10-8-4+Glycogen+Metabolism.pptVIP

* Glycogen Metabolism Glycogen Breakdown Glycogen Synthesis Glycogen Storage Diseases Glycogen Glycogen serves as storage carbohydrate in animals, insects and fungi Heavily branched to allow rapid mobilization of Glc Why use glycogen for energy storage? Muscles cannot mobilize fat as rapidly as glycogen. Fatty acid residues of fat cannot be metabolized anaerobically. Animals cannot convert fatty acids to Glc, so fat metabolism alone cannot adequately maintain essential blood Glc levels. Glycogen Breakdown Requires Three Enzymes A. Glycogen phosphorylase to cleave a1,4 linkages C. Phosphoglucomutase to convert to usable form B. Glycogen debranching enzyme a(1-4) glycosyl transferase and a(1-6) glucosidase activities - Glc-1-P and Glc Glc-1-P ---------- Glc-6-P Glycogen + Pi ---------- Glycogen + Glc-1-P n residues n-1 residues Glc-6-phosphatase is required for export from liver as Glc Glycogen Phosphorylase Dimer of identical 97 kDa subunits Structural Domains and Binding Sites Pyridoxal Phosphate is an Essential Cofactor for Phosphorylase Each phosphorylase subunit has N- and C-terminal domains. Allosteric effector binding sites and modification sites are in the N-terminal domain. Cofactor is linked in the C-terminal domain. The catalytic site is located at the interface of glycogen binding subdomain and regulatory domain with the C-terminal domain. Pyridoxal-5-phosphate (PLP), a vitamin B6 derivative, is covalently linked to phosphorylase via a Schiff base to Lys 679. In an unusual role, only the phosphate group participates in the catalytic process. Glycogen phosphorylase reaction mechanism 1. Formation of an E?Pi?glycogen ternary complex. 2. Oxonium ion intermediate (I) formation from the ?-linked terminal glucosyl residue involving acid catalysis by Pi facilitated by proton transfer from PLP. 3. Reaction of Pi with overall retention of configuration around C1 to form ?-D-Glc-1-phosphate. The glycogen, minus one