Glycogen Metabolism (Revised)

Glycogen Metabolism (Revised) - Chapter 18 Glycogen...

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Unformatted text preview: Chapter 18 Glycogen Metabolism Glycogen • • • • Branched glucose homopolymer 100-400 Å cytoplasmic granules 1-2% in muscle and <10% in liver Why glycogen (instead of fat) as energy storage? – Rapid utilization of glycogen in muscle – Aerobic metabolism of fat – Fatty acids cannot be converted to glucose in animal cells Structure of glycogen Enzymes for the glycogen breakdown • Glycogen phosphorylase (or phosphorylase): Glycogen (n residues) + Pi ↔ glycogen (n-1 residues) + G1P • Glycogen debranching enzyme – Branch removal – Hydrolysis of α(1→6) glycosidic bond to generate glucose • Phosphoglucomutase: G1P → G6P (directly used for glycolysis in muscle and hydrolyzed to glucose in liver) Glycogen phosphorylase • Homodimer • Allosteric regulation (-) ATP, G6P and glucose (+) AMP • Phosphorylation at Ser-14 – Phosphoenzyme: phosphorylase a (more active) – Dephosphoenzyme: phosphorylase b (less active) Reaction of glycogen phosphorylase Structure of glycogen phosphorylase Phosphorylase reaction mechanism Glycogen debranching enzyme Phosphoglucomutase G6P • Direct use in glycolysis or pentose phosphate pathway • G6P hydrolysis system in the liver – G6P translocase: G6P transport from cytosol to ER – Glucose-6-phosphatase (G6Pase): Hydrolysis of G6P to glucose in ER G6P + H2O → glucose + Pi – Transport of glucose and Pi from ER to cytosol – GLUT2: Glucose transport from liver to other tissues G6P hydrolysis system in the liver Glycogen synthesis Glycogen synthetic enzymes • UDP-glucose pyrophosphorylase G1P + UTP → UDPG + 2Pi • Glycogen synthase UDPG + glycogen (n residues) ↔ UDP + glycogen (n+1 residues) • Glycogen branching enzymes UDP-glucose pyrophosphorylase ΔGo' = -33.5 kJ/mol ΔGo' = ~0 Glycogen synthase Extension of an existing α(1→4) glucan chain Regulation of glycogen synthase • Allosteric regulation (-) AMP (+) G6P, ATP • Covalent modification (Phosphorylation) – Dephosphoenzyme: glycogen synthase a (more active) – Phosphoenzyme: glycogen synthase b (less active) Glycogen branching enzyme: amylo-(1,4→1,6)-transglycosylase α(1→4) hydrolysis: ΔGo' = -15.5 kJ/mol α(1→6) formation: ΔGo' = +7.1 kJ/mol Glycogenin Glycogenin • Initiation of glycogen synthesis • Attachment of glycogen primer (up to seven glucose units) to the OH group of its Tyr194 • Glycogen:glycogenin:glycogen synthase = 1:1:1 Optimum glycogen structure (Short chain length per branch: more points for phosphorylase attack, but less glucose released before debranching) ~2 branches per chain vs vs 8-14 residues per branch (Long chain length per branch: less points for phosphorylase attack, but more glucose released before debranching) Structure of the glycogen particle Control of glycogen metabolism • Coordinated regulation of glycogen breakdown and synthesis • Allosteric control of glycogen phosphorylase and glycogen synthase • Enzymatic phosphorylation cascades – Phosphorylation activates glycogen phosphorylase – Phosphorylation inactivates glycogen synthase • Hormonal effects – Glucagon and epinephrine: (+) glycogen degradation – Insulin: (+) glycogen synthesis The control of glycogen phosphorylase activity Predominant at physiological condition Predominant at physiological condition Conformational changes of phosphorylase Covalent modification of glycogen phosphorylase • The modified (m, phosphorylated) form is active (the a form) • The original (o, dephosphorylated) form is inactive (the b form) Cascade of phosphorylations Phosphorylase kinase • Four nonidentical subunits (αβγδ) • One catalytic (γ) and three regulatory (αβδ) subunits • Activated by Ca2+ binding to δ subunit (calmodulin) and phosphorylation of αβ subunits by protein kinase A ATP Catalytic (γ) subunit Calmodulin (CaM) Ubiquitous Ca2+ binding protein Calmodulin Ca2+ binding helix-loop-helix motif Calmodulin (CaM) Conformational change induced by Ca2+ binding allows CaM to bind to the phosphorylase kinase catalytic (γ) subunit Ca2+ - CaM dependent activation of protein kinases cAMP is generated by adenylate cyclase cAMP is an activator of protein kinase A R2C2 (inactive) + 4 cAMP ↔ 2C (active) + R2(cAMP)4 ATP cAMP Catalytic (C) subunit of PKA Regulatory (R) subunit of PKA Phosphoprotein phosphatase-1 (PP1) • The catalytic subunit (PP1c) binds to glycogen through a regulatory protein (GM subunit in muscles or GL subunit in the liver) • In muscles, the activity of PP1c and its affinity to GM subunit are regulated by phosphorylation of GM subunit at two separate sites • In the liver, PP1c is activated when bound to GL subunit and the activity of PP1c is strongly inhibited by the binding of m-phosphorylase a to GL subunit Regulation of PP1 in muscle Covalent control of glycogen synthase • The modified (m, phosphorylated) form is inactive (the b form) • The original (o, dephosphorylated) form is active (the a form) • Phosphorylase kinase and other kinases phosphorylate and thereby inactivate glycogen synthase Control of the glycogen metabolism in muscles Hormones for the glycogen breakdown In the liver In muscles and various tissues Hormonal control of the glycogen metabolism Amplifying hormonal signals by the cyclic cascades Hereditary glycogen storage diseases ...
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This note was uploaded on 10/16/2010 for the course CHEM 60280 taught by Professor Ryu during the Spring '09 term at TCU.

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