Bich 411 1st Edition Exam #3 Study Guide Lectures: 13-18Chapters 22-24Chapter 22 (lectures 13-15)Gluconeogenesis – forming glucose from metabolites, necessary for the body to maintain its own energy-mostly in the endoplasmic reticulum of the liver and kidneys-gluconeogenesis can use pyruvate, lactate, glycerol, amino acids, and all TCA intermediatesfatty acids can’t be used**note that it’s not just reversed glycolysis! (when one is on, the other is off “reciprocal regulation” -see figure 22.1 – it relates glycolysis and gluconeogenesis-gluconeogenesis uses steps 2 and 4-9 of glycolysis to produce glucose-pyruvate carboxylase and PEP carboxylase replace pyruvate kinase-Fructose-1,6-bisphosphatase replaces phosphofructokinase-Glucose-6-phosphatase replaces hexokinaseUnique Gluconeogenesis reactionsStep 1: pyruvate + HCO3- + ATPoxaloacetate + ADP + Pi with Pyruvate Carboxylase. Requires ATP and bicarbonate. It is also very biotin dependent (biotin linked with lysine). ***Acetyl-coA is an allosteric activator** Also note that when ATP or acetyl-CoA concentrations are high, pyruvate enters gluconeogenesis. This reaction is the initiation of gluconeogenesis!Step 2: Oxaloacetate + GTP PEP + GDP + CO2 with PEP carboxylase. This reaction gets its energy from decarboxylation and GTP hydrolysis. Step 3: Fructose-1,6-Bisphosphate + H2O Fructose-6-Phosphate + Pi with Fructose-1,6-Bisphosphatase. Fructose-1,6-Bisphosphatase is regulated by citrate (positively), and fructose-2,6-bisphosphatase and AMP (negatively). Step 4. Glucose-6-PhosphateGlucose, with Glucose-6-Phosphatase. This involves 3 transport proteins. T1 is responsible for taking Glucose-6-phosphate to the endoplasmic reticulum. T2 exports glucose to the cytosol. T3 exports inorganic phosphates to the cytosol. GLUT 2 transporter takes the glucose out of the endoplasmic reticulum and cell.Net equation: 2 pyruvate + 4ATP + 2 GTP + 2 NADH + 2 H+ + 6 H2O 1 glucose + 4 ADP + 2 GDP + 6 Pi + 2 NAD+Metformin stimulates the glucose transporters.3-Mercaptopicolinate and hydrazine inhibit the oxaloacetate PEP reaction.Chlorogenic acid inhibits glucose-6-phosphatase. S-3483 does the same. Cori cycle**The liver is very important during exercise! Lactate is reoxidized in the liver by lactate dehydrogenase (LDH) to pyruvate. The pyruvate is eventually converted to glucose.-note that the liver has high [NAD+]/[NADH] while the muscle has low [NAD+]/[NADH]RegulationFor glucose-6-phosphatase, the more substrate, the more enzyme is activated.-the other regulators are allosteric. (acetyl-CoA, AMP, citrate, Fructose-2,6-bisphosphate)**memorize figure 22.8**Glycogen-at the end of gluconeogenesis, glucose becomes glycogen (branched polymers). This involves glycogenolysis. -glycogen comes from anything consumed that’s starch – broken down by alpha-amylase (endoglycosidase, breaks alpha 1-4 bonds internally). Stops 4 units before branch.-debranching enzyme cleaves four remaining units (limit dextrin). Transfer the three outer glucose groups, cleaves the remaining glucose. -Glycogenolysis releases a glucose-1-phosphate, rearranges glycogen, and converts glucose-1-phosphate to glucose-6-phosphate. **The fate of glucose-6-phosphate depends on what is needed. It can enter glycolysis (like if you’re running), become glucose (if you’re hungry or starving), or enter the pentose phosphate pathway (electrons for biosynthesis or ribose for making nucleic acids). -special note:-Tissue glycogen (stored in the liver and muscle) is where the energy comes from when broken down. Glycogen phosphorylase cleaves glucose from non-reducing ends (remember thatalpha-amylase cleaves internal bonds! These have cleave differently!) The produce (sugar-phosphate) is a good glycolysis substrate. The product, Glucose-1-phosphate, doesn’t go to ATP.Glycogen synthesis -derivitizing glucose activates it-UDP-glucose pyrophosphorylase causes phosphoanhydride exchange – the reaction involves spontaneous hydrolysis. End result is UDP-glucose (activated form of glucose) for synthesis of glycogen.-glycogenin (protein) initiates glycogen formation. Glucose is added to –OH on Tyrosine. Sugar units added (glycogen synthase) via alpha 1-4 bonds. UDP-glucose loses glycosyl units to C-4 hydroxyl of glycogen strand. **an oxonium intermediate is involved** The branching enzyme isresponsible for forming the branches.Glycogen synthesis Net reaction:Glucose-6-Phosphate + ATP + Glycogenn + H2O Glycogenn+1 + ADP + 2 Pi (Enzymes involved: phosphoglucomutase, UDP-glucose pyrophosphorylase, Inorganic pyrophosphatase, glycogen synthase, nucleotide diphosphokinase)Issues with diabetes-ligation disease in diabetes:-glucose can form Schiff base linkages which undergo Amadori rearrangements to formGlycation end products (AGEs) – irreversible!-measure glycated hemoglobin for diagnosticsRAGE (receptor for advanced glycation end-products)-protein in immune systems – can trigger intracellular responses in diabeticsGlycogen Metabolism-glycogen metabolism is highly regulated -involves glycogen phosphorylase (GP) and glycogen synthase (GS) – reciprocal regulation – both regulations involve phosphorylation!-GP is activated by AMP (turns on), inhibited by ATP, glucose-6-Phosphate, and caffeine (turn off)-GS is stimulated by glucose-6-phosphate-regulated by covalent modification-GS-I = dephosphorylated form (insensitive to glucose-6-P)-GS-D = phosphorylated form (can be activated by glucose-6-phosphate)-dephosphorylation by phosphatase (like PP1) activates GS and inactivates GPInsulin-binding of insulin triggers protein kinase cascades, GS stimulated-has several effects (job is to lower blood sugar – wants to dump glucose out of blood to glycogen, ATP, amino acids, etc)-glucose uptake activates glycogen synthaseHormone regulation-glycogen metabolism regulated by hormones like insulin, glucagon, epinephrine, and glucocorticoids-insulin stimulates glycogen synthesis (gets rid of glucose)-glucagon and epinephrine cause glycogen breakdown (want to increase glucose)**Figure 22.20 is helpful to know for the quiz**-glucagon acts in liver and fat tissue, activates glycogen breakdown and gluconeogenesis(maintenance reactions)-epinephrine acts in liver and muscles, activates glycolysis (fight or flight reactions)-Glucocorticoids act on liver, skeletal muscle, and fatty tissue-Cortisol is catabolic – acts on skeletal muscle (protein breakdown) and liver
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