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GLUCONEOGENESIS SAFIYA RANSOME, P3 ([email protected]) PHARMACY BIOMEDICAL PREVIEW PROGRAM 2014 Gluconeogenesis: Introduction • Gluconeogenesis is an anabolic process that produces glucose from non-carbohydrate precursors. Glycerol Lactate Amino Acids Glucose Gluconeogenesis • Occurs primarily in the liver and somewhat in the kidney; overall, helps to maintain adequate blood glucose level so that tissues can meet metabolic demands. • Gluconeogenesis is NOT the reverse of glycolysis. Gluconeogenesis is NOT glycolysis in reverse! • Remember, three of the steps of glycolysis were irreversible. These steps are thermodynamically favored. (Produce a net decrease in free energy, ΔG.) • Gluconeogenesis has three of it’s own irreversible steps that bypass the irreversible steps of glycolysis. (These are the steps that we will examine in depth!) Gluconeogenesis Overview End Here! ➜ Start Here! Entering the Pathway • The various non-carbohydrate precursors are modified so that they may enter the gluconeogenesis pathway at different points. • Lactate is converted into pyruvate by lactate dehydrogenase. Pyruvate enters the pathway. • Glucogenic amino acids are converted into either pyruvate or oxaloacetate before entering the pathway. • Glycerol is converted into DHAP before entering the pathway. Glycolysis vs. Gluconeogenesis • To overcome the thermodynamic constraints, the irreversible steps of glycolysis are bypassed in the gluconeogenesis pathway. Glycolysis Step Pyruvate Kinase Gluconeogenesis Step 1. 2. Pyruvate carboxylase Phosphoenolpyruvate carboxykinase Phosphofructokinase Fructose-1,6-bisphosphatase Hexokinase Glucose-6-phosphatase Pyruvate Carboxylase • Converts pyruvate to oxaloacetate Phosphoenolpyruvate Carboxykinase • Converts oxaloacetate to phosphoenolpyruvate Fructose-1,6-bisphosphatase • De-phosphorylates Fructose-1,6-bisphosphate to produce Fructose-6-phosphate Glucose-6-phosphatase • De-phosphorlyates glucose-6-phosphate to produce glucose Regulating Glycolysis and Gluconeogenesis • Gluconeogenesis and glycolysis are coordinated so that, within a cell, one pathway is relatively inactive while the other is highly active. • This principle is known as Reciprocal Regulation. • The predominately active pathway is decided by the cellular energy charge. • Cell Energy Deficit ➜ Glycolysis active • Cell Energy Surplus ➜ Gluconeogenesis active CITRIC ACID CYCLE (TCA CYCLE, KREB’S CYCLE) PHARMACY BIOMEDICAL PREVIEW PROGRAM 2014 Citric Acid Cycle • Also known as the Tricarboxylic Acid (TCA) Cycle and the Kreb’s Cycle. • Primary Function: to harvest high energy electrons from carbon fuels. Electrons are stored in the form of NADH and FADH2. • NADH and FADH2 are later converted into ATP by oxidative phosphorylation via the electron transport chain. • Acetyl-CoA is the primary fuel for the citric acid cycle. • Other fuels can enter the cycle at different points. • Very little ATP is produced— just one molecule. Citric Acid Cycle: Overview Bridging the Gap: From Glycolysis to TCA Cycle • Recall that the final molecule produced by the glycolysis pathway is pyruvate and that the primary fuel of the citric acid cycle is acetyl-CoA. • The Pyruvate Dehydrogenase Complex converts pyruvate to Acetyl-CoA. This step is not considered a part of glycolysis or the citric acid cycle. Citric Acid Cycle: Important Steps • Produce NADH • Isocitrate Dehydrogenase (+ CO2 as well) • α-ketoglutarate dehydrogenase complex (+ CO2 as well) • Malate dehydrogenase • Produce FADH2 • Succinate dehydrogenase • Produce ATP • Succinyl-CoA Synthetase Tallying the Products • For one complete turn of the citric acid cycle (with input of 1 mol of Acetyl-CoA): • 3 NADH produced • 1 ATP produced • 1 FADH2 produced • 2 CO2 produced PENTOSE PHOSPHATE PATHWAY PHARMACY BIOMEDICAL PREVIEW PROGRAM 2014 Pentose Phosphate Pathway • Primary function: To produce NADPH and ribose-5-phosphate. • Glycolysis is linked: Glucose-6-phosphate (produced by hexokinase) is the entry molecule for this pathway. • Occurs in the cytosol (plasma membrane) • Alternate names: pentose shunt, hexose monophosphate shunt, phosphogluconate pathway. Primary Products • NADPH • A reducing molecule used in various anabolic biosynthesis pathways. NADPH also protects the cell from oxidative stress. • vs NADH? NADH is used in catabolic pathways. • Used in fatty acid biosynthesis, cholesterol biosynthesis, and nucleotide biosynthesis. • Ribose-5-Phosphate • Used in the production of RNA, DNA, and nucleotide + coenzymes (such as CoA, FAD, NAD, NADP ) Pentose Phosphate Pathway Pentose Phosphate Pathway • Consists of two phases: • Oxidative Phase: • NADPH is generated when glucose 6-phosphate is oxidized to ribulose 5-phosphate, which is subsequently converted into ribose 5-phosphate. • Non-oxidative Phase: • Pathway catalyzes the interconversion of three-, four-, five-, six-, and seven-carbon sugars in a series of nonoxidative reactions. • Five carbon sugars produced via interconversion can then enter into the glycolyic pathway.