MTChem2 Module 7: Carbohydrate Metabolism Notes

Carbohydrate Metabolism

Objectives

  • Demonstrate understanding of the role of biomolecules in the manifestation and maintenance of life.
  • Understand metabolic pathways for converting carbohydrates, fats, and proteins into biochemical substances necessary for life.

Overview

  • Glucose and oxygen are central to carbohydrate metabolism.

Glucose Metabolism

  • Molecules of glucose are the focal point of carbohydrate metabolism.
  • Glucose is either oxidized to yield energy or stored as glycogen.
    • Sufficient Oxygen: Glucose is totally oxidized to CO<em>2CO<em>2 and H</em>2OH</em>2O.
    • Absence of Oxygen: Glucose is partially oxidized to lactic acid.

Digestion & Absorption of Carbohydrates

  • Biochemical process: Food molecules are broken down into simpler chemical units via hydrolysis for metabolic needs of cells.
  • Begins in the mouth:
    • Salivary α\alpha-amylase catalyzes the hydrolysis of α\alpha-glycosidic linkages.
    • Inactivated by the acidic environment of the stomach.
  • Primary site: Small intestine.
    • Pancreatic α\alpha-amylase secreted.
    • Breaks down polysaccharide chains into shorter segments until maltose and glucose are dominant.
  • Final step: Outer membranes of intestinal mucosal cells.
    • Important disaccharidase enzymes: maltase, sucrase, and lactase.
    • Three major breakdown products: Glucose, Galactose, and Fructose.
    • Protein carriers mediate the passage of monosaccharides through cell membranes.
    • Monosaccharides are transported to the liver, where fructose and galactose are rapidly converted to glucose.

Glycolysis

  • Glucose is converted into 2 molecules of pyruvate (a C3 molecule).
  • Chemical energy in the form of ATP is produced, and NADH is produced.
  • Linear pathway that functions in almost all cells.
  • An oxidation process.
    • Oxidizing Agent: Coenzyme NAD+NAD^+.
  • Anaerobic Pathway.
  • All enzymes needed for Glycolysis are present in the cell cytosol.
  • Two stages:
    • 6-carbon stage.
    • 3-carbon stage.
Six-Carbon Stage (Glycolysis)
  • Energy-consuming stage.
    • Conversion of 2 ATP molecules to 2 ADP molecules is used to transform monosaccharides into monosaccharide phosphates.
    • Intermediates: Glucose or Fructose derivatives.
Step 1: Phosphorylation using ATP: Formation of Glucose-6-Phosphate
  • Begins with phosphorylation of glucose to yield glucose-6-phosphate.
  • Phosphate group is from an ATP molecule.
  • Enzyme: Hexokinase
  • Requires Mg2+Mg^{2+} ion for its activity.
  • Requires energy which is provided by the breakdown of an ATP molecule.
  • Phosphorylation of glucose provides a way of “trapping” glucose within the cell; changes glucose from a neutral molecule to a negatively charged substance.
Step 2: Isomerization: Formation of Fructose-6-Phosphate
  • Glucose-6-phosphate is isomerized to fructose-6-phosphate.
  • Enzyme: Phosphoglucoisomerase.
  • C1 of the glucose is no longer part of the ring structure.
Step 3: Phosphorylation using ATP: Formation of Fructose-1,6-Bisphosphate
  • ATP is the source of the phosphate and energy.
  • Enzyme: Phosphofructokinase.
  • Fructose molecule now contains 2 phosphate groups.
Three-Carbon Stage (Glycolysis)
  • Energy-generating stage.
  • Intermediates:
    • C3-phosphates (2 of which are high-energy species).
    • All phosphorylated derivatives of dihydroxyacetone, glyceraldehyde, glycerate, or pyruvate – derivatives of either Glycerol or Acetone.
  • Loss of phosphate effects the conversion of ADP molecules to ATP molecules.
Step 4: Cleavage: Formation of 2 Triose Phosphates
  • The reacting C6 species is split into 2 C3 (triose) species.
  • 2 trioses being produced are not identical because fructose 1,6 – bisphosphate is unsymmetrical.
  • Products: Dihydroxyacetone phosphate and Glyceraldehyde 3 – phosphate.
  • Enzyme: Aldolase.
Step 5: Isomerization: Formation of Glyceraldehyde-3-Phosphate
  • Glyceraldehyde 3 – Phosphate is a glycolysis intermediate.
  • Dihydroxyacetone phosphate is readily converted into Glyceraldehyde 3 – phosphate (Isomer).
  • Enzyme: Triosephosphate isomerase.
Step 6: Oxidation and Phosphorylation using Pi: Formation of 1,3 – Biphosphoglycerate
  • A phosphate group is added to glyceraldehyde 3 – phosphate to produce 1,3 – biphosphoglycerate.
  • The hydrogen of the aldehyde group becomes part of NADH.
  • The source of the added phosphate is inorganic phosphate (Pi).
  • Enzyme: Glyceraldehyde 3 – Phosphate dehydrogenase.
Step 7: Phosphorylation of ADP: Formation of 3 – Phosphoglycerate
  • The diphosphate species formed is converted back to monophosphate species.
  • ATP producing step.
  • C1 phosphate group of 1,3 – biphosphoglycerate is transferred to an ADP molecule to form the ATP.
  • Enzyme: Phosphoglycerokinase.
  • ATP production involves Substrate – level Phosphorylation - ATP is produced from ADP through direct transfer of a high-energy phosphoryl group from a reaction substrate to ADP.
Step 8: Isomerization: Formation of 2 – Phosphoglycerate
  • Phosphate group of 3 – phosphoglycerate is moved from carbon 3 to carbon 2.
  • Enzyme: Phosphoglyceromutase.
Step 9: Dehydration: Formation of Phosphoenolpyruvate
  • Alcohol dehydration reaction.
  • Result is another compound containing a high – energy phosphate group.
  • Enzyme: Enolase.
  • Requires Mg2+Mg^{2+}.
Step 10: Phosphorylation of ADP: Formation of Pyruvate
  • Substrate level phosphorylation again occurs.
  • Phosphoenolpyruvate transfer its high – energy phosphate group to an ADP molecule to produce ATP and pyruvate.
  • Enzyme: Pyruvate kinase.
  • Requires both Mg2+Mg^{2+} and K+K^+.
  • 2 ATP molecules are produced.

Entry of Galactose and Fructose into Glycolysis

  • Both Galactose and Fructose are converted, in the liver, to intermediates that enter into the glycolysis pathway.
  • Galactose begins with its conversion to Glucose 1 – Phosphate, then converted to glucose 6 – phosphate.
  • Fructose involves phosphorylation by ATP to produce fructose 1 – phosphate, which then splits into 2 trioses:
    • Glyceraldehyde: must be phosphorylated by ATP to glyceraldehyde 3 – phosphate before it enters the pathway.
    • Dihydroxyacetone phosphate: enters glycolysis directly.

Regulation of Glycolysis

  • Step 1: Conversion of Glucose to Glucose 6 – phosphate by the enzyme hexokinase – inhibited by glucose 6 – phosphate.
  • Step 3: Fructose 6 – phosphate is converted to fructose 1,6 – biphosphate by phosphofructokinase – inhibited by high concentrations of ATP and Citrate.
  • Step 10: Conversion of phosphoenolpyruvate to pyruvate by Pyruvate kinase – inhibited by high ATP concentrations.

Fates of Pyruvate

  • Varies with cellular conditions and the nature of the organism.
  • Pyruvate is converted to Acetyl CoA (aerobic), to Lactate and to Ethanol (anaerobic).
Oxidation of Acetyl CoA
  • Aerobic.
  • Pyruvate is oxidized to Acetyl CoA.
  • Involves both Oxidation and Decarboxylation (CO2CO_2 is produced).
  • Requires NAD, CoA – SH, FAD and 2 other coenzymes (lipoic acid and thiamin pyrophosphate).
Lactate Fermentation
  • Anaerobic reduction of pyruvate to lactate.
  • Conversion of NADH to NAD+NAD^+.
  • The lactate is converted back to pyruvate when aerobic conditions are again established in cell.
  • Purpose is to replenish NAD+NAD^+ supplies.
  • Produces 2 pyruvate and 2 lactates.
Ethanol Fermentation
  • Anaerobic.
  • Organisms (e.g., yeast) possess the ability to regenerate NAD through Ethanol.
  • The enzymatic anaerobic conversion of pyruvate to ethanol and CO2CO_2.
    1. Conversion of pyruvate to ethanol (decarboxylation) to produce Acetaldehyde.
    2. Acetaldehyde reduction to produce ethanol.

Terminology

  • -lysis means breakdown
  • -genesis means making
    • Glycolysis: glucose is converted into two molecules of pyruvate.
    • Glycogenesis: excess glucose 6-phosphate is converted into glycogen.
    • Glycogenolysis: breakdown of glycogen into glucose 6-phosphate.
    • Gluconeogenesis: formation of glucose from non-carbohydrate sources.

ATP Production for the Complete Oxidation of Glucose

  • Refer to Table 24.2 for a detailed breakdown of ATP production during glycolysis, oxidation of pyruvate, citric acid cycle, and electron transport chain.
  • Net Production of ATP: +30

Glycogen

  • Branched polymeric form of glucose.
  • Storage form of carbohydrates in humans and animals.
  • Found primarily in liver and muscle tissue.
Functions of Glycogen
  • In the liver: the synthesis and breakdown of glycogen is regulated to maintain blood glucose levels.
  • In muscle: the synthesis and breakdown of glycogen is regulated to meet the energy requirements of muscle cell.
Glycogenesis
  • Synthesis of glycogen from glucose 6-phosphate.
  • Requires 2 ATP molecules.
Steps of Glycogenesis
  1. Isomerization: Formation of glucose 1-phosphate from glucose 6-phosphate with the help of the enzyme phosphoglucomutase.
    • End product: Glucose 1-phosphate.
  2. Activation: Formation of UDP-glucose. The activator is the high energy UTP (uridine triphosphate). A UMP is transferred to glucose 1-phosphate with the help of the enzyme UDP-glucose pyrophosphorylase.
    • End product: UDP-glucose & Two inorganic phosphates.
  3. Linkage to Chain: The glucose unit of UDP-glucose is then attached to the end of a glycogen chain with the help of the enzyme Glycogen synthase.
    • End product: Glycogen & UDP.
      • Where does UDP go? UDP is converted back to UTP which can interact with another glucose 1-phosphate.
Glycogenolysis
  • Synthesis of glucose 6-phosphate from glycogen.
  • Not a reverse of glycogenesis.
  • Does not require UTP or UDP.
Steps of Glycogenolysis
  1. Phosphorolysis: The enzyme glycogen phosphorylase effects the removal of an end glucose unit from a glycogen molecule as glucose 1-phosphate.
    • End product: Glucose 1-phosphate & Glycogen.
  2. Isomerization: The enzyme phosphoglucomutase catalyzes the conversion of glucose 1-phosphate to glucose 6-phosphate.
    • End product: Glucose 6-phosphate
Notes:
  • In muscle & brain cells, an immediate need for energy is the stimulus that initiates glycogenolysis. Here, glucose 6-phosphate is converted into pyruvate.
  • In the liver, low blood glucose level will initiate glycogenolysis. Before entering the bloodstream, glucose 6-phosphate is converted to glucose.
Glycogenesis vs. Glycogenolysis
  • Refer to the diagram comparing the two processes, including enzymes and cofactors involved.

Gluconeogenesis

  • Formation of glucose from non-carbohydrate sources.
  • Location: Liver (mostly) & kidney.
  • Why? Meets the body’s need for glucose when there is insufficient carbohydrate from diet or glycogen reserves.
  • A supply of glucose is necessary for the nervous system.
  • Glycogen stores in muscle & liver are depleted within 12-18 hours of fasting.
Non-Carbohydrate Sources:
  • Lactate
  • Glycerol
  • Amino acids
How does Gluconeogenesis Happen?
  • The last step of glycolysis is the first step of gluconeogenesis.
  • Gluconeogenesis and glycolysis are not exact opposites.
  • 12 compounds are involved in gluconeogenesis and only 11 in glycolysis
  • Refer to the diagram outlining the specific steps and enzymes involved in gluconeogenesis.
Lactate and Glycerol as Precursors
  • Review the diagrams illustrating how lactate and glycerol enter the gluconeogenesis pathway.

Cori Cycle

  • Process in which glucose is converted to lactate in muscle tissue.
  • The lactate produced during strenuous exercise diffuses from muscle into the blood, where it is transported to the liver.
  • Enzyme lactate dehydrogenase converts lactate back to pyruvate.
  • The fate of pyruvate, is then converted back to glucose through GLUCONEOGENESIS.
  • Refer to the diagram for a visual representation of the Cori Cycle.

Pentose Phosphate Pathway

  • Glucose is degraded to produce:
    1. Synthesis of the coenzyme NADPH needed in lipid biosynthesis.
    2. Production of ribose 5-phosphate needed for the synthesis of nucleic acids and many coenzymes.
Two Stages:
  1. Oxidative Stage
  2. Non-Oxidative Stage
Oxidative Stage
  • Occurs first.
  • Conversion of glucose 6-phosphate to ribulose 5-phosphate.
  • Net equation:
    • Glucose 6-phosphate + 2NADP+ + H2O → ribulose 5-phosphate + CO2 + 2NADPH + 2H+
Non-Oxidative Stage
  • Ribulose 5-phosphate (a ketose) is isomerized to ribose 5-phosphate (an aldose).
Functions of Pentose Phosphate Pathway and its Intermediates
  1. When ATP demand is high, the pathway continues to its end products, which enter glycolysis.
  2. When NADPH demand is high, intermediates are recycled to glucose 6-phosphate, & further NADPH is produced.
  3. When ribose 5-phosphate is high, for nucleic acid and coenzyme production, most nonoxidative stage is nonfunctional, leaving ribose 5-phosphate as a major product.

Hormonal Control of Carbohydrate Metabolism

  • Hormones Involved:
    • Insulin
    • Glucagon
    • Epinephrine
Insulin
  • Produced by beta cells of the pancreas
  • Promotes uptake and utilization of glucose by cells
  • Lowers blood glucose levels
Glucagon
  • Produced in the pancreas by alpha cells
  • Released when blood glucose levels are low
  • Increases blood glucose concentration by speeding up the conversion of glycogen to glucose and gluconeogenesis.
Epinephrine
  • Also called adrenaline
  • Released by adrenal glands in response to anger, fear, or excitement.
  • Similar function to glucagon
  • Stimulation of glycogenolysis

B Vitamins and Carbohydrate Metabolism

  • Involved in glycolysis, gluconeogenesis, glycogenesis, glycogenolysis, & conversion of pyruvate to acetyl CoA and Lactate
  • What are these B vitamins?
    • NIACIN (NAD+,NADHNAD^+, NADH)
    • RIBOFLAVIN (FAD)
    • THIAMIN (TPP)
    • PANTOTHENIC ACID (CoA)
  • Two newly involved B vitamins
    • BIOTIN
    • Vitamin B6
Two Newly Involved B Vitamins
  • Biotin involvement occurs in the enzyme pyruvate carboxylase
  • Vitamin B6 in the form of PLP in glycogenosis

Summary of Carbohydrate Metabolism

  • Review the comprehensive diagram summarizing the interconnected pathways of carbohydrate metabolism and the roles of various B vitamins.

Lipid Metabolism

Overview

  • Triacylglycerol (TAG) molecules are the main focal point of lipid metabolism.
  • TAG is hydrolyzed with the assistance of the enzyme lipase.
    • Complete hydrolysis: 3 free fatty acids and glycerol
    • Incomplete hydrolysis: 2 free fatty acids and monoacylglycerol

Digestion and Absorption of Lipids

  • The major site of Lipid catabolism happens in the stomach:
    • Metabolism type: Minor change (10% of TAG): Chemical change
    • Metabolic agent/process: Hydrolysis by gastric lipase
    • Metabolite: Free fatty acids and glycerol/monoacylglycerol
  • Chyme triggers small intestine to release the hormone cholecystokinin
  • Gallbladder releases bile
  • Bile emulsifies TAG globules
  • Soluble TAG globules are hydrolyzed by pancreatic lipases
  • Products of hydrolysis: Free fatty acids and monoacylglycerol/glycerol
  • Bile will help the hydrolyzed products to combine into spherical droplets called micelle
  • Micelle will go to the intestinal wall
  • Free fatty acids and monoacylglycerol goes back to TAG
  • TAG combines with membrane lipids (phospholipid and cholesterol) and water-soluble proteins
  • Chylomicron is formed
  • Chylomicron will enter the bloodstream via the lymphatic system
  • TAG is released from the chylomicron upon reaching the target tissue
  • Lipoprotein lipases will hydrolyze TAG into free fatty acids and glycerol
  • Some products of hydrolysis will be broken down into acetylCoA for energy
  • Some products of hydrolysis will go back as TAG to be stored
Steps of Lipid Digestion and Transport
  1. Mouth: Saliva-no effect on digestion
  2. Stomach:
    • Fat droplets in chyme
    • Some monoacylglycerols
    • Churning action-produces small fat droplets (chyme)
    • HCI-denatures protein
    • Pepsin-hydrolyzes peptide bonds
  3. Small Intestine:
    • Bile solubilizes "droplets"
    • Pancreatic lipases-produce monoacylglycerols, which form fatty acid micelles
    • Trypsin, Chymotrypsin, Carboxypeptidase, Aminopeptidase hydrolyze peptide bonds
  4. Intestinal Active transport into Lining
  5. Lymphatic System: Monoacylglycerols in micelles, Micelles are repackaged into TAGS, which form chylomicrons
  6. Bloodstream: TAGS are hydrolyzed to free fatty acids

Hydrolysis of Triacylglycerol Schematic

  • Refer to the diagram illustrating the hydrolysis of triacylglycerol into glycerol and free fatty acids.

Glycerol Catabolism

  • Refer to the diagram illustrating the conversion of Glycerol to Dihydroxyacetone phosphate:
    • Glycerol + ATP + NAD+NAD^+ → Dihydroxyacetone phosphate + ADP+ NADH + H+H^+

Fatty Acid Catabolism by β-Oxidation

  • Refer to the diagram to review the oxidation steps:
    • Alkane → alkene → secondary alcohol → ketone + Chain cleavage
Steps of β-Oxidation
  1. Oxidation (dehydrogenation): Hydrogen atoms are removed from the α\alpha and β carbons, creating a double bond between these two carbon atoms. FAD is the oxidizing agent, and a FADH2 molecule is a product.
  2. Hydration: A molecule of water is added across the trans double bond, producing a secondary alcohol at the β-carbon position
  3. Oxidation (dehydrogenation): The β-hydroxy group is oxidized to a ketone functional group with NAD+NAD^+ serving as the oxidizing agent
  4. Chain Cleavage: The fatty acid chain is broken between the α\alpha and β carbons by reaction with a coenzyme A molecule. The result is an acetyl CoA molecule and a new acyl CoA molecule that is shorter by two carbon atoms than its predecessor.

Protein Metabolism

Dietary Protein

  • Review:
    • Mouth: Saliva has no effect on digestion
    • Stomach:
      • Fat droplets in chyme
      • Some monoacylglycerols
      • Churning action-produces small fat droplets (chyme)
      • HCI-denatures protein
      • Pepsin-hydrolyzes peptide bonds
    • Small Intestine:
      • Bile solubilizes "droplets"
      • Pancreatic lipases-produce monoacylglycerols, which form fatty acid micelles
      • Trypsin, Chymotrypsin, Carboxypeptidase, Aminopeptidase hydrolyze peptide bonds
    • Intestinal Active transport into Lining

Amino Acid Degradation

  • Carbon portion goes to:
    • Triacylglycerols via fatty acid biosynthesis
    • Glucose via gluconeogenesis
    • ATP via citric acid cycle
    • Ketone bodies via ketogenesis
  • Nitrogen portion:
    • Elimination via urea
    • Biosynthesis of nonessential amino acids
    • Biosynthesis of nonprotein nitrogen-containing compounds

Amino Group Catabolism Schematic

  • Refer to Diagram.

Carbon Skeleton Catabolism Schematic

  • Refer to the diagram illustrating the different fates of amino acid carbon skeletons, including their conversion to pyruvate, acetyl CoA, ketone bodies, oxaloacetate, fumarate, α-ketoglutarate, and succinyl CoA.