing ! Metabolomics: The comprehensive and quantitative analysis of all metabolites in a biological system Avoids exclusion of any metabolites Allows high sample throughput capabilities Attempts to incorporate findings into a broader picture, to improve the understanding of biochemical networks It is a systems biology approach Metabolite: Any organic molecule with a MW < 1000 Da Includes peptides, oligonucleotides, sugars, nucelosides, organic acids, ketones, aldehydes, amines, amino acids, lipids, steroids, and drugs (xenobiotics) Metabolome: a comprehensive term used to describe all the possible metabolites for a biological system (just as genome and proteome refer to all possible genes and proteins) ‘omics’ Genomics 30,000 Genes Genes 106 Proteins +++ Metabolites Proteomics Metabolomics Sample Metabolite List Sample (+)-(-)-Methylsuccinic Acid 2,5-Dihydroxyphenylacetic Acid 2-hydroxy-3-methylbutyric acid 2-Oxoglutaric acid 3-Hydroxy-3-methylglutaric acid 3-Indoxyl Sulfate 5-Hydroxyindole-3-acetic Acid Acetamide Acetic Acid Acetoacetic Acid Acetone Acetyl-L-carnitine Alpha-Glucose Alpha-ketoisocaproic acid Benzoic Acid Betaine Beta-Lactose Citric Acid Creatine Creatinine D(-)Fructose D-(+)-Glyceric Acid D(+)-Xylose Dimethylamine DL-B-Aminoisobutyric Acid DL-Carnitine DL-Citrulline DL-Malic Acid Ethanol Formic Acid Fumaric Acid Gamma-Amino-N-Butyric Acid Gamma-Hydroxybutyric Acid Gentisic Acid Glutaric acid Glycerol Glycine Glycolic Acid Hippuric acid Homovanillic acid Hypoxanthine Imidazole Inositol isovaleric acid L(-) Fucose L-alanine L-asparagine L-aspartic acid L-Histidine L-homocitrulline L-Isol...
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