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Workshop 2: Understanding the Control of Metabolism

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Workshop 2: Understanding the Control of Metabolism Understanding the Control of Metabolism C1net Workshop 2; Day 2 David Fell [email protected] http://mudshark.brookes.ac.uk C1netW2 2015 L3: - p. 1 Outline Introduction ● Outline ● The context: manipulating ■ Elements of Metabolic Control Analysis (MCA) metabolism ● The rate–limiting step concept ◆ The flux control coefficient ● Quotes ● Critique of ‘rate–limiting’ steps Control Coefficients ◆ Control coefficients and enzyme kinetics Control coefficients and enzyme kinetics ◆ Flux control coefficients in context Elasticities Connectivity theorem Relevance of flux control coefficients Problems C1netW2 2015 L3: - p. 2 The context: manipulating metabolism Introduction Two different problems: ● Outline ● The context: manipulating ■ Easy: stopping flux to a product through a pathway. (Pick an metabolism ● The rate–limiting step concept essential enzyme; knock out by mutation or inhibition.) ● Quotes ● Critique of ‘rate–limiting’ steps Control Coefficients ■ Hard: increasing flux to a product through a pathway. Control coefficients and enzyme kinetics Elasticities Connectivity theorem Why isn’t the solution to the hard problem: Relevance of flux control 1. find the rate–limiting enzyme, and coefficients Problems 2. increase the amount of this enzyme? C1netW2 2015 L3: - p. 3 The rate–limiting step concept Introduction ● Outline ● The context: manipulating metabolism ● The rate–limiting step concept When a process is conditioned as to its rapidity by a number of ● Quotes ● Critique of ‘rate–limiting’ steps separate factors, the rate of the process is limited by the pace Control Coefficients of the slowest factor. Blackman (1905). Control coefficients and enzyme kinetics Elasticities Connectivity theorem Relevance of flux control coefficients Problems C1netW2 2015 L3: - p. 4 Quotes Introduction ● Outline ■ The first committed step being irreversible . most metabolic ● The context: manipulating metabolism pathways are controlled by regulating . their first committed ● The rate–limiting step concept ● Quotes steps (Voet & Voet, 1990). ● Critique of ‘rate–limiting’ steps Control Coefficients ■ ...an entire pathway can be controlled by regulating only the Control coefficients and enzyme enzyme that catalyzes the first step in the pathway (Zubay et kinetics al, 1995). Elasticities Connectivity theorem ■ The first enzyme of a pathway is usually a strategic place for Relevance of flux control control (Elliott & Elliott, 1997). coefficients Problems ■ In a multistep pathway the first enzyme is ususally regulated and the others are not (Zubay, 1998). C1netW2 2015 L3: - p. 5 Critique of ‘rate–limiting’ steps Introduction ● Outline ● The context: manipulating ■ It is not possible for one step in a pathway to be ‘slower’ than metabolism ● The rate–limiting step concept the others. ● Quotes ● Critique of ‘rate–limiting’ steps Control Coefficients ■ The flux through multistep pathways, even with simple Control coefficients and enzyme kinetics kinetics, has long been known to depend in principle on all Elasticities the steps. Connectivity theorem Relevance of flux control ■ The experimental evidence is that the genuinely rate–limiting coefficients step is rare. Problems C1netW2 2015 L3: - p. 6 Introduction Control Coefficients ● Metabolic Control Analysis ● The flux–enzyme relationship ● The flux–enzyme relationship ● A specimen pathway ● Definition of the flux control coefficient Control Coefficients ● Definition of the flux control coefficient ● Values of the flux control coefficient ● Definition of the flux control coefficient ● Experimental effect of reduced SBPase. ● The flux summation theorem ● Flux control is a system property ● The Concentration Control Coefficent ● Concentration Control Summation Control coefficients and enzyme kinetics Elasticities Connectivity theorem Relevance of flux control coefficients Problems C1netW2 2015 L3: - p. 7 Metabolic Control Analysis Introduction originated with: Control Coefficients ■ Henrik Kacser & Jim Burns (Edinburgh) and ● Metabolic Control Analysis ● The flux–enzyme relationship ● The flux–enzyme relationship ● A specimen pathway ■ Reinhart Heinrich & Tom Rapoport (Berlin) ● Definition of the flux control coefficient ● Definition of the flux control independently in 1973 (based in part on earlier work by Joe coefficient ● Values of the flux control Higgins). coefficient ● Definition of the flux control coefficient ● Experimental effect of Kacser, H. and Burns, J. A. (1973) Symp. Soc. Exp. Biol. 27, 65–104. Reprinted in Biochem. Soc. Trans. 23, 341–366, reduced SBPase. ● The flux summation theorem (1995). ● Flux control is a system property Heinrich, R. and Rapoport, T. A. (1974) Eur. J. Biochem. 42, 89–95, 97–105. ● The Concentration Control Coefficent ● Concentration Control Summation Control coefficients and enzyme kinetics Elasticities Connectivity theorem Relevance of flux control coefficients Problems C1netW2 2015 L3: - p. 8 The flux–enzyme relationship 10 Introduction Control Coefficients ● Metabolic Control Analysis 8 ● The flux–enzyme relationship ● The flux–enzyme relationship ● A specimen pathway ● Definition of the flux control 6 coefficient ● Definition of the flux control coefficient ● Values of the flux control coefficient 4 ● Definition of the flux control coefficient ● Experimental effect of Tryptophan flux reduced SBPase. ● The flux summation theorem 2 ● Flux control is a system property ● The Concentration Control Coefficent 0 ● Concentration Control Summation 0 20 40 60 80 100 120 Control coefficients and enzyme kinetics Try 2,3-dioxygenase Elasticities A typical example: Tryptophan 2,3–dioxygenase was adjusted Connectivity theorem by various dietary and hormonal treatments Relevance of flux control Results of Salter et al (1986). coefficients Problems C1netW2 2015 L3: - p. 9 The flux–enzyme relationship Introduction Control Coefficients ● Metabolic Control Analysis ● The flux–enzyme relationship ● The flux–enzyme relationship ● A specimen pathway ● Definition of the flux control coefficient ● Definition of the flux control coefficient ● Values of the flux control coefficient ● Definition of the flux control coefficient ● Experimental effect of reduced SBPase. ● The flux summation theorem ● Flux control is a system property ● The Concentration Control Coefficent ● Concentration Control Summation Control coefficients and enzyme kinetics Elasticities A typical example: dependence of carbon assimilation flux on Connectivity theorem rubisco levels in transgenic tobacco plants. Relevance of flux control Results of Laurer et al, Planta 190 332-345 (1993). coefficients Problems C1netW2 2015 L3: - p. 10 A specimen pathway Introduction Control Coefficients ● Metabolic Control Analysis ● The flux–enzyme relationship xase ydh zase ● The flux–enzyme relationship ● A specimen pathway X0 −→ Y −→ Z −→ X1 ● Definition of the flux control coefficient ● Definition of the flux control coefficient ● Values of the flux control coefficient ● Definition of the flux control coefficient ● Experimental effect of X0 is termed the source reduced SBPase. ● The flux summation theorem ● Flux control is a system property X1 is the sink ● The Concentration Control Coefficent ● Concentration Control Summation Y and Z are the variable metabolites that reach constant levels Control coefficients and enzyme at steady state, when their rates of formation equal their rates kinetics of utilization. Elasticities Connectivity theorem Relevance of flux control coefficients Problems C1netW2 2015 L3: - p. 11 Definition of the flux control coefficient Introduction Control Coefficients Suppose a small change, δE , is made in the amount of ● Metabolic Control Analysis xase ● The flux–enzyme relationship enzyme Exase, and that this produces a small change in the ● The flux–enzyme relationship ● A specimen pathway flux through the step catalyzed by ydh. ● Definition of the flux control coefficient ● Definition of the flux control coefficient Jydh ● Values of the flux control The flux control coefficient Cxase is approximately the % coefficient ● Definition of the flux control change in Jydh produced by a 1% change in Exase. coefficient ● Experimental effect of reduced SBPase. ● The flux summation theorem ● Flux control is a system property ● The Concentration Control Coefficent ● Concentration Control Summation Control coefficients and enzyme kinetics Elasticities Connectivity theorem Relevance of flux control coefficients Problems C1netW2 2015 L3: - p. 12 Definition of the flux control coefficient Introduction @ J ydh . ... ... ... ... .. ... ... .. @ E . ... ... .. .. ... ... .. xase . ... .. .. .. Control Coefficients . ... .. .. ... .. .. ... .. .. .. .. ... .. .. .. .. .. .. ... .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. ● . .. .. .. .. .. Metabolic Control Analysis . .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. ● .. .. .... .. ..... ..... .. The flux–enzyme relationship .... ... .. .... ... .. ... .. .... .. .. ... .. .... .. ... .. .. .... .. .. ... ... .. ... ... ● ... ... ... The flux–enzyme relationship . ... ... ... ... ... ... j . ... ... ... .. .. .. ... ● ... .. .. .. A specimen pathway ... .. .. .. .. ... ... .. .. .. ... .. .. .. .. ... .. .. .. .. ● .. Definition of the flux control . .. .. .. .. .. .. .. coefficient . .. .. .. .. ● .. Definition of the flux control . .. .. coefficient . ydh . ● . Values of the flux control . J . @ J J . ydh . ydh . e . coefficient . C . xase . ● . Definition of the flux control . @ E j . xase . coefficient . ● . Flux . Experimental effect of . reduced SBPase. ● . The flux summation theorem . ● . Flux control is a system . property . ● . The Concentration Control . Coefficent . ● . Concentration
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