BBMB 405 1nd Edition Lecture 7 Jan 28 Outline of Last Lecture VII Chapter 20 The Calvin Cycle and the Pentose Phosphate Pathway E Glucose 6 phosphate Dehydrogenase plays key role in protection against reactive oxygen species X Handout 1 23 XI Handout 1 26 XII Chapter 21 Glycogen Metabolism A Glycogen Breakdown requires the interplay of several enzymes B Phosphorylase is regulated by allosteric interaction and reversible Outline of Current Lecture XII Chapter 21 Glycogen Metabolism C Epinephrine and glucagon signal the need for glycogen breakdown D Glycogen is synthesized and degraded by different pathways E Glycogen breakdown and synthesis are reciprocally regulated Current Lecture X Chapter 21 Glycogen Metabolism C Epinephrine and glucagon signal the need for glycogen breakdown 1 G proteins transmit signal for initiation of glycogen breakdown a Hormonal regulation of glycogenolysis trigger glycogenolysis These notes represent a detailed interpretation of the professor s lecture GradeBuddy is best used as a supplement to your own notes not as a substitute i Glucagon fasting low blood sugar level pancreas releases glucagon glucagon receptors on liver membrane ii Epinephrine in response to exercise released from adrenal gland beta receptors on muscle cells major glycogen breakdown alpha receptors on liver cells iii iv Amplification process Regulatory cascade for glycogen breakdown primarily in muscle A Signal molecules epinephrine or glucagon bind to 7TM receptor specific external signal is transmitted into cell through structural changes B GTP bound to receptor then activates adenylate cyclase which catalyzes formation of cAMP from ATP C cAMP activates protein kinase A cAMP activates protein kinase A PKA R2C2 Inactive 4cAMP 2R cAMP2 2C active D Protein kinase A phosphorylates phosphorylase kinase which activates glycogen phoshporylase E v Liver phosphoinositide cascade b Intracellular messengers i cAMP glucagon receptor and beta receptor ii Ca alpha receptor used in phosphoinositide cascade in liver 2 Glycogen breakdown must be rapidly turned off when necessary a So we don t breakdown all the glycogen it is regulated b When hormone is no longer present glycogen phosphorylase is automatically shut down c All activated molecules turn back to inactive forms AMP GDP phosphorylase kinase 1 phosphoryl group glycogen phosphorylase b 3 Regulation of glycogen phosphorylase became more sophisticated as enzyme evolved D Glycogen is synthesized and degraded by different pathways 1 UDP glucose is activated form of glucose a Synthesis Glycogenn UDP Glucose glycogenn 1 UDP b Degradation Glycogenn 1 Pi glycogenn glucose 1 phosphate c UDP Glucose adds glucose on to non reducing end of glycogen is activated form of glucose d Reaction catalyzed by UDP glucose pyrophosphorylase e f Note theme in biochemistry is many biosynthetic reactions are compelled by hydrolysis of pyrophosphate 2 Glycogen synthase catalyzes transfer of glucose from UDP glucose to growing chain a Linkage is made at C4 of terminal residue forming an alpha 1 4 glycosidic linkage b Reaction catalyzed by glucogen synthase which is a key regulatory enzyme when building glycogen c d Glycogen synthesis needs a primer because it can only add glucosyl residue to chain that contains more than four residues glycogenin e Glycogen synthesis handout 1 28 i Glycogenin 2 subunits 16 UDPG auto glucosylation onto tyrosine Glucose 8 Glycogenin Glucose 8 conversion of nUDPG to nUDP Glycogen ii Glucose 8 Glycogenin Glucose 8 is basic building block of glycogen 3 A branching enzyme forms alpha 1 6 linkage a Glycogen synthase only makes alpha alpha 1 4 linkages and branching enzymes forms alpha 1 6 linkage b Branch reacted by breaking alpha 1 4 linkage and forming an alpha 1 6 link different from debranching c Conditions at least 7 glucose units transferred attached at least 4 glucose units away from other branch chain must have at least 11 units d e Branching increases solubility of glycogen important branching also increases rate of glycogen synthesis and degradation 4 Glycogen synthase is key regulatory enzyme in glycogen synthesis a Covalent modification Phosphylation i Changes lead to inactivation Glycogen synthase kinase GSK Protein kinase A ii Activation glycogen synthase phosphorylase b Allosteric regulation activate phosphorylase b with high levels of glucose 6 phosphate 5 Glycogen is efficient storage form of glucose a Synthesis of glycogen is very efficient only requires 1 ATP and if make 31 ATP per glucose is 97 efficient b E Glycogen breakdown and synthesis are reciprocally regulated 1 The same glucagon and epinephrine triggered cAMP cascades that initiate glycogen breakdown in liver and muscle respectively also shut off glycogen synthesis Glucagon and epinephrine control both glycogen breakdown and glycogen synthesis through protein kinase A Biochemistry p 630 2 Protein phosphatase 1 reverses regulatory effects of kinase on glycogen metabolism a b Protein phosphatase 1 is key in regulating glycogen metabolism it inactivates phosphorylase a and phosphorylase kinase activates glycogen synthase by removing phosphoryl groups activated by insulin insulin increases glycogen synthesis c Glycagon and epinephrine stimulate glycogenolysis and control activity of protein kinase A and slows down PP1 activity d Regulatory subunits bound to catalytic subunits GM in heart and muscle GL in liver Regulatory subunits act as scaffolds bringing together phosphatase and its substrates in context of glycogen particle Biochemistry p 631 e 3 Insulin stimulates glycogen synthesis by inactivating glycogen synthase kinase a Insulin binds to receptor tyrosine kinase and activates it to phosphorylate insulin receptor substrates IRSs which trigger pathways that lead to activation of protein kinases that inactivate glycogen synthase kinase kinase can not longer maintain glycogen synthase so PP1 dephosphorylates glycogen synthase and activates it and restoring glycogen reserves net effect of insulin replenishment of glycogen stores b 4 Glycogen metabolism in liver regulates blood glucose level a b Conversion of a into b is accompanied by release of PP1 which then is free to activate glycogen synthase and dephosphorylate glycogen phosphorylase c Activity of glycogen synthase only increases after most of phosphorylase a is converted to b this lag prevents two pathways from operating simultaneously d 5 Biochemical understanding of glycogen storage diseases is possible a