DENTAL BIOCHEMISTRY 2015 Lecture 11 PENTOSE PHOSPHATE PATHWAY AND GLYCOGEN METABOLISM Michael Lea

LECTURE OUTLINE Functions of the pentose phosphate pathway Oxidative reactions leading from glucose 6- phosphate to ribose 5-phosphate Non-oxidative reactions leading to the formation of intermediates of glycolysis Glycogen structure and function Glycogen synthesis and breakdown Suggested reading : Lippincott’s Biochemistry, 6 th edition, pages , ,

FUNCTIONS OF THE PENTOSE PHOSPHATE PATHWAY Provide reduced NADP for synthetic reactions, e.g. fatty acid synthesis and reduction of glutathione Provide pentose phosphate for nucleic acid synthesis

GLYCOGEN FUNCTION AND LOCATION Glycogen serves as a storage form of carbohydrate In a well fed individual the concentration per gram tissue is highest in liver but the glycogen in liver can be depleted by a 24 hour fast. Glycogen is less readily depleted in muscle and there is more total glycogen in muscle than in any other tissue of the body. Brain has a very low glycogen concentration. The brain is largely dependent upon circulating glucose for the carbohydrate that it requires.

GLYCOGEN STRUCTURE Glycogen is a polysaccharide in which glucosyl residues are joined by glycosidic links. The major linkage between glucosyl residues are  1-> 4 with branch points in the chain that are  1-> 6 and occur at an average spacing of 8 to 12  1 -> 4 links.

GLYCOGEN SYNTHESIS Glucose 6-phosphate is converted to glucose 1-phosphate in a reversible reaction catalyzed by phosphoglucomutase Glucose 1-phosphate + UTP -> UDP-glucose + pyrophosphate catalyzed by UDP-glucose pyrophosphorylase Glycogen synthase catalyzes the transfer of glucose from UDP-glucose to glycogen with the formation of an alpha 1-> 4 link. Branch points are formed by glycogen branching enzyme (amylo 1-4 -> 1-6 transglucosylase).

GLYCOGEN BREAKDOWN Alpha 1-> 4 links in glycogen are broken by a phosphorolytic cleavage that requires inorganic phosphate and produces glucose 1- phosphate. The reaction is catalyzed by the enzyme glycogen phosphorylase. Branch points are cleaved by a hydrolytic reaction that produces free glucose and is catalyzed by glycogen debranching enzyme. This enzyme also has a transferase activity that can transfer a small oligosaccharide near a branch point to a longer alpha 1-> 4 linked chain.

REGULATION OF GLYCOGEN METABOLISM Glycogen metabolism is regulated by the activities of glycogen synthase and glycogen phosphorylase. Phosphorylation by protein kinases activates glycogen phosphorylase and inactivates glycogen synthase. The phosphorylation is reversed by phosphoprotein phosphatase activity. Glucagon and epinephrine increase glycogen breakdown by activating adenylate cyclase. This produces 3’5’-cyclic AMP which activates protein kinase A.

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LECTURE OBJECTIVES After studying this lecture material you should be able to Describe the functions of the pentose phosphate pathway Distinguish the oxidative and non-oxidative parts of the pentose phosphate pathway Describe glycogen structure and function Distinguish the reactions in glycogen synthesis and breakdown Describe how regulation of glycogen metabolism involves the phosphorylation status of glycogen synthase and glycogen phosphorylase