Biochemistry 401 Lecture 24 Today we re going to talk about the regulation of glycogen metabolism We re going to discuss both local signals and global signals that affect glycogen metabolism Now if you ll recall glycogen catabolism is catalyzed by the enzyme glycogen phosphorylase and this is one of the primary sites of regulation for this pathway The glycogen phosphorylase enzyme is shown here It is a homodimer that is allosterically regulated One of the subunits of this dimer is shown in yellow and the other one is shown in white Now this enzyme is generally found attached right to glycogen But its activity is dictated by its phosphorylation state and also by the presence or the absence of noncovalent allosteric regulators Now glycogen phosphorylase enzyme exists in two different states a tense state and a relaxed state The tense state is less active and the relaxed state is more active Now the thing is the enzyme shifts back and forth between the tense state and the relaxed state but different factors can shift the equilibrium between the tense and the relaxed state to favor either one or the other conformation Now in the tense state the active site for the enzyme is partially blocked by an alpha helix that extends into the active site When the enzyme is phosphorylated this helix is kept out of the way and so the enzyme is more apt to be relaxed When phosphorylated glycogen phosphorylase is known as phosphorylase a and in this phosphorylation state the enzyme is more apt to be in the relaxed state whereas when glycogen is not phosphorylated it s known as phosphorylase b and in this state the enzyme is more apt to be in the tense state and we can see this in the figure Now this figure is little complex but let me walk you through it In the upper panel we see phosphorylase b and phosphorylase a both of which are in the relaxed state and in the bottom of the diagram we see glycogen phosphorylase b and a when they re in the tense state Now if you look at the length of the arrows that lie between phosphorylase b in the relaxed state and in the tense state you can see that arrows indicate that phosphorylase b is most often in the tense state and in this state the alpha helices extend into the active site and so phosphorylase b is more often tense and more often inactive In phosphorylase a on the other hand the arrows are shown to favor the relaxed state And so when glycogen phosphorylase is phosphorylated the conformation exists such that it favors the relaxed state and in the relaxed state glycogen 1 phosphorylase is more active As we shall see in a minute the phosphorylation of glycogen phosphorylase occurs in response to global signals And so to recap when glycogen phosphorylase b becomes phosphorylated it is known as glycogen phosphorylase a Glycogen phosphorylase a is more apt to be in the relaxed conformation in which the active site is open and accessible When glycogen phosphorylase a becomes dephosphorylated it is known as phosphorylase b and again in this conformation glycogen phosphorylase is more apt to be in the tense state in which an alpha helix extends partially into the active site and so glycogen phosphorylase will be less active Now the phosphorylation of glycogen phosphorylase happens by way of glycogen phosphorylase kinase So far we know that glycogen phosphorylase is regulated by phosphorylation such that when phosphorylated phosphorylase b is turned into phosphorylase a which is the more active confirmation But what phosphorylates this enzyme Well that is phosphorylase kinase that is shown here This is a homo tetramer consisting of alpha beta gamma and delta subunits four of each and it s arranged in a molecule that looks like a butterfly Now in this homo tetramer the subunits have different functions Gamma is catalytic the alpha beta delta subunits are regulatory The beta subunit is a phosphorylation site and the delta subunit is a calmodulin homolog It binds calcium Both phosphorylation and calcium binding partially activate the kinase However when calcium is bound and when the beta subunit is phosphorylated phosphorylase kinase is maximally active And so now we have two pieces of the puzzle We know that glycogen phosphorylase b is activated when it s phosphorylated to become phosphorylase a and we also know that this happens through phosphorylation through the action of phosphorylase kinase We also know the phosphorylase kinase is activated by both phosphorylation and by calcium So now what we need to know is what phosphorylates phosphorylase kinase and also how is it that there s an increase in calcium in the cell This happens by two different methods through global regulation and local regulation In the global regulation in muscles this phosphorylation occurs through the action of Protein Kinase A PKA and the local regulation occurs 2 through an increase in intracellular calcium and this happens in response to nerve impulse and muscle contraction When muscles contract one of the things that happens is calcium is released from intracellular stores to allow this contraction to actually occur and so muscles will have an increase in intracellular calcium when they re contracting and let s face it if your muscles are contracting that means you re going to be burning energy and you re going to need glucose and so this is a really good signal In the liver the global regulation is by phosphorylation through Protein Kinase A also and also through an increase in intracellular calcium So now we have another piece of the puzzle but how is it that PKA becomes activated What about those global regulators Global regulation occurs through two different signals epinephrine which is also known as adrenaline and glucagon Now epinephrine is released from the adrenal glands that are shown here in yellow These glands sit on top of the kidneys and are about the size of a walnut Epinephrine is released from cells that are found in the adrenal medulla This is the central portion of the adrenal glands in response to a fight or flight mechanism that s initiated And so when do you release epinephrine Well you release epinephrine during the fight or flight response This can be activated when you re really hungry or when you re really upset and afraid of something So I don t know if you ve experienced this but sometimes when you have gone without food for a while you can become agitated You can see this in children quite often because they become especially cranky when they re hungry
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