CARBOHYDRATE METABOLISM (DIGESTION) The main reaction of carbohydrate digestion to monosaccharides is hydrolysis:

CARBOHYDRATE METABOLISM (continued) Carbohydrates: account for 45-55% of daily energy needs in the typical American diet. are digested into glucose, fructose, and galactose, which are absorbed into the bloodstream through the lining of the small intestine and transported to the liver. In the liver, fructose and galactose are rapidly converted to glucose or compounds that are metabolized by the same pathway as glucose.

Glucose Metabolism Overview Glycogen Polysaccharide Energy Storage Glycogenesis High glucose present, β cells in pancreas realease insulin Glycogenolysis Muscles need energy or fear, anger conditions or absence of glucose Glucose Ribose RNA Gluconeogensis During starvation  breakdown of proteins from muscle cells Glycolysis 10 step process Pyruvate Energy

BLOOD GLUCOSE LEVELS Blood glucose levels are: also known as blood sugar levels. measured after a fast of 8-12 hours. highest about 1 hour after a carbohydrate-containing meal. returns to normal after 2-2½ hours. regulated by the liver. Hypoglycemia is a blood sugar level below normal fasting level. Hyperglycemia is a blood sugar level above normal level.

BLOOD GLUCOSE LEVELS (continued) The renal threshold is: a blood sugar level above 180 mg/100 mL. the blood sugar level at which the sugar not completely reabsorbed by the kidneys. exceeded when glucose is excreted in the urine, a condition called glucosuria. Prolonged hyperglycemia at glucosuric levels: is considered serious. means something is wrong with the body’s normal ability to control blood sugar level.

BLOOD GLUCOSE LEVELS (continued) The liver is the key organ in regulating the blood glucose levels. It responds to increase in blood glucose after a meal by removing glucose from bloodstream. The removed glucose is converted to glycogen or triglycerides. When blood glucose levels are low, glycogen is converted to glucose.

GLYCOLYSIS Glucose (C6) is catabolically oxidized through a many step process to pyruvate (C3). In addition to the two molecules of pyruvate, two molecules of ATP, two molecules of NADH, four molecules of H+, and two molecules of H2O are produced. Glycolysis occurs in the cellular cytoplasm. Net reaction for glycolysis:

GLYCOLYSIS (continued)

GLYCOLYSIS (continued)

GLYCOLYSIS (continued) Fructose enters glycolysis as dihydroxyacetone phosphate and glyceraldehyde-3-phosphate. Galactose enters glycolysis as glucose-6-phosphate.

GLYCOLYSIS – REGULATION Several steps of the glycolysis pathway are regulated: Glucose-6-phosphate competitively inhibits hexokinase (feedback inhibition). The allosteric enzyme phosphofructokinase is inhibited by ATP and citrate and activated by ADP and AMP. The allosteric enzyme pyruvate kinase is inhibited by ATP. As glycolysis occurs, so does the citric acid cycle and electron transport chain which produce ATP. If the ATP level is low, then AMP and ADP levels are high.

GLYCOLYSIS – REGULATION (continued)

THE FATES OF PYRUVATE After glycolysis, pyruvate can be: oxidized to acetyl CoA (aerobic conditions). reduced to lactate (anaerobic conditions). reduced to ethanol (anaerobic conditions for some prokaryotic organisms). Note: All processes must regenerate NAD+ from NADH so glycolysis can continue.

THE FATES OF PYRUVATE (continued)

PYRUVATE OXIDATION TO ACETYL CoA Pyruvate oxidation to acetyl CoA occurs in the mitochondria. Most of the acetyl CoA will be completely oxidized to CO2 in the citric acid cycle. Some acetyl CoA will serve as starting material for fatty acid biosynthesis. NAD+ is regenerated when NADH transfers its electrons to O2 in the electron transport chain.

PYRUVATE REDUCTION TO LACTATE Pyruvate reduction to lactate occurs in cells after strenuous or long-term muscle activity because the cellular supply of oxygen is not adequate for the reoxidation of NADH to NAD+. Under anaerobic conditions, animals and some microorganism can obtain limited energy through lactate fermentation.

PYRUVATE REDUCTION TO ETHANOL Under anaerobic conditions, some microorganisms can obtain limited energy through glycolysis and the two step conversion of pyruvate to ethanol. Overall equation: Step-wise equations:

THE CITRIC ACID CYCLE The citric acid cycle: has other names, including: the tricarboxylic acid cycle. the Krebs cycle. is the principle process for generating the reduced coenzymes NADH and FADH2. is the source of intermediates for biosynthesis. occurs within the matrix of the mitochondrion. includes eight reactions.

THE CITRIC ACID CYCLE (continued) Pyruvate oxidized to acetyl CoA can enter the citric acid cycle where it will be further oxidized to two molecules of CO2, producing one molecule of GTP and the reduced forms of three molecules of NAD+ (NADH) and one molecule of FAD (FADH2) which can then enter the electron transport chain to produce ATP. The overall reaction is:

THE CITRIC ACID CYCLE (continued)

THE CITRIC ACID CYCLE (continued)

THE CITRIC ACID CYCLE (continued)

CITRIC ACID CYCLE – REGULATION There are three main points of regulating citric acid cycle activity. Citrate synthetase is an allosteric enzyme for the first step of the cycle is inhibited by ATP and NADH and activated by ADP. Isocitrate dehydrogenase is an allosteric enzyme for the third step of the cycle is inhibited by NADH and activated by ADP. a-Ketoglutarate dehydrogenase complex is a group of allosteric enzymes for the fourth step of the cycle is inhibited by succinyl CoA, NADH, and ATP. The rate of citric acid cycle is reduced when cellular ATP levels are high. The rate of citric acid cycle is increased when ATP supplies are low and ADP levels are high.

CITRIC ACID CYCLE – REGULATION (continued)

THE ELECTRON TRANSPORT CHAIN NADH and FADH2 are produced by the citric acid cycle. They enter the electron transport chain where they can be used to supply hydrogen ions and electrons to reduce oxygen to water. Net equation: The electron transport chain occurs in a series of reactions. 4H+ + 4e− + O2 → 2H2O

THE ELECTRON TRANSPORT CHAIN (continued) The electron transport chain is found in the inner membrane of the mitochondria and involves iron-containing enzymes (cytochromes). Generated NAD+ and FADH enter citric acid cycle again Electron carriers are lined up in increasing electron affinity

THE ELECTRON TRANSPORT CHAIN (continued) As electrons are transported along the electron transport chain, a significant amount of free energy is released (52.6 kcal/mol). Some free energy is conserved in oxidative phosphorylation (production of ATP from ADP and Pi). Approx. 25% - 34% of energy is conserved

OXIDATIVE PHOSPHORYLATION: CHEMIOSMOTIC HYPOTHESIS The chemiosmotic hypothesis states that the electron transport chain pumps H+ across the inner mitochondrial membrane, H+ then flows back across the membrane, causing the formation of ATP by F1-ATPase. Oxidative phosphorylation conserves approximately 34% of the energy released from the electron transport chain for each mole of NADH. Oxidative phosphorylation conserves approximately 25% of the energy released from the electron transport chain for each mole of FADH2.

OXIDATIVE PHOSPHORYLATION: CHEMIOSMOTIC HYPOTHESIS

OXIDATIVE PHOSPHORYLATION FROM ELECTRON TRANSPORT The conversion of NADH to NAD+ generates 2.5 ATP from ADP during oxidative phosphorylation. The conversion of FADH2 to FAD generates 1.5 ATP from ADP during oxidative phosphorylation. The energy yield for the entire catabolic pathway (citric acid cycle, electron transport chain, and oxidative phosphorylation combined):

THE COMPLETE OXIDATION OF GLUCOSE NADH produced in cytoplasm does not pass through the mitochondrial membrane to the site of the electron transport chain. Brain and muscle NADH employ a transport mechanism that passes electrons from cytoplasm NADH through the membrane to FAD molecules inside mitochondria. Cytoplasmic NADH generates only 1.5 molecules of ATP. Liver, heart, and kidney cytoplasmic NADH have a more efficient shuttle that results in one molecule mitochondrial NADH (and 2.5 molecules ATP) for every cytoplasmic NADH.

THE COMPLETE OXIDATION OF GLUCOSE (continued) Free energy available in glucose: Free energy stored in the synthesis of ATP: Free energy from the complete oxidation of glucose:

THE COMPLETE OXIDATION OF GLUCOSE (continued) The efficiency of the complete oxidation of glucose: Living cells can capture 34% of the released free energy and make it available to do biochemical work. Automobile engines make available 20-30% of the energy actually released by burning gasoline.

THE COMPLETE OXIDATION OF GLUCOSE (continued)

GLYCOGEN METABOLISM – SYNTHESIS The synthesis of glycogen from glucose (glycogenesis) involves UTP. Glycogen metabolism can occur in all cells, but is an especially important function of liver and muscle cells. Glycogen is mainly stored in liver and muscle tissue. The liver can store 110 g glycogen. The muscles can store 245 g glycogen.

GLYCOGEN METABOLISM – BREAKDOWN During glycogenolysis, glycogen can be broken down to glucose monomers via its a(1→4) and a(1→6) linkages. Glycogenolysis occurs in the liver, kidney, and intestinal cells, but not in the muscle cells. Glucose 6-phosphate can then be catabolized by the glycolysis pathway. (glucose)n + Pi → (glucose)n−1 + glucose 1-phosphate glycogen glycogen with one fewer glucose unit glucose 1-phosphate ⇆ glucose 6-phosphate glucose 6-phosphate + H2O → glucose + Pi

GLYCOGEN METABOLISM – BREAKDOWN (continued) Muscle cells: cannot form free glucose from glycogen. can carry out the first two steps of glycogenolysis to produce glucose-6-phosphate, which: is the first intermediate in glycolysis pathway. can be used to produce energy. utilize glycogen only for energy production. The liver: maintains a relatively constant level of blood glucose. has capacity to degrade glycogen all the way to glucose, which is released into the blood during muscular activity and between meals.

GLUCONEOGENESIS Gluconeogenesis: is the synthesis of glucose from noncarbohydrate molecules. synthesizes glucose from lactate, certain amino acids, and glycerol. primarily occurs in the liver (~90%). does not occur much in the kidneys, brain, skeletal muscle, or heart, even though these organs have a high demand for glucose. (lactate, certain amino acids, glycerol) → pyruvate → glucose

THE CORI CYCLE Under anaerobic conditions, lactate produced by muscles is reconverted to glucose by the liver through the Cori Cycle. During active exercise: lactate levels increase in muscle tissue and lactate diffuses into the blood; lactate is taken to liver and converted back to pyruvate; pyruvate is converted to glucose by gluconeogenesis; and glucose enters the blood and returns to the muscles.

THE CORI CYCLE (continued)

SUMMARY OF MAJOR PATHWAYS IN GLUCOSE METABOLISM

HORMONAL CONTROL OF CARBOHYDRATE METABOLISM Three main hormones control carbohydrate metabolism: insulin, which: decreases blood glucose levels. increases absorption of glucose by cells. increases the synthesis of glycogen, fatty acids, and proteins. stimulates glycolysis. glucagon, which: increases blood glucose levels. activates glycogen breakdown in liver. epinephrine, which: stimulates glycogen breakdown in muscle.

HORMONAL CONTROL OF CARBOHYDRATE METABOLISM (continued) Biochemical balance is maintained between the stored glycogen level and the blood sugar level by two opposing hormones, insulin and glucagon.

HORMONAL CONTROL OF CARBOHYDRATE METABOLISM (continued)