We, primates, lost the ability to make ascorbate. Therefore we are genetically deficient.

1. 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).

2. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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 lecture we will begin with regulatory mechanisms involved in glycogen metabolism