Sugar nucleotides and glycogen metabolism Several nucleotides can activate sugars. In the case of glucose for glycogen synthesis it is UTP. See next page The first reaction a), is reversible but it is coupled to b) that releases -5 kcal/mol and favors reaction a).

Sugar nucleotides of glucose or of any other carbohydrate are called activated because sugars bound to nucleotides can be transferred by specific enzymes to proteins and other molecules or can be subjected to enzymatic modifications possible only with activated sugars. UDP-glucuronic is important for detoxification of many drugs and metabolites. Below is shown the formula of conjugated bilirubin: We, primates, lost the ability to make ascorbate. Therefore we are genetically deficient.

Galactose metabolism Fructose is an ketose, therefore it is not a substrate of aldose reductase and causes no cataracts. Glucose and galactose are aldoses and they do cause cataracts Deficiency of galactokinase causes a mild form of galactosemia (galactose deficiency) that causes cataracts. Deficiency of hexose-1-phosphate-uridylyl transferase causes the sever type of galactosemia with liver failure, mental retardation and cataracts. The name galactose-1-phosphate-uridylyl transferase is simply wrong but commonly used including in the NBE. The correct name is hexose-1-phosphate uridylyl transferase. This is so because it transfers equally well glucose as it does galactose. So, the name in the fig is not in agreement with the commission for enzyme nomenclature but it is used in most books and in the NBE. The 4 epimerase uses NAD+ as cofactor and the transition state is 4 keto hexose. Why a deficiency of the 4 epimerase was never reported (as far as I know)? Unrelated to this topic, in glycosaminoglycans a 5 epimerase transforms beta-D- glucuronyl into alpha-L-iduronic. Do you remember that, actually it is “cute” but not too important for medical practice.

Synthesis of uridinediphosphoglucose or UDPGlu Synthesis of Glycogen Synthesis of uridinediphosphoglucose or UDPGlu Do you remember phosphoglyceromutase? Any similarities with phosphoglucomutase? PPi is hydrolyzed by a pyrophosphorylase in a reaction coupled with the pyrophosphorylase to dissipate energy as heat thus making the synthesis of UDP-Glu thermodynamically favorable.

Why do we need to waste 2 ATPs and make glycogen? Deficiency of branching enzyme gives long branches. Causes death at about to years of age. Andersen’s disease The content of glycogen is about 10 % of the wet weight of the liver and 2% of muscle.

Glycogen synthase only adds glucoses to an existing chain of at least 4 glucose residues. Glycogenin acts by catalyzing the addition of glucose to itself (autocatalysis) by first binding glucose from UDP-glucose to the hydroxyl of Tyr-194 from UDP-glucose, by glycogenin's glucosyltransferase. Once sufficient residues have been added, glycogen synthase takes over extending the chain. Glycogenin remains covalently attached to the reducing end of glycogen.

Glycogen degradation The breakdown of glycogen and entry into glycolysis as glucose-6-P is achieved by three enzymes: glycogen phosphorylase, debranching enzyme and phosphoglucomutase. Glycogen phosphorylase produces glucose-1-P plus limit dextrin. The debranching enzyme has a transferase and glycosidase (hydrolase) activities. Hexokinase is bypassed when glucose comes from glycogen! Deficiency of phosphorylase (Mc Adler’s) causes muscle cramps and no lactate formation during exercise. Deficiency of debranching enzyme causes accumulation of limit dextrin In the next slide we will address the regulatory mechanisms involved in glycogen metabolism

After this hasty and nasty introduction to cell signaling we will study the regulation of glycogen synthase and glycogen phosphorylase and a regulatory enzyme called phosphorylase b kinase. For the three enzymes we will use the diagram shown below. Please, understand the diagram. Later we will integrate all this in a graph. The granule of glycogen contains the three enzymes mentioned above plus other regulatory enzymes. Glycogen synthase can be D, or dependent on glucose-6-P, or I, independent of the presence of glucose -6-P. Please, remember that the immediate precursor of glycogen is UDP-glucose not glucose-6-P. The latter is only an allosteric regulator of glycogen synthase.

Glycogen phosphorylase b kinase also phosphorylates the synthase and should actually be called synthase phosphorylase b kinase. The phosphorylation of the alpha subunit regulates the dephosphorylation of the beta subunit. The delta subunit is calmodulin. The direct interaction of Ca2+ with calmodulin activates this enzyme. This effect is specially relevant in muscle.

Integration of the regulation of glycogen synthesis and breakdown Glucagon Epinephrine Receptors Adenylyl Cyclase cAMP ATP AMP Phosphodiesterase R2C2 R2(cAMP)4 2C ACTIVE PKA Glycogen synthase Phosphorylase b Kinase Glycogen Phosphorylase activation inhibition

Integration of the regulation of glycogen synthesis and breakdown Glucagon Epinephrine Receptors Adenylyl Cyclase cAMP ATP AMP Phosphodiesterase R2C2 R2(cAMP)4 2C ACTIVE PKA Glycogen synthase Phosphorylase b Kinase Glycogen Phosphorylase Protein Phosphatase activation Protein Phosphatase Inhibitor inhibition

Integration of the regulation of glycogen synthesis and breakdown Glucagon Epinephrine Receptors Adenylyl Cyclase cAMP ATP AMP Phosphodiesterase R2C2 R2(cAMP)4 Ca2+ 2C ACTIVE PKA Glycogen synthase Phosphorylase b Kinase Glycogen Phosphorylase Protein Phosphatase activation Protein Phosphatase Inhibitor inhibition

Insulin activates glycogen synthesis

Insulin stimulates glucose transport in muscle and adipose cells by stimulating translocation of glucose transporter 4 (GLUT4) to the plasma membrane.

or inhibition of inhibition is as good as activation Integration of the regulation of glycogen synthesis and breakdown Glucagon Epinephrine Receptors Heart, muscle and other Insulin-R PI3-K PKB/Akt GSK-3 Adenylyl Cyclase Remember that (-1) x (-1)=+1 or inhibition of inhibition is as good as activation cAMP ATP AMP Phosphodiesterase R2C2 R2(cAMP)4 Ca2+ 2C ACTIVE PKA Glycogen synthase Phosphorylase b Kinase Glycogen Phosphorylase Protein Phosphatase activation Protein Phosphatase Inhibitor inhibition Akt inhibits glycogen synthase kinase 3 (GSK-3) which then stops inhibiting the glycogen synthase