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23 Kevin Aherns Biochemistry Gluconeogenesis
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1. Contact me at [email protected] / Friend me on Facebook (kevin.g.ahern) • 2. My lectures with The Great Courses - https://www.thegreatcourses.com/cours... • 3. My Lecturio videos for medical students - https://www.lecturio.com/medical-cour... • 4. Course materials at http://davincipress.com/bb450.html • 5. Take my free iTunes U course at https://itunes.apple.com/us/course/bi... • 6. Course video channel at http://www.youtube.com/user/oharow/vi... • 7. Check out all of my free workshops at http://davincipress.com/freebies.html • 8. Check out my Metabolic Melodies at http://www.davincipress.com/ • 9. My courses can be taken for credit (wherever you live) via OSU's ecampus. For details, see http://ecampus.oregonstate.edu/soc/ec... • 10. Download my free biochemistry book at http://www.davincipress.com/freeforal... • Glycolysis • 1. Pyruvate kinase is regulated both allosterically and by covalent modification (phosphorylation/dephosphorylation). Phosphorylation of the enzyme by a protein kinase turns the enzyme activity down, whereas F1,6BP acts as an allosteric activator. This activation is known as feedforward activation. • 2. Feed forward activation is rare in metabolism. It is a term used to describe a metabolic product (such as F1,6BP above) that ACTIVATES an enzyme that catalyzes a reaction further ahead of it in a metabolic pathway. In glycolysis, feedforward activation acts to start the pyruvate kinase reaction and PULLs the reactions forward to get over the energy hump of the aldolase reaction. • 3. Hypoxia refers to the condition where cells are short of oxygen. Since oxygen is necessary for maximum energy production from glucose, they must respond to this condition. One way they respond is by making a transcription factor known as Hypoxia Induction Factor 1 (HIF-1). HIF-1 activates transcription of genes involved in glucose transport and glycolysis. Cancer cells are frequently hypoxic and induce HIF-1, as well. • Gluconeogenesis • 1. Gluconeogenesis reverses glycolysis - synthesis of glucose from pyruvate using four different enzymes to replace three energetically unfavorable reactions in glycolysis. • 2. Gluconeogenesis does not occur in all tissues of the body. The primary gluconeogenic organs of the body are the liver and part of the kidney. • 3. Enzymes unique to gluconeogenesis are Pyruvate Carboxylase, PEP carboxykinase (PEPCK), Fructose 1,6 Bisphosphatase (F1,6BPase), and Glucose-6-phosphatase (G6Pase). • 4. F1,6BPase and G6Pase clip a phosphate from their substrates and thus avoiding synthesis of ATP, which is what would be required if the glycolysis reactions were simply reversed. • 5. The reaction catalyzed by pyruvate carboxylase occurs in the mitochondrion and yields the four carbon intermediate, oxaloacetate. The carboxyl group is added in forming oxaloacetate thanks to the coenzyme biotin, which carries carbon dioxide for attachment. The remaining reactions all occur in the cytoplasm, except for the G6Pase reaction, which occurs in the lumen of the endoplasmic reticulum. • 6. Anabolic and catabolic pathways occurring at the same time and place create a futile cycle. Futile cycles generate heat, but that is the only product they make. Reciprocal regulation of catabolic and anabolic pathways is a very efficient means of control. • 7. The enzymes of glycolysis that are regulated have corresponding gluconeogenesis enzymes that are also regulated. PFK and F1,6BPase exhibit the most complicated regulation. Both are controlled by several mechanisms. The most important one is the allosteric regulation by fructose-2,6-bisphosphate (F2,6BP). F2,6BP activates PFK and inhibits F1,6BPase. • 8. F2,6BP is made and degraded by two different portions of the same protein. The portion of the PFK2 catalyzing the synthesis of F2,6BP from F6P is PFK2. The portion of the protein catalyzing the breakdown of F2,6BP to F6P is FBPase-2. When phosphorylated, the PFK2 part of the enzyme is inactive and the FBPase-2 is active. When dephosphorylated by phosphoprotein phosphatase, the PFK2 becomes active and the FBPase-2 becomes inactive. • 9. Phosphorylation of the enzyme by protein kinase A is favored by 7TM signaling. Dephosphorylation by phosphoprotein phosphatase is activated by signaling by insulin. • 10. Thus phosphorylation of the PFK2 favors the breakdown of F2,6BP and the activation of gluconeogenesis and deactivation of glycolysis. Dephosphorylation of PFK2 favors the synthesis of F2,6BP and the activation of glycolysis and the deactivation of gluconeogenesis. • 11. Pyruvate kinase is activated by feedforward activation by F1,6BP and is inhibited by ATP and alanine. Pyruvate kinase is also controlled by covalent modification. • 12. Regulation of glycolysis and gluconeogenesis occurs mostly allosterically using molecules that are indicative of the energy state of the cell.
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