Carbohydrate Metabolism Lecture 1

Carbohydrate Metabolism (Lecture 1)

• The lecture is about carbohydrate structure, function, digestion, and storage.
• The lecturer is John Barrow, [email protected].

Aims of Carbohydrate Lectures 1 & 2

• Review carbohydrate structures and functions
• Review carbohydrate digestion and absorption
• Review the initial fate of glucose when it enters the cells of the body
• Review glycolysis and substrate-level phosphorylation
• Review gluconeogenesis and anabolic pathways

Carbohydrates

• Highly oxidizable
• Sugar and starch molecules have "high energy" H-atom associated electrons.
• Carbohydrates are a major energy source.
• Carbohydrate catabolism is the major metabolic process for many organisms
• Function to store potential energy (starch in plants, glycogen in animals)
• Have structural and protective functions (in plant cell walls, extra cellular matrices of animal cells).
• Contribute to cell-cell communication (e.g., ABO blood groups)

Monosaccharides

• Three important hexoses (6-carbon sugars) in human biochemistry: glucose, galactose, fructose.

Disaccharides

• Formed from monomers linked by glycosidic bonds.
• Different anomers are mirror images of each other (left- and right-handed forms).
• Carbon #1 on the glucose residue is the anomeric carbon).
• It stabilizes the structure of glucose.
• It is the only residue that can be oxidized.
• Important disaccharides in human biochemistry are maltose, lactose, and sucrose.

Maltose

• Breakdown product of starch, found in beer.
• Anomeric C-1 is available for oxidation, so maltose is a reducing sugar.

Lactose

• Main sugar in milk.
• Formed from a glycosidic bond between galactose and glucose.
• Anomeric carbon on the glucose is available for oxidation (reducing sugar).

Sucrose

• Common table sugar
• Only made by plants
• Approximately 25% of dietary carbohydrate, sweetener in processed foods, non-reducing sugar.

Polysaccharides

• Polymers of medium to high molecular weight
• Distinguished by the identity of their recurring monosaccharide units, their length, bond types, and branching patterns.
• Homopolysaccharides: single monomeric species
• Heteropolysaccharides: two or more monomeric species.

Starch

• Contains two types of glucose polymer: amylose (20-25% of starch), amylopectin (75-80% of starch).
• Has many non-reducing ends.
• Amylose and amylopectin form alpha-helices.

Glycogen

• Animal cells use a similar strategy as plants to store glucose (polymer of glucose).
• Glucose (α1→4) linked sub-units with (1→6) branches every 8 to 12 residues: makes glycogen extensively branched, compared to starch.
• Primarily found in liver and skeletal muscle.

Why Store Glucose in Polymers?

• Compactness (amylopectin and glycogen have many non-reducing ends).
• Readily synthesized and degraded, speeding up formation and breakdown.
• Not osmotically active in solution.

Glycoproteins

• Proteins that have carbohydrates covalently attached
• Most extracellular eukaryotic proteins have associated carbohydrate molecules
• Carbohydrate content by mass varies between 1-80%
• Increases solubility, influences protein folding, protects from degradation, acts as communicator.

Glycosaminoglycans (GAGs)

• Unbranched polymers made from repeating units of hexuronic acid and amino-sugar.
• Alternate through the chains.
• Include Chondroitin 6-sulfate, Keratan sulfate, Heparin, and Hyaluronate, Dermatan sulfate.

Proteoglycans

• Formed from GAGs covalently attached to proteins.
• Macromolecules found on cell surfaces or in extracellular matrix.
• Part of many connective tissues in the body.

Glycoproteins

• Similar in structure and function to proteoglycans; found on plasma membranes, extracellular matrix, and within cells of secretory system.
• Some cytoplasmic and nuclear proteins are also glycoproteins.

Cellulose and Hemicellulose

• Cannot be digested by gut.
• Increase faecal bulk and decrease transit time.
• Broken down by gut bacteria (Yielding CH₄ and H₂).

Disaccharidase Deficiencies

• Genetic or resulting from severe intestinal infection, gut lining inflammation/damage/removal, or drugs).
• Characterized by abdominal distension and cramps.
• Diagnosis requires enzyme tests of intestinal secretions (checking for lactase, maltase, or sucrase activity).

Lactose Intolerance

• Most common disaccharide deficiency (loss of lactase activity).
• Western whites generally retain lactase activity into adulthood.
• Ingestion of milk may cause gas buildup, irritation, osmotic diarrhea if lactase is absent or low.
• Symptomatic relief can be achieved by avoidance of milk products or supplementation with lactase.

Fate of absorbed Glucose

• Glucose diffuses through intestinal epithelium cells, into portal blood and to liver.
• immediately phosphorylated into glucose-6-phosphate, trapped by absence of GLUT transporters.
• Liver and other tissues enzymes trap Glucose-6-phosphate: Glucokinase and Hexokinase.

Glucokinase/Hexokinase

• Hexokinase’s low Km means it can grab Glc even at low concentrations
• Glucokinase’s high Vmax means it can phosphorylate Glc quickly, trapping it in the liver
• Blood glucose levels impact the efficiency of each enzyme.

Fates of glucose-6-phosphate (G-6-P)

• The liver metabolizes glucose-6-phosphate
• Other tissues use it for the pentose phosphate pathway or glycolysis.

Glycogen

• 90% in the liver and skeletal muscle.
• In the liver, glycogen is used to maintain blood glucose levels (e.g., after blood glucose falls, glycogen is converted to glucose-6-phosphate, then to glucose).
• In skeletal muscle, glycogen is used as a source of energy (glycogen → glucose-6-phosphate → pyruvate → lactate).

Synthesis of Glycogen (Step 1)

• Glycogen does not form directly from glucose monomers.
• Glycogenin initiates the process by covalently binding UDP-glucose for branching.
• Glycogen synthase takes over subsequently forming chains of approximately 8 glucose residues.

Synthesis of Glycogen (Step 2)

• Glycogen synthase chains are re-attached by glycogen branching enzyme.
• Attached via (α1→6) bonds creating a branch points.

Degradation (Mobilization) of Glycogen

• Glc monomers are one-by-one removed from glycogen nonreducing ends.
• Glycogen-phosphorylase breaks (α1→4) bonds.
• Debranching enzyme removes a set of three glucose residues.
• The set is re-attached to the nonreducing end of another chain.

What happens to all this glycogen?

• Liver: Glucose-6-phosphate (G-6-P), then Glucose.
• Skeletal muscles: Glucose-6-phosphate → pyruvate → lactate

Von Gierke's Disease

• Liver (and kidney, intestine) glucose 6-phosphatase deficiency.
• Symptoms include high liver glycogen, low blood glucose, and high lactate.
• Treatment includes regular carbohydrate feeding (often, every 3 to 4 hours)

McArdle's Disease

• Skeletal muscle glycogen phosphorylase deficiency
• Symptoms include high muscle glycogen, weakness and cramps after exercise, and no increased blood glucose after exercise.
• Treatment involves avoiding strenuous activity, and using brief periods of anaerobic activity to be followed by aerobic exercise.