Gluconeogenesis and Glycogen Metabolism 2024 PDF

Gluconeogenesis and Glycogen Metabolism JEFF POWERS, PH.D. DEPARTMENT OF MOLECULAR BIOLOGY  Learning Objectives Talking bout what happens...

Gluconeogenesis and Glycogen Metabolism JEFF POWERS, PH.D. DEPARTMENT OF MOLECULAR BIOLOGY  Learning Objectives Talking bout what happens inpast a Name the reactions in gluconeogenesis that circumvent the irreversible steps of glycolysis, including the enzymes that are specific to gluconeogenesis Identify the precursors of glucose and their entry points. Describe the physiologic roles of the Cori cycle and glucose-alanine (Cahill) cycle Describe the hormonal regulation gluconeogenesis/glycogenolysis including activation/inactivation of bifunctional enzymes to prevent futile cycles List the metabolites that provide carbon skeletons for gluconeogenesis, where they come from, and under what conditions List the anatomical locations where gluconeogenesis occurs and what proportion of gluconeogenesis occurs in each based on the metabolic state of the body List the locations within the cell where each step of gluconeogenesis takes place the the shuttles/substrates between the cellular locations Know the inputs and outputs of gluconeogenesis in terms of energy and redox reactions Explain the pathophysiology of von Gierke disease, pyruvate carboxylase deficiency, and alcohol-induced hypoglycemia Describe the processes of glycogen synthesis and glycogenolysis, as well as the hormones that mediate these processes in liver and skeletal muscle List the anatomical locations and approximate distribution of glycogen stores in the body Describe the enzyme deficiency and pathophysiology of glycogen storages diseases 0 through 6 Type1/4 Class)  In the cytoplasm bla in Liver 6 Lur dephosphorylate dreversible shows steps / O - gets ride of 1 up I reversible The carbon up until here reversible Oxidative ↓ Phosphorylated m Undergoesa · mitochondria ↓ decarboxylated I decarboxylation phosphorylated Carboxylated g 3 from To go 54C  I shown good a Takes place in Mitochondria sethree t cytoplasm  a a couple ca o take 42 - Oxalodatate-imperable to Shuttles: shuttle lycrd-3 Shutte + Malate Mitochondria is used in so mito PEP to make it 13ways dif it has PEP to make - cytsol its it Oxalodatake can make as it out of lowes Mitochondria way Mitochondria Couple dre tr e thin a  What is gluconeogenesis? Literally making new glucose Six-carbon glucose is made from various three-carbon precursors Lactate Alanine Glycerol  Overview of Gluconeogenesis Gluconeogenesis Glycolysis (GNG) Enzymes Enzymes unique unique to GNG to glycolysis = Activators Allosteric + somere For regulators - - Inhibitors PECK Gluconeogenesis only take place in the liver and the kidneys Typically, the liver accounts for around 90% of gluconeogenesis and the kidneys account for the other 10% In starvation, the ratio shifts to around 50/50 Skeletal Muscle at Glucos very gooddamine A breakdown produces Alanine-Glutamine alot of tidmysoverty flu  have you when in minimum comp aBare Glucose dietary When does gluconeogenesis take place? Kinda last Resource body Uses) When there is no dietary glucose in the blood and liver glycogen stores begin to run out As liver glycogen stores diminish, an increasing amount of blood glucose is produced by gluconeogenesis when there's dieting Lee s wh graph of · refer back to Glucose Blood glucce thre-out day ↳ Not Only rue not gluconeogemsis start to ramp up breaky down Glycogen - realy only see unc glycogen stores start to run out (which is overnight) b day weAre storing so he medls if you'r eaty 3 day - overcourse of a ↳ won't you realy have much pland glucose being mode from gluconeogenesis ↳ so usually only happens when you're your quieta while wout eaty Glycogen  Lactate 30 precursors b/itochondria no blome aeo ↓ so pyruvat lactate ana Produced by RBC’s and exercising muscle = - Since RBC’s do not have mitochondria, pyruvate must be reduced to lactate to regenerate NAD+ for glycolysis to continue Once lactate gets produced by RBC’s and muscle, it circulates to the liver where it is oxidized back to pyruvate by LDH (producing NADH) ↳This als Cori Cycle to lve (Latate goes Back · Must have back to lactate produced converted tgoes > - pyruvate b - in order 4 to continue-> glycolysis in RBCs must have a centure amount of NAD + Muchawtorgener LAcctet NADY is regaedtid 4 GAPDH Step in Glycolysis  Alanine Alanine is mainly the result of protein degradation in skeletal muscle in is de e ruvate Pyruvate produced in glycolysis gets aminated by ALT Skeletal Muscle when glycolysis happen in it produces pyruvate broken down ↳ And AnOther A A ther. bey get rid of there nitrogen t Ambe go by it transferedonto pyruvate to have havy - it become Alanme  Once alanine leaves the muscle, it circulates to the liver and gets deaminated by ALT in the liver, making pyruvate Pyruvate Alanine & X &  Once pyruvate is made from lactate or alanine, the pyruvate is transported into the - mitochondria Creoxidized) - deaminated Glanim-deaminated- pyruvate route ① lactate-reoxidized - pyruvate see Anytime w/ carboxylation - B7 ② Rxn-it's to use consume going Aminated BIOTIN as or it camb decarboxylated 1(44) Cofactor ↓ to blim phosphorylated PEPleave) (reduced) b Itoleaveas  Once pyruvate is in the mitochondria, it can either be decarboxylated by the PDH complex to acetyl-CoA or carboxylated to oxaloacetate (OAA)  OAA cannot pass through the inner mitochondrial membrane, so it must either be reduced to malate or aminated to aspartate PEP  Once in the cytosol, malate or aspartate are converted by to OAA, which is then decarboxylated and phosphorylated by phosphoenolpyruvate carboxykinase (PEPCK) to form PEP This step requires 1 molecule of GTP I but we would in total how used 2ATp its an intensive process energy -  Cortisol Stimulates Gluconeogenesis The rate of GNG is increased - GNG turned dendent Up down or Epinephine Stimulates Glycogenolyss by increased transcription of - is by Inst stimulate & how much PEPCK by cortisol) PEPCK gene, which is being is made increased by increased cAMP Camp Activates (glucagon signaling) and cortisol Ylife 6hrs of & thigh insulm will step it Prommola botodarme macorticoid produced = Contra E 3 ·Stimulate by Stimulating transcript of Mare PEPCK see dresse -Incred Inhibitory  Glycerol Fatty Acids 6 + glyard Glycerol enters Come from Triacyle glanrols gluconeogenesis at the level of DHAP It is produced by the lipolysis of TG in the liver Enters bepategte DHAP E g  B-oxidation = breaks down Falty Acids Other GNG precursors Sugar-fatt fat * Sugar b Acetyl Cot-cant go to 3C pyruvate z(G) it become only way can - A sugar (Schan) b nowa (A) precursor Can be metabolized to become & TCA Cijde Intermediate b ↓ can blane OOA b Glucose  Fructose-1,6-bisphosphatase this side directions Glucongenie F2,6-BP, in addition to on stayed previous Inotures - being a potent - allosteric stimulator latien hosphory on Turned dep by y so goh, in glycolytic direction of PFK-1 (recall from signalig ↳ dusulin - protei => - Phosphatase I - glycolysis lecture), ↳ dephosphorylate powerful Allostense PFK 2 b - Activator also inhibits Turna n Ki S - b Also speed In phosphorylates Inhibits up will - Fructor-6-phos Some of enzyme fructose-1,6-bisphosp F-1-6 gluconeogenic b , BPase around PS- Fructure 2-6 the goes bisphosphate hatase In fasting now: so Insulin going down ↓ GlucagonA ↓ stimulate dephosphorylate Protein-Kindse A to turn of Kindle ↓ Activity Phosphorylaty PFKZ TurningOn Phosphate s Phosphoryltohotase ↓ Activity dephosphorylate 3 F-26 - BP - Fl b.BPase , ,  Fructose-1,6-bisphosphatase F-1,6-Bpase is also inhibited by AMP  Around 3 Thusforgame  - dephosphorylates glucose In ER ER & m⑳ - 6-6-phosphatase Transporter Each have oh get to out Hepatocyte gets usy GLT2 - Kinda 2 way transporte  look & EnergyRequirements Gluconeogenesis requires 6 ATP equivalents to produce one molecule of glucose Breakdown of this glucose betongenesis -Supressed by disul through glycolysis produces 2 ↳ Acids BOxidation Fatty of net ATP, so the net requirement b to produce one molecule of Actyl-ot ovided b glucose is 4 ATP glucos Tissue being full, into bran betoneboding is Adipose Fatts from going About 26 - mobdue Since this occurs when there is ↓ so lot t ATP & & Sourc high glucagon, there is also high ↳drivg Ketones of And state glucagon lange lipolysis, so the energy for butounT how brain is ↑ epough- lipolys · gluconeogenesis is provided by equals stores I beta-oxidation of fatty acids in ↳ Even if it Can't fally Acids gluconeogenesis use - directly the liver ↓ Maky Glucose & Energy froa - is tatois fully tads  timm ( drives whole &'Therectan op Gluconeogenesis Pyruvate Carboxylase  Overview: Regulation of hepatic glucose metabolism A schematic overview of key enzymes and metabolites involved in the regulation of gluconeogenesis and hepatic glucose output. Flux through these metabolites is tightly regulated to control net gluconeogenesis or glycolysis. How insulin (blue) or glucagon (red) affect these key enzymes and metabolites is highlighted.  Pyruvate Carboxylate Deficiency Presents at birth with failure to thrive, developmental Prequent delay, and Causeshuts Hypoglycemia up recurrent seizures OAA can’t be synthesized from pyruvate, prohibiting almost all GNG · Can still break down some Triacyl-Glyard Cytosolie Pathway Joiry & DHAP Step of GNG  Alcohol-Induced Hypoglycemia Every molecule of ethanol that gets metabolized produces 2 equivalents of NADH Increased NADH/NAD+ ratio can inhibit gluconeogenesis If a person is fasted and their glycogen stores are depleted, severe hypoglycemia can result  Von Gierke Disease Deficiency in Glucose 6-phosphatase - Glycogen storage disease Type I Results in enlarged liver and kidneys, growth failure, severe fasting hypoglycemia, acidosis, lipidemia, thrombocyte dysfunction platelet · feedy baby Curnstarch CanPix this Glycogen Metabolism Star Main ↓justhere & - 16. Glycosidic Skeletal Muscle blacks glucose-6 ↑ Phosphotase Y - monomer  mobilize · all glucoseonce allows glucose storagei space Small Glycogen Synthesis Glycogen degradation  Glycogen Synthesis take a G6P converted to G1P by Ingested Glucose- Punsulin how we Glucose preexisty phosphoglucomutase chan of add I monome storing ↓ - it G1P converted to So now to it UDP-glucose by = UDP-glucose goinge e pyrophosphorylase (glucose ↓ - is activated and can be fromrated added to glycogen - molecule) Glucose from UDP glucose to end of added a+ -4 linkage by then added to the end of Synthas the chain (a-1,4 linkage) by glycogen synthase - =  As chain gets longer (>10 Glycogen Synthesis units or so), branching - - enzyme cleaves 7 glucose residues from growing end and adds them to the 6 carbon of (a-1,6 linkage) to form a branch This process repeats making more and more branches but only works on pre-existing glycogen molecules (8 glucose residues or more) To create this brance P arethe ne O > - of Converts Imbage g type other en  De novo glycogen synthesis Glycogen Synthesis requires glycogenin, which When there's no preexisting Glycogen modes adds 8 glucose residues to itself from UDP-glucose buildy Glycogen stores from stratch Once there are at least 8 glucose residues, glycogen synthase can take over they Glycogen - Synthesis proceeds - as norm. Looking At Glycogen ↓ - - - Glycogenolysis in Skeletal Muscle  Glycogenolysis (AKA glycogen degradation or glycogen high Glucagon breakdown) Glycogen phosphorylase creates G1P from glucose residues on the nonreducing ends of - glycogen When branches are 4 glucose residues long, debranching enzyme does two things: Removes 3 residues from branch and adds it - eache e to end of core chain (4:4 transferase deb activity) Removes remaining glucose that is a-1,6 linked (a-1,6-glucosidase activity) G1P is converted to G6P by phosphoglucomutase G6P is converted to glucose by G6Pase breaks ↓ kee  Regulation of Glycogenolysis Process the became Muscle breakdown dre a propels Skeletal Muscle he need to make who quickly · ↓ protects Lilycemia Us Prom we diety Glucose has a run out Gluconeogeness [ 3 has kicked up yet high Glucapon - Gluco - - i - Phosphon Safe , Kinde & how ·ait O O deautate Syn im 3 -Stimulate - Dressa Glycogenolysis in Skeletal Muscle Stimulates S Ca2" productio * breakdown ↳ ↳ buildp ·  Summary of Glycogen Storage Diseases For Enterzena to ↳e Questions?