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PSL425 Lecture 2.docx

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PSL425 Lecture 2 Glycogen - Stores excess energy to be utilized later on by the brain when fasting, obligatory glucose utilization - Need system to release glucose from our body when fasting (not eating carbohydrates)– storing of glucose in glycogen - Glycogen stored in muscle (meat) is important for the muscle to provide muscle with glucose to be broken down when exercising - Muscle does not have glucose-6-phosphate - Glycogen in liver (not much) – important for quick adaptation of glucose to exercise, to avoid hyperglycemia; important for the quick regulation of plasma glucose - Glycosidic bond (interior) formed by 2 –OH of glucose (decondensation) 1-4 and 1-6 bonds Glycogen synthesis - Diff enzymes affecting synthesis vs. breakdown for regulation - Glycogen synthesis has to occur at time of glucose elevation, stimulated by glucose itself and by insulin - As soon as glucose is phosphorylated, it doesn’t leave the cell (hormone intermediate of fixing glucose inside cell – then handled in diff ways) - Synthesis starts from glucose 1-phosphate (isomerization from G6P) by Pglucomutase - G1P and G6P completely interconvertible ; synthetic reaction – requires energy!! - G1P + UTP, gets energy from high energy bond of trinucleotide – UDP-glucose + PP; energy released which allows synthesis of bigger product - Final rxn where UDP-glucose deposits glucose on residues of glycogen forming glycogen with one more glucose with release of UDP, accompanied by release of high energy bond from PP into 2P - The whole system here regulated at the end at the level of glycogen synthase; one of few examples of regulation at end (generally at beginning of system) o Take into account 1) G6P if accumulates, is allosteric regulator of glycogen synthase (good), stimulates glycogen synthase by itself; It tends to accumulate if mutase blocked o 2) Need to have energy independent of the fine regulation b/c synthetic reaction, so if you don’t have enough energy from high energy phosphates (permission) - Get stimulus to form glycogen PROVIDED that you have enough energy (deduced reason) - Primer is something that initiates something, if no glycogen at all: glycogen synthase has to put glucose moiety on a glycogen, but in a system with no glycogen, there is possibility of putting glucose directly on protein called glycogenine – protein can be glycosylated, so glycogen synthase puts glucose on it to start glycogenesis - Normally physiologically there always glycogen in our livers - Branching important: there will be an enzyme that switches the bonds to make straight chains into ramified ones, important b/c there are diseases where you lack some of the branching enzyme where you have abnormal glycogen – pathology: difficulty in releasing glucose, and accumulation of glycogen in liver (big liver) Glycogen breakdown (glycogenolysis) - glycogen synthase positively regulated by insulin - has to occur quickly (need glucose sometimes in emergency situation); glycogen phosphorylase down-regulated by insulin (regulation in beginning) - glycogen phosphorylase up-regulated by glucagon and epinephrine - glycogen forms glucose 1-phosphate + glycogen, phosphorylysis to form G1P directly - G1P intercovertable directly into G6P by Pglucomutase - G6P in muscle – glycolysis utilized, utilized by KREBS in muscle - G6P in liver – hydrolyzed by G6phosphatase and glucose released into blood Regulation of Glycogen synthesis and breakdown - glucagon released when in fasting state, in hypoglycemia (important regulator of this) - epinephrine released in stress (exercise, or for brain) - epinephrine and glucagon interact with mmbrn receptor in liver, and the receptor will be coupled with stimulation of enzyme (adenylate cyclase) – formation of cAMP – activates PKA - PKA phosphorylates phosphorylase kinase, which activates the enzyme - Phosphorylase kinase also a kinase for glycogen synthase (in addition to phosphorylase) - and inactivates glycogen from active to inactive form (b) - Phosphorylase kinase activates phosphorylase from inactive to phosphorylated form (active) – breaks glycogen into glucose - Multiplies action, stimulates breakdown and same time decreases synthesis of glycogen Hormonal control of glycogen phosphorylase - phosphorylase that starts the breakdown of glycogen, active when phosphorylated by phosphorylase kinase - In muscle Ca2+ itself can stimulate phosphrylase-mediated breakdown, important during muscle contraction when you need glucose from glycogen breakdown? - Phosphrylase also acted upon phosphatase PP1 (also phosphatase of glycogen synthase) - Don’t know a lot about PP1, but we do know that PP1 is kind of ubiquitous enzyme, can actually split phosphate off a number compounds, but it is generally associated with glycogen- targeted subunits; diff subunits in liver, and diff ones in muscle (current research) - PP1 takes off a phosphate from phosphorylase a and makes it inactive (b); PP1 under the control of insulin (kinase under control glucagon, epinephrine) in a way that we are not completely sure, just know that insulin interacts with subunit of PP1 - Complex interactions: backup systems - Backup system: PKA phosphorylates an inhibitor of PP1 making it inactive, and PP1 itself dephosphorylates and inhibits the inhibitor-1 - Glucagon increases phosphorylase, and it basically activates inhibitor of PP1 Hormonal control of glycogen synthase - phosphorylase active when phosphorylated, but synthase active in de-phosphorylated state - insulin activates PP1, which will de-phosphorylate glycogen synthase b into active form (a) - PKA will also activate inhibitor and inhibit the phosphatase (PP1) - don’t know signaling cascade of insulin that activates PP1 - phosphorylase kinase is kinase for glycogen synthase, PKA also can do it directly - The important kinase under regulation of insulin is: GSK-3 (glycogen synthase kinase-3) - PKA can be kinase of glycogen synthase - GSK-3 = substrate of PKB, when phosphorylated by PKB, it is inhibited – glycogen remains in the active state – i.e. inhibited its inhibition: double inhibition - Insulin leads to phosphorylation GSK-3 and makes it inactive, which can’t phosphorylate and inhibit glycogen synthase Don’t really know: how glucose regulates glycogen synthesis itself – would make sense that independent of insulin, that it stimulates glycogen synthase and inhibits the phosphorylase We don’t know the mechanism, we know that glucose in some way has a permissive action: allows for insulin action to occur on the synthase Glucose facilitates action of insulin on the phosphatase G6P itself s allosteric stimulator of glycogen synthase Glucose metabolism – generally mean liver, but other tissues can do certain pathways, but not others; whole system subject to tissue specialization Liver - Important in glucose metabolism - Can utilize and produce glucose - glycogenolysis: pathway goes to formation of glucose - Liver can ALSO UTILISE GLUCOSE: depend on metabolic and hormonal condition (e.g. after feeding, liver can put glucose into glycogen (synthetic glycogen pathway) stimulated by insulin and simultaneously inhibit glycogenolysis - G6P can go glycogen, or to pyruvate which can go to form lactate or acetyl CoA - Liver can not only utilize glucose to produce ATP, but when ATP enough: from acetyl CoA and get out of mitochondrial mmbrn via citrate and go to synthesis fatty acids (de nouvo lipogenesis) - Lactate is freely permeable through hepatocyte membrane; the liver can produce lactate and use lactate (from muscles after exercise) and use lactate to produce glucose b/c liver is a gluconeogenic organ Muscle – some put not all glucose metabolism - Can get glucose and p
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