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Lecture 13

BCH210 2014 Lecture 13.pdf

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Stavroula Andreopoulos

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Lecture 13 Hormone Signalling Metabolic Regulationbiogenergetics the production and utilization of energy via cellular processesprotein signalling pathways determine whether catabolic or anabolic pathways are activeyou wont have both of these pathways on at the same time so you need to turn one pathway on and turn the other one off otherwise they are going to be competing for different substratesglucose homeostasis maintained via hormone signalling to ensure cells have adequate glucoseepinephrineglucagon and insulin are competing protein hormones catabolism vs anabolism epinephrine and glucagon and are 2 molecules that play 2 different role but we will see that their signaling pathways are similar catabolism Insulin antagonist of epinephrine and glucagon will signal for anabolic pathways to take placeremember glycogen is a storage form of glucose in muscleliver that can be used to storesupply glucose for later energy requirementsremember glucose is addedremoved at the nonreducing endsHormone Signalling We will start with the catabolic hormonesbreak down glycogen so that we can use glucose in other parts of the body o Say you are running we have this hormone epinephrine which also goes by adrenalineo It is this fight or flight response hormone that is going to get released and is a derivative of tyrosine made from an AAadrenal gland releases epinephrinebind to muscle cells and through a signaling pathway we will see how glycogen will be broken down to produce sugar and then that can go through glycolysis and oxidative phosphorylation in order to generate ATPEpinephrine can also bind to fat cells to break down FA chains and use those to make more ATP as well exerciseepinephrine adrenaline releasemuscle responseglycogen breakdown for energy productionATP production in muscle goes upfat catabolism is also stimulated ATP increaseswhen blood glucose goes downglucagon from the pancreas is released released by the pancreasThe pancreas is going to be able to tell if you have enough glucose in the body if your glucose drops below lets say 2 millimolar then glucagon is going to get releasedalso a polypeptide hormone that can bind to the liver and break down liver glycogenliver responds by mobilizing its glycogen reserves to support blood glucose levelsliver is going to mobilize its glycogen or remove glucose from the non reducing ends the glucose is going to be released into the blood stream so that other parts of the body will use to generate ATPGProtein Signalling GPCRsGprotein coupled receptors GPCRs are a class of membrane receptors that contain 7 TMsBinding to a hormone on the extracellular face results in a conformational change on the inner portion of the membrane proteinGPCRs have an alpha subunit that is realised in the GTP bound formGalphaGTP activates adenylate cyclaseCatabolism via G Protein Signalling The reason why we are grouping these epinephrine and glucagon together is bc they have similar signaling pathwaysEach hormone is able to bind to different receptors but they have the same general structure the 7 TM receptor helix structureWhen either epinephrine or glucagon binds you will get similar signaling pathwayThe hormone is going to bind to the outside of the cell a conformational change in the membrane portiontransduce the signal inside of the cellConformational change in membrane G protein is going to be released and we get an exchange of GDP for GTP in the alpha subunit so it is a heterotrimeric G protein meaning that there are 3 different subunits So the alpha subunit is releasedGTP bound GTP is bound in the active state and it can then go on and activate other proteinsThe target in this signaling pathway is Adenylate cyclase which is able to take ATP and convert it to AMPCyclic AMP cAMP Acts as a Secondary Messenger to Activate Other Enzymeswe have GTP bound to the alpha subunit in the active stateactivates Adenylate cyclasecatalyzes the conversion of ATP to cAMPstructure of ATP and adenylate cyclase that is now in the active form piryl phosphate gets hydrolyzed offand we now have a cyclic structure between a 3 and the 5 carbon in our ribose ring signaling pathwayneed a way to turn it off o either the hormone can stop binding to the G protein coupled receptor hydrolysis or you can turn off the signal by breaking down cAMP o we can get GTP hydrolysis to inactivate it to go back to GDP o or turn off the signal by breaking down cAMP catalyzed by an enzyme called phosphodiasterase which will break the cyclic structure to from AMP from cAMPRemember that cAMP is a secondary structure that is acting inside of the cellnow can activate other proteins as well ex PKAcAMP Binding to Protein Kinase A PKAPKA is one of those enzymes that is both a catalytic subunit and a regulatory subunit the structure on the left2 catalytic subunits shown in blue and 2 regulatory subunits shown in yellowthe regulatory subunit has a cAMP binding sitewhen cAMP is made by adenylate cyclase it can then bind to the regulatory subunit and release the catalytic subunitactiveSo essentially we are going to get a change in the quaternary structure of PKA releasing the active kinases to catalyze the reactionsRemember that kinases phosphorylates so that will be the next stepPKA can then use ATP as a substrate and transfer a phosphate onto another protein such as protein X to form a phosphorylated protein PKA Phosphorylates Protein Targets PKA then uses ATP as a substrateCant have catabolic and anabolic pathways at the same timeSome enzymes are active when phosphorylated others are inactive when phosphorylatedin order to make sure that one pathway is on and the other is off we will phosphorylate some to activate them and phosphorylate others to inactivate themDownstream effects of hormone signaling is central for bioenergeticshormone binding outside of the cell conformational changesignal cascadeactivate this pathway to generate energy or use energy
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