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Lecture 8 in Powerpoint format

To thus a key link between thus catabolism and

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Unformatted text preview: sed “high energy” compounds used by cells to support work. to Thus a key link between Thus catabolism and anabolism catabolism Phosphoryl group transfer ‘activates’ compounds for pathway reactions Examples: Examples: Glucose Glucose is “primed”/activated for entry into glycolysis by its phosphorylation to Glu 6-P by FA and AA are primed before lipid and protein FA synthesis (ATP) synthesis Disruption of PPi from activated nucleoside triphosphates in assembly of nucleotide units in RNA and DNA PhosphocreatinePhosphocreatine- a short-term, limited supply of ‘phosphorylation potential’ ‘phosphorylation M ? A B X C D ? Assessing the Control of Pathway Flux Pathway 1. Traditional Methods 2. Metabolic Control Metabolic Analysis Analysis Control of metabolic pathway flux Control ? A ? B C D M… X… ‘Flux’ refers to the rate of movement of metabolites through a Flux’ pathway pathway The idea that there is just one rate-controlling step is outdated The just (and wrong!) The flux through a pathway is actually controlled by all steps, to variable extents. by Real metabolic pathways are more complicated than simple Real linear pathways: linear Many metabolites can be derived from more than one Many precursor, or give rise to more than one product (e.g., glu-6P is a product or substrate for 5 reactions) The questions are – how can we determine which reactions are The the most important control sites, and how is control quantitatively distributed amongst the reactions? quantitatively Thermodynamic Considerations Thermodynamic In cells none of the reactions in a given pathway is In none at equilibrium, otherwise there would be no flux at through the pathway through However many reactions are near equilibrium However near i.e., their mass action ratios, MAR = [products]/[substrates], are close to their Equilibrium Constants. Equilibrium K’eq = [products]/[substrates] when reaction is at equilibrium equilibrium These reactions are controlled largely by [Substrates] These reactions are thus responders, not These responders not controllers. controllers. 5 Traditional Methods to Identify Rate-controlling Steps: Rate-controlling 1. 2. Examine ∆ G’o values: Enzyme is likely to have a large Examine negative standard free energy change (∆ G’o) negative “Location, location, location”: Enzyme is likely near the Location, beginning of the pathway, or in the case of a branched pathway, just after a branch point pathway, ? A 3. ? B C D Measure activities: Enzyme activity is often low Measure Enzyme M… X… 4. Measure Mass Action Ratios Measure One of the best traditional methods; allows you to answer: One “How close are the reactions to equilibrium?” “How In intact cell, measure MARs Incubate tissue under defined conditions, Incubate then flash freeze the tissue. then Extract without thawing in deproteinizing Extract agent like trichloroacetic acid, and measure the metabolite concentrations. concentrations. Calculate MAR for each reactio...
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