Let me try to summarize key points: I.

Carbohydrate Structures: There is vocabulary that should already be familiar from undergraduate school. You should know the difference between a hexose (glucose) and a pentose (ribose). You should know that carbohydrates can be aldehydes (glucose) or ketones (fructose). You should understand that glucose, galactose and mannose are all stereoisomers of the same chemical structure. However, you will not be asked to draw or even name specific structures. With respect to carbohydrate structures, you should recognize a glycosidic bond and be able to name it (e.g. glucose alpha 1,4 glucose) because these bonds are the key to structures. You should also know the composition of the major disaccharides (maltose, lactose and fructose). You should understand the differences in plant starches (amylose, which is linear, amylopectin, which is branched) as well as the branched structures in glycogen (the human polyglucose). The major glycosaminoglycans (GAGSs) (hyaluronate, chondroitin sulfate, keratan sulfate, dermatan sulfate, and heparin) are sufficiently important that you should be able to recognize what they are when they come up. You do not need to know any specific structures, but you should know their general structure, which is that they are long, with repeating disaccharide units, linear structures with considerable negative charge. Reactions between carbohydrates and other carbohydrates and between carbohydrates and proteins: Non-enzymatic glycosylation of proteins (glycation) can occur by simple chemical reaction of protein side chain and carbohydrate. You should realize that enzymatic formation of di- or polysaccharides requires activation of sugar that is accomplished by formation of sugar nucleotides (e.g. UDP-glucose). The enzymatic formation of polysaccharides occurs one sugar at a time using an enzyme of the correct specificity and the appropriate substrates. Glycoprotein structure: Except for O-GlcNac, the sugars of glycoproteins are outside (lumen of the e.r., outside of the plasma membrane, secreted from) the cell. O-linked structures are largely built on ser/thr residues one sugar at a time. N-linked sugars (to asparagine) are initially added in a 14 sugar block (do not learn the structure) constructed on dolichol phosphate lipid. Initial transfer is usually cotranslational in the endoplasmic reticulum. Both N- and Ocarbohydrate structures are processed as the glycoprotein traffics from endoplasmic reticulum through the Golgi apparatus. Glycoprotein Breakdown: The lysosome contains many enzymes that can degrade glycoprotein sugars. When these enzymes fail, you get lysosomal storage disease (mucopolysacchridoses) that can be single enzyme defects (e.g. Pompe disease) or multienzyme defects (I cell disease from a failure of the mannose-6-phosphate trafficking system). The diseases are generally characterized by cellular inclusions Glycoprotein Function: Proteoglycans (name this way because of their high [up to >90%] sugar content) are important structural components. They are part of the matrix that makes up tissue structure and are found places like cartilage. They are hydrated so they can provide cushioning and also because of their charge can bind things like growth factors and chemokines/cytokines.

What You Should Know (Schaffhausen).

More generally glycoproteins serve in biological recognition. Without being able to name structures in detail, you should be aware that carbohydrate structures underlie the differences in ABO blood groups, contribute to the ability of viruses (flu) or bacteria (H. pylori) to infect, and mediate cell-cell contacts (leucocyte adhesion deficiency disease II). Inside the cell, mannose-6-phosphate mediates trafficking of enzymes to the lysosomal compartment. II. Absorption: You should know basic caloric requirements and the effect of infections, trauma and burns to increase them. You should be aware that fat (~9 Cal/gram) has a higher content that carbohydrate or protein (~4 Cal/gram). The glycemic index summarizes the effect of a particular food on blood glucose. Digestion: You should be able to name the major enzymes (!-amylase, maltase, isomaltase aka dextrinase, sucrase and lactase) and their specificities digesting polysaccharides and oligo- and disaccharides in saliva and in the intestine. You understand why cellulose, a polyglucose like amylase, is not a useful source of food (it has beta linkages our enzymes cannot cleave). You should understand how bacterial metabolism in the colon leads to clinical pathology that results from digestive enzyme (e.g. lactase) deficiency. Transport: You should be able to distinguish between the three forms of transport (diffusion [uncommon], facilitated diffusion and active transport [sodium linked for glucose and galactose]). You should know which processes apply to intestinal absorption of different sugars (glucose/galactose active, fructose facilitated) and release from intestinal cells (facilitated). You need to know that glucose is transported by facilitated diffusion into most cells. It is important to know that the Glut4 transporter is regulated by insulin leading to increased uptake in muscle, fat and white cells. (NOT liver). This helps control blood glucose concentration. You should be aware that carbohydrate and other substances enter the portal circulation with the liver as an initial destination. Glucose Metabolism: You should be able to describe how blood glucose levels change after eating and the effect of insulin on those levels as observed in type I diabetics (high to start, higher in response to food, slower to come down). You should be able to describe the hexokinase reaction producing glucose 6-phosphate. You should the differences between hexokinases and glucokinase. Hexokinases are ubiquitous while glucokinase is found in liver and pancreatic " cells. Hexokinases, which have a high affinity for glucose, are inhibited by glucose-6 phosphate product so that glucose uptake is limited in most cells to when it is now needed. Glucokinase has a high Km so that its activity becomes important when blood glucose concentrations are high. In liver this helps take up glucose to limit the circulating concentration. In the pancreatic " cell, glucokinase leads to increased production of ATP that acts on the potassium channel leading to insulin release. In Mature Onset Diabetes in the Young (MODY) a genetic deficiency in glucokinase (or a transcription factor) leads to a defect in the insulin response. III-VIII. Pathways In general you need to understand where pathways occur. This means appreciating tissue differences (glycolysis is everywhere, but gluconeogenesis occurs in liver and kidney, while glycogen metabolism is primarily liver and muscle, red cells have no mitochondria and hence no TCA cycle). You should also know intracellular location (glycolysis, pentose phosphate shunt
What You Should Know (Schaffhausen). 2

and glycogen metabolism are cytoplasmic; the TCA cycle inside the mitochondrion; gluconeogenesis starts in the mitochondrion, continues in the cytoplasm and ends producing glucose in the endoplasmic reticulum. III. Glycolysis: conditions: You should understand the basic equations of glycolysis under aerobic

GLUCOSE + 2 Pi + 2 ADP + 2NAD+ # 2 PYRUVATE + 2ATP + 2NADH + 2H+ + 2H2O You should understand that the conversion of pyruvate to lactate is a way of maintaining an NAD+ supply under anaerobic conditions: 2 PYRUVATE + 2NADH + 2H+ # 2 LACTATE + 2NAD+ Thus: Glucose + 2 ADP + 2 Pi # 2 Lactate + 2 ATP + 2 H2O under anaerobic conditions. This means that only 2 molecules of ATP come directly from glycolysis for each glucose. You should know why glycolysis is especially important in red cells and in muscle. Red blood cells lack mitochondria and use only glycolysis for energy production. They produce lactate, which is transported to the liver for resynthesis to glucose. A deficiency in pyruvate kinase is the most common glycolytic disorder in red cells, causing persistent anemia. In hard exercise, the rate of glycolysis in skeletal muscle increases greatly and more pyruvate is produced than can be oxidized in mitochondria. Much pyruvate is then converted to lactate, regenerating NAD+ in the cytoplasm, and the working muscle gets a large additional amount of ATP from glycolysis. In muscle, mutations in phosphofructokinase 1 (Taruis disease) causes exercise intolerance. I expect that for the purposes of the boards you will need to know every step entire pathway. For our purposes, you need to know the reactions that use ATP (hexokinase, phosphofructokinase), make ATP (phosphoglycerate kinase, pyruvate kinase), and the reactions that are points of regulation (hexokinase, phosphofructokinase 1 and pyruvate kinase). You should know that the glyceraldehyde 3-phosphate dehydrogenase reaction uses phosphate and NAD+. Glycolysis can be inhibited by lack of phosphate (e.g. in hereditary fructose intolerance). The requirement for NAD+ means that under anaerobic conditions, NADH product needs to be recycled back to NAD+ by the conversion of pyruvate to lactate. NAD+ is a coenzyme designed to support biological oxidation (think ethanol to acetaldehyde). We get its precursor as the vitamin niacin. Deficiencies give rise to pellagra, and are characterized by dermatitis, diarrhea and dementia. You should know which glycolytic intermediates give rise to other useful metabolites. Glucose-6-phosphate can be used for biosynthesis of glycogen, polysaccharides, glycoproteins, pentoses, or NADPH. Fructose-6-phosphate and glyceraldehyde-3-phosphate can be produced from, or converted to pentoses such as ribose. Dihydroxyacetone-phosphate connects glycolysis to fat and phospholipid metabolism. 2,3 bisphosphoglycerate to regulate hemoglobin can be made from 1,3 bisphosphoglycerate. Glycolytic intermediates can be used to produce amino acids (3-phosphoglycerate/serine, pyruvate/alanine. Pyruvate can be oxidized to acetyl CoA,
What You Should Know (Schaffhausen). 3

which is used for synthesis of fatty acids, cholesterol, steroid hormones and for oxidative metabolism. Three reactions of the glycolytic pathway (hexokinase, phosphofructokinase 1 and pyruvate kinase) that are far from equilibrium are sites of regulation. Hexokinase is inhibited by glucose-6-phosphate product; glucokinase activity regulates insulin secretion and this is defective in MODY. Pyruvate kinase in liver can be inhibited by phosphorylation in response to glucagon, the hormone of the starved state, but the muscle form is not. Phosphofructokinase 1 is the major regulated enzyme. It is inhibited by ATP (and citrate) and activated by AMP. Fructose-2,6 bisphosphate is a key small molecule regulator that activates PFK 1. This molecule is synthesized by phosphofructokinase 2. PFK 2 synthesizes F2,6BP when the enzyme is unphosphorylated. This increases glycolysis. When phosphorylated PFK2 is a phosphatase hydrolyzing F2,6BP. This decreases glycolysis. Phosphorylation of PFK 2 is promoted by glucagon, the hormone of starvation, and dephosphorylation is promoted by insulin. You should know a few of the toxic chemicals that target glycolysis (2deoxyglucose/hexokinase, arsenate/glyceraldehyde-3-phosphate dehydrogenase, fluoride ion/enolase ). IV. Other Sugars and Alcohol: You should be aware of how other sugars are passed into the glycolytic pathways (mannose to fructose-6-phosphate, fructose to glyceraldehyde 3-phosphate and dihydroxyacetone phosphate, galactose to glucose 6-phosphate via glucose 1-phosphate. Fructose can be made from or converted to sorbitol by sorbitol dehydrogenase. Glucose can also be converted to sorbitol by aldol reductase. These interchanges can be good with sorbitol as food in sperm, or bad as sorbitol can cause osmotic issues in the eye. Fructokinase converts fructose to fructose 1-phosphate. A fructokinase deficiency should not be serious although fructose will be found in the urine. Fructose 1-P can be cleaved to DHAP and glyceraldehyde by aldolase B (liver). A deficiency in aldolase B can be quite serious. Tissue damage results from tying up phosphate and blocking both glycolysis and oxidative phosphorylation. Fructose-1-phosphate also inhibits glycogen breakdown. Galactose is initially phosphorylated by galactokinase to galactose-1-phosphate. A galactokinase deficiency should not be serious although cataracts can begin to form because of the conversion of galactose to galactitol by aldol reductase. G1P is converted by UDP-galactose by the enzyme Gal-1-P-uridylyl transferase using UDP-glucose as a substrate. A deficiency in the transferase give rise to classic galactosemia. This is a serious problem, characterized by cataracts, hepatomegaly, cirrhosis, renal failure, cataracts, and brain damage. UDP-galactose is converted to UDP-glucose by epimerase. UDP-glucose in turn can be hydrolyzed to glucose-1phosphate than can be converted to glucose-6-phosphate by phosphoglucomutase. UDP-glucose can be converted to UDP-glucuronic acid. This can be used to make glycoproteins. It can also be conjugated to drug or bile targets to make them more soluble for excretion. You should be able to describe where and how ethanol is absorbed (~20% stomach, 80% intestine. Factors that affect how blood alcohol levels change after drinking include sex (young
What You Should Know (Schaffhausen). 4

women higher and faster than young men), fatter people faster than skinny, alcoholics can drink more than none alcoholics, alleles of alcohol dehydrogenase (ADH)). You should know that alcohol is converted to acetaldehyde by ADH. Acetaldehyde is converted to acetic acid by aldehyde dehydrogenase 2 (ALDH2). You should be aware that polymorphisms of ALDH2 affect how long the hangover will last. The Asian populations have a higher percentage of low activity allele. The metabolism of alcohol converts NAD+ to NADH. This changes the NADH/NAD+ ratio. As a result, gluconeogenesis is inhibited. The increase in NADH/NAD+ ratio also favors synthesis of triglycerides. Habitual drinkers activate a cytochrome p450 based system that also converts alcohol to acetaldehyde. As a result they clear alcohol faster than others. Alcoholic may forget to eat properly. If gluconeogenesis is also impaired they may have a problem with hypoglycemia. They may also be malnourished, with a thiamine deficiency that leads to Wernicke-Korsakoff syndrome, presenting as mental confusion, eye muscle paralysis and gait problems. The acetic acid product of ALDH2 can be used to make acetyl CoA, but it also produces acidosis. Both methanol and ethylene glycol are metabolized by the same enzymes that metabolize ethanol, giving rise to toxic products. V. TCA Cycle: Pyruvate connects glycolysis to the TCA cycle by acting as a substrate for pyruvate dehydrogenase to produce acetyl CoA. Acetyl CoA, in turn is condensed with oxaloacetate to produce citrate. The TCA cycle occurs in the mitochondrion so pyruvate is transported inside. You should be aware that some substances (acyl-CoA compounds, oxaloacetate, NAD+, NADH) cannot cross the inner mitochondrial membrane, while transport systems exist for many others (e.g. pyruvate, citrate, malate, aspartate, ATP, ADP, Pi). You should know the pyruvate dehydrogenase reaction: Pyruvate + HSCoA + NAD+ # Acetyl CoA + CO2 + NADH + H+

You should be able to name the other coenzymes (thiamine, lipoate, and FAD) that participate in this reaction. It would be good to be aware that thiamine (vitamin B1) participates in decarboxylations and two carbon transfers, that lipoate (a target of arsenic poisoning or organic mercurials) is a disulfide that is used to generate activated acetate to be added to CoA, that FAD (derived from riboflavin, vitamin B2) is used to regenerate lipoate so the reaction can continue and that NAD+ regenerates FAD. Besides Wernicke-Korsakoff, thiamine deficiency produces beri beri (either dry, characterized by peripheral neuropathy, or wet, with cardiac issues such as cardiomegaly and cardiomyopathy.) You should understand the regulatory mechanisms that control this reaction (inhibition by product, control by an associated kinase [stimulated by ATP, inhibited by substrates or ADP] that phosphorylates the enzyme to an inactive form and an associated phosphatase [stimulated by Ca++ and insulin] that activates the enzyme. A partial deficiency of pyruvate dehydrogenase activity leads to metabolic acidosis from the buildup of pyruvate (and of lactate and alanine, which are in equilibrium with pyruvate). This enzyme deficiency is associated with neurological disorders, particularly cerebellar dysfunction.

What You Should Know (Schaffhausen).

The TCA cycle aka Citric Acid Cycle aka Krebs Cycle:
Acetyl CoA + 3NAD+ + FAD + GDP + Pi +2H2O # 2CO2 + 3NADH + FADH2 + GTP + 2H+ + CoA

You may have memorized the TCA cycle for MCATs. I expect that for the purposes of the boards you will need to know every step of the entire pathway. Can I Keep Selling Sex For Money Officer is an often used memory device (citrate, isocitrate, !-ketoglutarate, succinylCoA, succinate, fumarate malate, oxaloacetate). For present purposes you will want to know which steps generate CO2 (isocitrate dehydrogenase, !-ketoglutarate dehydrogenase), which steps generate reduced coenzymes (isocitrate dehydrogenase, !-ketoglutarate dehydrogenase, succinate dehydrogenase, and malate dehydrogenase (notice the names). ! Ketoglutarate dehydrogenase is an arsenic target because it uses lipoate. You should know that succinyl-CoA synthetase produces GTP directly. Since NADH can yield up to 3 ATP/NADH and FADH2 can yield up to 2 ATP/FADH2, and GTP can be converted to ATP, this means a single molecule of glucose can yield up to 38 ATP. The actual number is somewhat smaller. Clearly much more ATP comes from the TCA cycle than from glycolysis. The TCA cycle as a source of biosynthetic precursors: Citrate is exported to cytoplasm for fatty acid synthesis. Succinyl-CoA is a precursor for heme biosynthesis. Malate and aspartate derived from oxaloacetate are exported to the cytoplasm to make glucose. Cycle intermediates provide substrates for amino acid synthesis (or may represent intermediates in degradation of amino acids). Until the lectures later about amino acids, you do not need to know any of these specifics. The rate of the TCA cycle depends on the concentration of intermediates. These are replenished by anaplerotic reactions. Most important is the formation of oxaloacetate from pyruvate, catalyzed by pyruvate carboxylase. In addition to amino acids as mentioned above, malate can be derived from pyruvate. Regulation: You should know that cycle activity is dependent on intermediate concentrations, particularly oxaloacetate. You should be able to deduce the small molecule regulation. The reactions that produce NADH (isocitrate dehydrogenase, !-ketoglutarate dehydrogenase, and malate dehydrogenase) are all inhibited by it. When energy is plentiful, ATP inhibits citrate synthase, isocitrate dehydrogenase and !-ketoglutarate dehydrogenase. ADP, on the other hand, activates citrate synthase and isocitrate dehydrogenase. Calcium, indicative of muscle activity, activates isocitrate dehydrogenase and !-ketoglutarate dehydrogenase. Insulin causes a back up of citrate that can be exported and used to make fatty acids. VI. Gluconeogenesis: Maintaining sufficient blood glucose is a high priority. Failure to do so results in adrenergic (anxiety, palpitation, shakiness, sweat, often cold, pale grey or red face) or neuroglycopenic (headache-confusion, slurred speech, seizures, coma) problems. Gluconeogenesis is carried out in the liver (80-90%) and the kidney (10-20%, more in starvation). In contrast to glycogenolysis, gluconeogenesis can provide glucose for weeks.
What You Should Know (Schaffhausen). 6

Glucose is made from pyruvate, which in turn can be derived from lactate or alanine, or it can be made from glycerol derived from triglycerides. It costs an NADH and 6ATPs to make glucose. The pathway: In many respects it looks like glycolysis in reverse. However the three regulated reactions of glycolysis (hexokinase, phosphofructokinase 1 and pyruvate kinase) are reversed by different enzymes: glucose-6-phosphatase, fructose-1,6-bisphosphatase (FBPase) and pyruvate carboxylase/PEP carboxykinase (PEPCK). Pyruvate, lactate and alanine start at the beginning. Glycerol is converted to dihydroxyacetone phosphate so it enters the gluconeogenic pathway much further down. The pathway starts with pyruvate in the mitochondrion. Pyruvate carboxylase makes oxaloacetate. Biotin is used as the coenzyme; its general role is to activate CO2 for transfer. The mitochondrial membrane is not permeable to oxaloacetate. You should know that it is converted to malate or aspartate to get it to the cytoplasm where it is recovered. PEPCK converts oxaloacetate to phosphoenolpyruvate. The process remains cytoplasmic until glucose 6phophate is formed. G6P is transported to the e.r. for hydrolysis by glucose 6-phosphatase. Glucose and Pi are then transported back to the cytoplasm and glucose can be exported from the cell. Deficiency of either glucose 6-phosphatase or the G6P transporter is a serious problem, (von Gierkes disease). REGULATION: Small molecules regulate pyruvate carboxylase (acetyl-CoA activates) and fructose-1,6-biphosphatase (AMP and fructose-2,6-bisphosphate inhibit, and citrate activates). You should notice that FBPase regulation is inverse that of PFK1 in the other direction. Hormonal regulation is important. PEPCK activity is increased by glucagon and steroids such as cortisol, but antagonized by insulin. By inhibiting pyruvate kinase, glucagon promotes gluconeogenesis. Key hormonal regulation occurs through fructose-2,6-bisphosphate. When phosphorylated in response to glucagon, PFK2 is a phosphatase hydrolyzing F2,6BP. This reduces activation of PFK1 and relieves inhibition of FBPase, stimulating gluconeogenesis. Insulin promotes dephosphorylation of PFK2, promoting fructose-2,6-bisphosphate production that stimulates glycolysis and inhibits gluconeogenesis. TISSUE COOPERATION: Since muscle or red blood cells do not produce glucose, lactate is transported to the liver for gluconeogenesis. The glucose formed this way is exported into the blood and can be reacquired by muscle (or red cells). This is the Cori Cycle. Notice that if anaerobic glycolysis yields 2ATP/ glucose, it costs more energy in liver to make the glucose than you get back out. This is acceptable because you are moving the energy source (glucose) to where it is needed. In muscle, pyruvate can also be converted into the amino acid alanine. Alanine is then transported to the liver, where it is reconverted to pyruvate, giving up its amino group in another transamination reaction. This is the Cahill Cycle. VII. Pentose Phosphate Shunt: You should know that the pentose phosphate shunt takes glucose-6-phosphates and convert them back into glycolytic intermediates, producing three different pentose phosphates (ribulose 5-phosphate, ribose 5-phosphate, and xylulose 5phosphate), other sugars (sedoheptulose 7-phosphate, erythrose 4-phosphate) as well as 2 molecules of NADPH and CO2 along the way. Like glycolysis, it is a cytoplasmic pathway. In the oxidative portion of the pathway glucose 6-phosphate dehydrogenase converts glucose 6What You Should Know (Schaffhausen). 7

phosphate to 6-phosphogluconate producing one NADPH molecule. 6-phosphogluconate is decarboxylated by 6-phosphogluconate dehydrogenase to produce CO2 and a second NADPH molecule and ribulose 5-phosphate. In non-oxidative reactions, ribulose 5-phosphate is converted to ribose 5-phosphate by phosphopentose isomerase or to xylulose 5-phosphate by phosphopentose epimerase. You should know that sugars can then be intercoverted by transketolase, a thiamine containing enzyme, that moves two carbon units or transaldolase that transfers 3-carbon units. (In this way two pentoses can be converted to sedoheptulose 7-phosphate and glyceraldehyde 3-phosphate. Sedoheptulose 7-phosphate and glyceraldehyde 3-phosphate can be converted to erythrose 4-phosphate and fructose 6-phosphate. Erythrose 4-phosphate + xylulose 5-phosphate become glyceraldehyde 3phosphate and fructose 6-phosphate. Dont worry about learning the specific conversions.) Overall, you should know that 3 pentoses are converted to 2 fructose 6-phosphate and one glyceraldehyde 3-phosphate, i.e. glycolytic intermediates. Regulation: Glucose 6-phosphate dehydrogenase controls the rate and is usually functions around 1% of Vmax. If the need for ribose and NADPH is balanced, the shunt operates as described. If ribose, but not NADPH is needed, the enzymes of the non-oxidative parts of the pathway can make it from glycolytic intermediates. If a great deal of NADPH is needed, the glycolytic intermediates can be cycled back to glucose 6-phosphate to start over. NADPH: You should be aware that NADPH differs from NAD+ by an additional phosphate that has nothing to do with the chemistry of the coenzyme. This phosphate provides a handle so that different enzymes can recognize it. NADPH works with the opposite polarity from NAD+, in that it participates in reductions, such as in the production of fatty acids. Because of this the NADPH/NADP ratio is very high, while the NADH/NAD ratio is very low. NADPH provides protection from oxidative damage. Reactive oxygen species (superoxide, hydrogen peroxide and hydroxyl radicals) are all produced as a natural consequence of biology. These can damage proteins, carbohydrates or DNA. Superoxide dismutase converts superoxide to hydrogen peroxide. Peroxides can be inactivated by catalase or by glutathione peroxidase that uses the tripeptide glutathione as a cofactor. Oxidized glutathione is reduced by glutathione reductase. This reaction uses NADPH which is generated by the pentose phosphate shunt. Glucose 6-phosphate dehydrogenase deficiencies arise from many different very common mutations. Disease is marked by Heinz bodies in red cells indicating protein precipitation in red cells, and fragility of those cells resulting in hemolytic anemia marked by decreased red cells, increased reticulocytes, hemoglobin in the blood, elevated bilirubin. Episodes can be triggered by exposure to drugs (including quinine derivatives, antibiotics and pain medications), moth balls and even some foods such as fava beans. VIII. GLYCOGEN: Glycogen is a storage of glucose. You should know that glycogen is a polyglucose structure involving ! 1,4 glycosidic linkages with ! 1,6 branches, and is found in liver and in muscle. While the liver content is higher as a percentage of weight of the tissue, the absolute amount (~100g) is less than that found in muscle (~400g). Unlike fat, the total amount of glycogen that can be stored is limited. Glucose from glycogen found in liver is used to buffer

What You Should Know (Schaffhausen).

blood glucose between meals, while glucose from muscle glycogen is retained there to support exercise, because muscle has no glucose 6-phosphatase to release free glucose. SYNTHESIS: Glycogen is synthesized starting with a primer made on the protein glycogenin. Glycogen synthase uses UDP-glucose to add glucose to the 4 position end of a growing chain. This is the regulated limiting step in glycogen synthesis. Branching enzyme typically transfers a block of 7 residues (5-8) from non-reducing end chain at least 11 long. A new branch must be at least four residues away from an existing one. Glycogen degradation is carried out by phosphorylase, which cleaves a single glucose from the end of the chain and which uses phosphate to produce glucose 1-phosphate. This is the limiting regulated step in breakdown. Phosphorylase cannot cleave branches. Debranching enzyme has two activities: it transfers a 3 glucose piece to the end of a 1,4 chain and it hydrolyzes a 1,6 linkage to produce 1 free glucose. (This means some glucose can be produced without glucose 6-phosphatase.). Regulation: Regulation of glycogen metabolism, in both liver and muscle, operates by controlling the rates of glycogen phosphorylase and glycogen synthase reactions. Glycogen metabolism is regulated by small molecules, ATP, glucose 6-phosphate and glucose can block breakdown, while AMP, Ca++ activate it. Glucose-6-phosphate also promotes activation of glycogen synthase as an allosteric activator. Covalent phosphorylation is a key regulatory mechanism. Phosphorylase is activated by phosphorylation, while glycogen synthase is inhibited. Glucagon, as the hormone of starvation, activates glycogen breakdown and blocks synthesis. It does this by stimulating production of cyclic AMP, a second messenger, that activates protein kinase A (PKA). PKA phosphorylates and inhibits glycogen synthase. PKA phosphorates another kinase (phosphorylase kinase) that phosphorylates, and thereby activates, phosphorylase. Insulin stimulates glycogen synthesis and inhibits glycogen breakdown by promoting dephosphorylation. In muscle, insulin also promotes glycogen synthesis by stimulating GlutT mediated transport. Epinephrine (flight or fright) stimulates breakdown both by cyclicAMP and also, like neuromuscular stimulation, by promoting release of calcium. Calcium activates phosphorylase kinase. Glycogen storage diseases: Type I: Glucose-6-phosphatase deficiency (von Gierke) can arise from either a glucose 6-phosphate defect or a defect in transport of G6P to the e.r.. There is severe fasting hypoglycemia unresponsive to epinephrine or glucagon. This disease primarily affects liver, kidney and intestine. Decreased glycogen mobilization produces hepatomegaly. Decreased gluconeogenesis causes leads to lactic acidosis. There is poor growth Type II: Lysosomal acid maltase, (! 1# 4 glucosidase) deficiency (Pompe) is a lysosomal storage disease arising from lack of (!1#4 acid) glycosidase. The result is cellular inclusions from inability to digest polysaccharide. Type III. Debranching enzyme deficiency (Cori). Abnormal glycogen with limit dextrin type structure (short outer branches). This can present with growth retardation, hepatomegaly and hypoglycemia. It is not as severe as type I. Type IV. Branching enzyme deficiency (Andersen). Abnormal glycogen is formed, with little branching. It is treated as a foreign body with death by the second year.

What You Should Know (Schaffhausen).

Type V. Muscle phosphorylase deficiency (McArdle). Muscle cramps occur during hard exercise. Usually seen in adulthood, there is no rise in lactate after hard exercise. There may be myoglobinuria Type VI. Liver phosphorylase (Hers) or phosphorylase kinase deficiency. A deficiency of liver phosphorylase kinase has the same biochemical consequences as a lack of liver phosphorylase. The consequences are not severe, because glucose can still be supplied by gluconeogenesis. Type VII. Muscle phosphofructokinase deficiency (Tarui) Muscle glycogen content is increased when there is a deficiency of the glycolytic enzyme phosphofructokinase. Similar, but more severe, than type V it results in muscle cramping and exercise intolerance. It can be helped by fructose.

What You Should Know (Schaffhausen).

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