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Glycogen Synthesis

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Glycogen Synthesis BI/CH 422/622 ANABOLISM OUTLINE: Overview of Photosynthesis Carbohydrate Biosynthesis in Animals Key experiments: precursors Light causes oxygen, which is from water splitting (Hill) NADPH made (Ochoa) Cori cycle Separate from carbohydrate biosynthesis (Rubin & Gluconeogenesis Kamen) Light Reactions reversible steps energy in a photon irreversible steps – four pigments energetics HOW 2-steps to PEP Light absorbing complexes mitochondria Reaction center Pyr carboxylase-biotin Photosystems (PS) PEPCK PSI – oxygen from water splitting FBPase PSII – NADPH G6Pase Proton Motive Force – ATP Overview of light reactions Glycogen Synthesis Carbon Assimilation – Calvin Cycle UDP-Glc Stage One – Rubisco Glycogen synthase Carboxylase Oxygenase Branching Glycolate cycle Stage Two – making sugar Pentose-Phosphate Pathway Stage Three - remaking Ru 1,5P2 Oxidative phase Overview and regulation Calvin cycle connections to biosyn. Non-oxidative/recycling phase C4 versus C3 plants ROS and NADH/NADPH shuttles Kornberg cycle - glyoxylate Regulation of Carbohydrate Metabolism Anaplerotic reactions Glycogen Synthesis Storing a ready-reserve of carbohydrate 1 Glycogen Synthesis Glycogen is Synthesized by Glycogen Synthase Glycogenin Starts a New Glycogen Chain Takes 2 “ATPs” to put Glc into polymer (Glc1P & UDP-Glc), but get 33 ATP of potential energy. Glycogen Synthesis Glycogen Is Synthesized by Glycogen Synthase Glycogenin Starts a New Glycogen Chain Takes 2 “ATPs” to put Glc into polymer (Glc1P & UDP-Glc), but get 33 ATP of potential energy. 2 Glycogen Synthesis General Structure of a Glycogen Particle 29 – 212 x 12-14 = 5–50,000 Glc per glycogen (MW = 106 – 107) fourth – 12th tier Synthesis of Branches in Glycogen Pentose Phosphate Pathway Providing reduced electrons and ribose 3 Pentose Phosphate Pathway Pentose Phosphate (oxidative) Pathway, sometimes called the pentose- phosphate shunt, is linked to Glycolysis (Non-oxidative) Dr. Kornberg: Lecture 02.13.17 (7:28-8:56) 1.5 min Pentose Phosphate Pathway • Included in Anabolism because it provides the NADPH needed for so many biosynthetic reduction reactions, as well as the synthesis of pentoses. • But, can also be used for a shunt in the catabolism of Glc 6-P. • The main products are NADPH and ribose 5-phosphate (Rib 5-P). • Oxidative Phase oxidizes Glc 6-P to make NADPH • Non-oxidative Phase re-cycles pentoses to hexoses if not needed for biosynthesis. Uses of Pentose Phosphate Pathway (PPP): ØNADPH is an electron donor. – reductive biosynthesis of fatty acids and steroids – reductive biosynthesis of amino acids and nucleotide bases – repair of oxidative damage ØRibose 5-phosphate is a biosynthetic precursor of nucleotides. – used in DNA and RNA synthesis – or synthesis of some coenzymes 4 Pentose Phosphate Pathway Oxidative Phase Generates NADPH and a Pentose Allosteric inhibition by product NADPH Mechanism lactone Pentose Phosphate Pathway Oxidative Phase Generates NADPH and a Pentose Allosteric inhibition by product NADPH Mechanism lactone 5 Pentose Phosphate Pathway 5 Mechanism Mechanism Pentose Phosphate Pathway 5 Mechanism Mechanism 6 Pentose Phosphate Pathway (aldose) (ketose) (ketose) Phosphohexose isomerase (aldose) 2C′s 3C′s Ru 5-P (ketose) (ketose) (aldose) (aldose) 2C′s (ketose) (aldose) Non-oxidative Phase Interconverts Rib 5-P to form Glc 6-P • No ATP is used in the non-oxidative phase. • Complete conversion of ribose-5-phosphate to glucose-6- phosphate requires 6 Rib 5-P (30 carbons) to make 5 Glc 6-P (30 carbons). Pentose Phosphate Pathway (aldose) (ketose) (ketose) Phosphohexose542 6 isomerase (aldose) 26 2 2 2C′s 3C′s Ru 5-P 24 2 2 12 (ketose) (ketose) (aldose) (aldose) 2C′s 2 (ketose) (aldose) Non-oxidative Phase Interconverts Rib 5-P to form Glc 6-P • No ATP is used in the non-oxidative phase. • Complete conversion of ribose-5-phosphate to glucose-6- phosphate requires 6 Rib 5-P (30 carbons) to make 5 Glc 6-P (30 carbons). 7 Pentose Phosphate Pathway (ketose) (aldose) (aldose) (ketose) Transaldolase Mechanism CH2OH : H+ | E-NH + Ketose ⇌ E–N=C Protonated Schiff 2 base (e– sink) TPP | HOCH | HC–O-H :B | R This carbanion is protonated in aldolase In transaldolase, it makes a nucleophilic attack on the aldehyde of the second- ℗ substrate aldose. TPP Pentose Phosphate Pathway NADPH Regulates Partitioning into Glycolysis versus Pentose Phosphate Pathway Dihydroxyacetone- phosphate phosphate phosphate •Used in tissues •Used in tissues requiring needing both Rib more NADPH than Rib 5-P – such as the liver and adipose tissue 5-P & NADPH – ATP is plentiful •Used in tissues requiring more Rib 5-P than NADPH – such as the lymphocytes and fast growing tissues/cancer cells 8 Pentose Phosphate Pathway Reactive Oxygen Species (ROS) Glutathione (GSH) gECG Pentose Phosphate Pathway •Ubiquinone is naturally “leaky” and facilitates partial reduction of non-Complex III targets. –Single electron transfers result in free radicals. •One method by which the cell can correct free-radicals is the production of reduced Glc 6-P Dehydrogenase (G6PD) Deficiency glutathione (GSH), which fuels the glutathione shuttle Reactive Oxygen Species (ROS) Can Damage Biological Macromolecules Glutathione 9 Pentose Phosphate Pathway How do we get NADPH from PPP in cytosol into mitochondria? •Ubiquinone is naturally “leaky” and facilitates partial reduction of non-Complex III targets. –Single electron transfers result in free radicals. •One method by which the cell can correct free-radicals is the production of reduced Glc 6-P Dehydrogenase (G6PD) Deficiency glutathione (GSH), which fuels the glutathione shuttle Reactive Oxygen Species (ROS) Can Damage Biological Macromolecules Glutathione Pentose Phosphate Pathway Malate-Aspartate Converting Cytosolic Electron Carriers Shuttle (NADH & NADPH) to the Mitochondria NADPH antiporter NADP+ •This more complicated shuttle is mostly present in liver, heart, and kidney. •It moves NADH & NADPH equivalents antiporter from cytosol to NADH & NADPH equivalents in the mitochondria. 10 Regulation of Carbohydrate Metabolism Catabolism vs. Anabolism Catabolism vs. Anabolism Regulation of Carbohydrate Metabolism Gene controlled Catabolism Anabolism Glycogenolysis Glycogen versus Glycogen Glycogen Synthase Phosphorylase Phosphorylase Glycogen Glycogen Synthesis Synthase UDP-Glc UDP-glucose Glycolysis pyrophosphorylase versus Glc 1-P Gluconeogenesis phosphoglucomutase Hexokinase Glucose 6- • Regulated enzymes phosphatase often correspond to points in the pathways Phosphofructo- Fructose 1,6- kinase-1 bisphosphatase that have the same -1 substrate and product, but a different enzyme. • Also where there are junctions. • Can you name those Pyruvate Kinase – PEPCK – Pyruvate enzymes? Pyruvate carboxylase Dehydrogenase Acetyl-CoA Complex 11 Regulation of Carbohydrate Metabolism Regulation of Pyruvate Dehydrogenase Complex • Allosteric regulation by energy charge and substrate/product –ADP & pyruvate activates –ATP/NADH & acetyl-CoA inhibit • Regulated by reversible phosphorylation of E1 –phosphorylation: inactive –dephosphorylation: active • PDH kinase and PDH phosphatase are part of mammalian PDH complex. –Kinase is activated by ATP. • high ATP à phosphorylated PDH à less acetyl-CoA • low ATP à kinase is less active and phosphoprotein phosphatase removes phosphate from PDH à more acetyl-CoA 12.
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