Carbohydrate Metabolism

22.1 Digestion of Carbohydrates

• Digestion: The breakdown of food into small molecules.

• The first stage of catabolism is digestion, which involves:

  • Physical grinding, softening, and mixing of food.

  • Enzyme-catalyzed hydrolysis of carbohydrates, proteins, and fats.

• Digestion begins in the mouth, continues in the stomach, and finishes in the small intestine.

• Products of digestion are mostly small molecules, absorbed from the intestinal tract via millions of villi (surface area as big as a football field).

• These molecules are transported into target cells for further breakdown.

• Process of Carbohydrate Digestion:

  • Mouth: Salivary α-amylase breaks down dietary carbohydrates (starch, glycogen, sucrose, and lactose) into polysaccharides, sucrose, lactose, and maltose.

  • Small Intestine: Pancreatic α-amylase, maltase, sucrase, and lactase further break these down into monosaccharides, which are absorbed into the bloodstream.

22.2 Glucose Metabolism: An Overview

• Glucose is the major fuel for the body, especially for the brain, working muscle cells, and red blood cells.

• When glucose enters a cell:

  • It's converted to glucose 6-phosphate.

  • This phosphorylation is highly exergonic.

  • Phosphorylated molecules cannot cross the cell membrane, trapping glucose within the cell.

• Metabolic Pathways of Glucose 6-phosphate:

  • Glycolysis: Conversion of glucose to pyruvate.

  • Gluconeogenesis: Synthesis of glucose from amino acids, pyruvate, and other noncarbohydrates.

  • Glycogenesis: Synthesis of glycogen from glucose.

  • Glycogenolysis: Breakdown of glycogen to glucose.

  • Pentose Phosphate Pathway: Conversion of glucose to five-carbon sugar phosphates.

• When energy is needed, glucose 6-phosphate proceeds through Glycolysis to pyruvate and then to acetyl-coenzyme A, which enters the citric acid cycle.

• When cells are well supplied with glucose, excess glucose is:

  • Converted to glycogen (glycogenesis).

  • Converted to fatty acids.

  • Enters the pentose phosphate pathway, yielding NADPH and ribose 5-phosphate (needed for nucleic acids synthesis).

22.3 Glycolysis

• Glycolysis is a series of 10 enzyme-catalyzed reactions that break down each glucose molecule into two pyruvate molecules, yielding two ATP molecules and two NADH molecules.

• Overall Reaction:

  • Glucose → 2 Pyruvate + 2 ATP + 2 NADH

• Step 1: Phosphorylation

  • Glucose is phosphorylated by hexokinase, requiring an ATP investment, to form glucose 6-phosphate.

  • $Glucose + ATP \rightarrow Glucose-6-phosphate + ADP$$$Glucose + ATP \rightarrow Glucose-6-phosphate + ADP$$

  • Glucose 6-phosphate acts as an allosteric inhibitor of hexokinase.

• Step 2: Isomerization

  • Glucose 6-phosphate is converted to fructose 6-phosphate by glucose 6-phosphate isomerase.

  • $Glucose-6-phosphate \rightleftharpoons Fructose-6-phosphate$$$Glucose-6-phosphate \rightleftharpoons Fructose-6-phosphate$$

• Step 3: Second Energy Investment

  • Fructose 6-phosphate is converted to fructose 1,6-bisphosphate by phosphofructokinase, requiring another ATP investment.

  • $Fructose-6-phosphate + ATP \rightarrow Fructose-1,6-bisphosphate + ADP$$$Fructose-6-phosphate + ATP \rightarrow Fructose-1,6-bisphosphate + ADP$$

  • Phosphofructokinase is activated by ADP and AMP (when energy is low) and inhibited by ATP and citrate (when energy is high).

• Steps 4 and 5: Cleavage and Isomerization

  • Fructose 1,6-bisphosphate is cleaved into dihydroxyacetone phosphate and glyceraldehyde 3-phosphate by aldolase.

  • $Fructose-1,6-bisphosphate \rightleftharpoons Dihydroxyacetone phosphate + D-Glyceraldehyde-3-phosphate$$$Fructose-1,6-bisphosphate \rightleftharpoons Dihydroxyacetone phosphate + D-Glyceraldehyde-3-phosphate$$

  • Only glyceraldehyde 3-phosphate can continue in glycolysis; dihydroxyacetone phosphate is isomerized to glyceraldehyde 3-phosphate by triose phosphate isomerase.

• Steps 6-10: Energy Generation

  • Step 6: Glyceraldehyde 3-phosphate is oxidized to 1,3-bisphosphoglycerate by glyceraldehyde 3-phosphate dehydrogenase, producing NADH.

  • $Glyceraldehyde-3-phosphate + NAD^+ + HOPO_3^{2-} \rightarrow 1,3-Bisphosphoglycerate + NADH + H^+$$$Glyceraldehyde-3-phosphate + NAD^+ + HOPO_3^{2-} \rightarrow 1,3-Bisphosphoglycerate + NADH + H^+$$

  • Step 7: 1,3-bisphosphoglycerate transfers a phosphate group to ADP, generating ATP, catalyzed by phosphoglycerate kinase.

  • $1,3-Bisphosphoglycerate + ADP \rightarrow 3-Phosphoglycerate + ATP$$$1,3-Bisphosphoglycerate + ADP \rightarrow 3-Phosphoglycerate + ATP$$

  • Step 8: 3-phosphoglycerate is isomerized to 2-phosphoglycerate by phosphoglycerate mutase.

  • $3-Phosphoglycerate \rightleftharpoons 2-Phosphoglycerate$$$3-Phosphoglycerate \rightleftharpoons 2-Phosphoglycerate$$

  • Step 9: 2-phosphoglycerate is dehydrated to phosphoenolpyruvate (PEP) by enolase.

  • $2-Phosphoglycerate \rightleftharpoons Phosphoenolpyruvate + H_2O$$$2-Phosphoglycerate \rightleftharpoons Phosphoenolpyruvate + H_2O$$

  • Step 10: PEP transfers a phosphate group to ADP, generating ATP and pyruvate, catalyzed by pyruvate kinase.

  • $Phosphoenolpyruvate + ADP \rightarrow Pyruvate + ATP$$$Phosphoenolpyruvate + ADP \rightarrow Pyruvate + ATP$$

• Overall Results of Glycolysis:

  • Conversion of glucose to two pyruvate molecules.

  • Net production of two ATP molecules.

  • Production of two molecules of NADH from NAD+.

22.4 Entry of Other Sugars into Glycolysis

• Other monosaccharides (fructose, galactose, and mannose) also enter the glycolysis pathway.

• Fructose:

  • In muscle cells, fructose is phosphorylated to fructose 6-phosphate.

  • In liver cells, fructose is converted to glyceraldehyde 3-phosphate.

• Galactose:

  • Galactose (from lactose hydrolysis) is converted to glucose 6-phosphate via a five-step pathway starting with galactokinase.

• Mannose:

  • Mannose (from plant polysaccharides) is converted to fructose 6-phosphate via hexokinase and a multi-step rearrangement.

22.5 The Fate of Pyruvate

• Pyruvate's fate depends on oxygen availability.

  • Under aerobic conditions, pyruvate is converted to acetyl-CoA.

  • Under anaerobic conditions, pyruvate is reduced to lactate.

  • Yeast converts pyruvate to ethanol under anaerobic conditions.

• Aerobic Oxidation of Pyruvate to Acetyl-CoA:

  • Pyruvate is transported across the mitochondrial membranes.

  • In the mitochondrial matrix, the pyruvate dehydrogenase complex converts pyruvate to acetyl-CoA.

• Anaerobic Reduction to Lactate:

  • Under aerobic conditions, NADH is reoxidized during electron transport.

  • Under anaerobic conditions, NADH accumulates, and pyruvate is reduced to lactate, reoxidizing NADH to NAD+.

• Alcoholic Fermentation:

  • Yeast converts pyruvate to ethanol and carbon dioxide under anaerobic conditions.

  • This process is used in producing alcoholic beverages and bread.

22.6 Energy Output in Complete Glucose Catabolism

• Total energy output from glucose oxidation is the sum of:

  • Glycolysis

  • Conversion of pyruvate to acetyl-CoA

  • Citric acid cycle

  • Electron transport and oxidative phosphorylation

• Net Result of Catabolism of One Glucose Molecule:

  • $$Glucose + 2NAD^+ + 2HOPO3^{2-} + 2ADP \rightarrow 2Pyruvate + 2NADH + 2ATP + 2H2O + 2H^+$$

  • $2Pyruvate + 2NAD^+ + 2HSCoA \rightarrow 2Acetyl-CoA + 2CO_2 + 2NADH + 2H^+$$$2Pyruvate + 2NAD^+ + 2HSCoA \rightarrow 2Acetyl-CoA + 2CO_2 + 2NADH + 2H^+$$

  • $$2Acetyl-CoA + 6NAD^+ + 2FAD + 2ADP + 2HOPO3^{2-} + 4H2O \rightarrow 2HSCoA + 6NADH + 6H^+ + 2FADH2 + 2ATP + 4CO2$$

  • $$Glucose + 10NAD^+ + 2FAD + 2H2O + 4ADP + 4HOPO3^{2-} \rightarrow 10NADH + 10H^+ + 2FADH2 + 4ATP + 6CO2$$

• Four ATP molecules are produced directly per glucose molecule.

• The remainder are generated via electron transport and oxidative phosphorylation.

• Complete catabolism of 1 glucose molecule produces 38 ATP molecules (assuming 3 ATP/NADH and 2 ATP/FADH2).

22.7 Regulation of Glucose Metabolism and Metabolism During Stress

• Stable blood glucose concentration is vital (normal range: 65-100 mg/dL).

  • Hypoglycemia: Low blood glucose (weakness, confusion, coma).

  • Hyperglycemia: High blood glucose (increased urine flow, coma).

• Hormonal Regulation:

  • Insulin: Released when blood glucose rises; decreases blood glucose by signaling cells to take in glucose, speeds up Glycolysis, increases glycogen synthesis.

  • Glucagon: Released when blood glucose drops; increases blood glucose by stimulating glycogen breakdown and gluconeogenesis.

• Metabolic Response to Starvation:

  • Declining blood glucose leads to glycogen release.

  • As glycogen is exhausted, protein breakdown increases.

  • Lipid catabolism is mobilized, leading to acetyl-CoA accumulation.

  • Acetyl-CoA is converted to ketone bodies.

  • Brain can use ketone bodies for up to 50% of its ATP needs.

  • After about 40 days, metabolism stabilizes using about 25 g protein and 180 g fat per day.

22.9 Metabolism in Diabetes Mellitus

• Diabetes Mellitus:

  • Type I (Juvenile-Onset): Pancreatic cells fail to produce enough insulin.

  • Type II (Adult-Onset): Insulin is present but fails to promote glucose passage across cell membranes (insulin resistance).

  • Metabolic Syndrome (Pre-diabetic): Elevated fasting blood glucose levels and impaired glucose response.

• Symptoms of Diabetes (Type I):

  • Excessive thirst, frequent urination, high glucose in urine and blood, wasting of the body.

• Type II Diabetes:

  • Cell membrane receptors fail to recognize insulin.

  • Treatment involves drugs, diet modification, and exercise.

• Type I Diabetes:

  • Autoimmune disease where the immune system destroys pancreatic beta cells.

  • Treatment: insulin injections.

• Complications of Diabetes:

  • Cataracts, blood vessel lesions, gangrene.

• Ketoacidosis:

  • Build-up of acidic ketones due to uncontrolled diabetes.

  • Can lead to coma, reversible with insulin.

• Hypoglycemia (Insulin Shock):

  • Due to insulin overdose or failure to eat.

  • Can cause nerve damage or death if untreated.

• Diagnosis and Monitoring:

  • Frequent urination, excessive thirst, rapid weight loss (Type I).

  • Random blood glucose > 200 mg/dL.

  • Fasting blood glucose > 140 mg/dL.

  • Sustained blood glucose > 200 mg/dL after glucose challenge.

  • Daily blood glucose monitoring.

22.8 Glycogen Metabolism: Glycogenesis and Glycogenolysis

• Glycogen: Storage form of glucose in animals; branched polymer of glucose.

• Glycogenesis (Glycogen Synthesis): Occurs when glucose concentrations are high.

  • Step 1: Glucose 6-phosphate is isomerized to glucose 1-phosphate by phosphoglucomutase.

  • Step 2: Pyrophosphorylase attaches glucose 1-phosphate to uridine triphosphate (UTP), producing UDP-glucose.

  • $Glucose-1-phosphate + UTP \rightarrow UDP-Glucose + PPi$$$Glucose-1-phosphate + UTP \rightarrow UDP-Glucose + PPi$$

  • Step 3: Glycogen synthase adds UDP-glucose to a glycogen chain, lengthening the chain and freeing UDP.

  • $$(Glucose)n + UDP-Glucose \rightarrow (Glucose){n+1} + UDP$$

• Glycogenolysis (Glycogen Breakdown): Breakdown of glycogen to free glucose.

  • Step 1: Glycogen phosphorylase hydrolyzes α-1,4 glycosidic bonds and phosphorylates glucose units, yielding glucose 1-phosphate.

  • $$(Glucose)n + HOPO3^{2-} \rightarrow (Glucose)_{n-1} + Glucose-1-phosphate$$

  • Step 2a (Muscle Cells): Phosphoglucomutase isomerizes glucose 1-phosphate to glucose 6-phosphate, which enters glycolysis.

  • Step 2b (Liver Cells): Glucose 6-phosphatase hydrolyzes glucose 6-phosphate to glucose.

  • $$Glucose-6-phosphate + H2O \rightarrow Glucose + HOPO3^{2-}$$

22.10 The Biochemistry of Running

• Epinephrine readies the body for action.

• Initial ATP is used up quickly.

• Creatine phosphate provides additional ATP.

• After 30-60 seconds, creatine phosphate is depleted, and glucose from glycogenolysis becomes the chief energy source.

• During maximum exertion, oxygen is limited, and pyruvate is converted to lactate.

• Avoiding muscle exhaustion in a long race involves running just under the anaerobic threshold.

22.9 Gluconeogenesis: Glucose Synthesis from Noncarbohydrates

• Gluconeogenesis synthesizes glucose from noncarbohydrates.

• Cori Cycle: Converts lactate into pyruvate, the substrate for gluconeogenesis.

  • Lactate is produced in red blood cells and muscle cells during activity.

  • Lactate is converted to pyruvate in the liver, which is then used to synthesize glucose.

  • The new glucose is returned to the muscles.

• Steps of Gluconeogenesis:

  • Step 1: Pyruvate is converted to oxaloacetate by pyruvate carboxylase in mitochondria.

  • $$Pyruvate + ATP + HCO3^- \rightarrow Oxaloacetate + ADP + HOPO3^{2-} + H^+$$

  • Oxaloacetate is reduced to malate, transported to the cytosol, and reconverted to oxaloacetate.

  • Step 2: Phosphoenolpyruvate carboxykinase adds a phosphate group and rearranges oxaloacetate to produce phosphoenolpyruvate.

  • $Oxaloacetate + GTP \rightarrow Phosphoenolpyruvate + GDP + CO_2$$$Oxaloacetate + GTP \rightarrow Phosphoenolpyruvate + GDP + CO_2$$

  • The next reactions (5 steps) are reversible, using the same enzymes as in glycolysis.

  • Step 8: Fructose 1,6-bisphosphate is converted to fructose 6-phosphate by fructose 1,6-bisphosphatase.

  • $$Fructose-1,6-bisphosphate + H2O \rightarrow Fructose-6-phosphate + HOPO3^{2-}$$

  • The next reaction converts fructose 6-phosphate to glucose 6-phosphate.

  • The final reaction is the hydrolysis of glucose 6-phosphate to glucose by glucose 6-phosphatase.

  • $$Glucose-6-phosphate + H2O \rightarrow Glucose + HOPO3^{2-}$$

• Glycerol is converted to dihydroxyacetone phosphate and enters the pathway at step 7.

• Carbon atoms from certain amino acids enter gluconeogenesis as pyruvate or oxaloacetate.