Cellular Regulation & Carbohydrate Metabolism

Cellular Regulation of Metabolic Pathways

• Metabolic pathway regulation occurs at multiple levels:
  • Reaction rate determined by pH, substrate, product, and cofactor concentrations
  • Regulatory enzymes control metabolic sequences
  • Enzyme synthesis rates are genetically regulated
  • Hormones, neurotransmitters, and nutrient availability signal metabolic state to individual cells

Carbohydrate Metabolism Introduction

• Carbohydrates are polyhydroxy aldehydes or ketones with the formula (CH2O)n
• Can contain phosphate, amino, or sulfate groups
• Classified into four major groups:
  • Monosaccharides (simple sugars): CnH2nOn formula, not hydrolyzed further
    • Subdivided by carbon atom count (trioses, tetroses, pentoses, hexoses)
    • Subdivided by functional groups (aldoses: -CHO, ketoses: -C=O)
  • Disaccharides: Yield two monosaccharides upon hydrolysis (Cn(H2O)n-1 formula)
    • Examples: maltose, lactose, sucrose
  • Oligosaccharides: Yield 3-10 monosaccharide units upon hydrolysis (e.g., maltotriose)
  • Polysaccharides (Glycans): Yield more than 10 monosaccharides upon hydrolysis ((C6H10O5)n formula)
    • Examples: starch, glycogen, cellulose, dextrins

Biomedical Importance of Carbohydrates

• Primary energy source: Glucose is the preferred energy source for most tissues, especially brain cells
• Components of complex lipids and conjugated proteins
• Degradation products can act as "promoters" or "catalysts"
• Certain carbohydrate derivatives are used as drugs (glycosides, antibiotics)
• Lactose is the main sugar in milk, produced by the lactating mammary gland
• Sucrase converts sucrose to glucose and fructose
• Indigestible polysaccharides (e.g., cellulose) are part of dietary fibre, passing through the intestine into the feces

Absorption of Glucose, Fructose, and Galactose

• Only monosaccharides are absorbed by the intestine. Absorption rates:
  • Fastest: galactose
  • Moderate: glucose
  • Slowest: fructose
• Pentoses are absorbed slowly
• Absorption mechanisms:
  • Simple Diffusion: Dependent on concentration gradients between intestinal lumen, mucosal cells, and blood plasma. All monosaccharides likely absorbed passively to some extent.
  • Active Transport:
    • Glucose, fructose, and galactose are absorbed by intestinal epithelial cells
    • Glucose has specific transmembrane protein transporters:
      • Sodium Dependent Glucose Transporter-1 (SGluT-1): Co-transports from lumen to intestinal cell, mediated by Na+:
        • Carrier protein binds Na+ and glucose
        • Specific for glucose, mobile, Na+ dependent, and energy dependent
        • Intestinal transporter: SGluT-1
        • Kidney transporter: SGluT-2
        • SGluT-1 deficiency: glucose-galactose malabsorption
        • SGluT-2 deficiency: congenital renal glycosuria
      • Glucose Transporters (GluT): Uniport system releasing glucose into blood, facilitated diffusion:
        • Multiple GluT molecules (GluT-1 to 14)
        • GluT-2: Operates in intestinal epithelial cells, not Na+ dependent
        • GluT-4: Primarily in muscles and adipose tissue, insulin-regulated, moves between cytoplasm and membrane
        • GluT-1: Primarily in red blood cells and brain, also present in retina, colon, and placenta

Absorption of Other Sugars

• D-fructose and D-mannose likely absorbed by "facilitated transport" (carrier protein required, no energy needed)
• Pentoses and L-isomers of glucose and galactose are absorbed passively by simple diffusion

Factors Influencing Absorption Rate

• State of mucous membrane and contact time:
• Hormones:
  • Thyroid hormones increase hexose absorption
  • Adrenal cortex hormone deficiency decreases hexose absorption (reduced body fluid Na+ concentration)
  • Insulin does not affect glucose absorption
• Vitamins: B-vitamin deficiency reduces hexose absorption
• Inherited enzyme deficiencies (e.g., sucrase, lactase): Interfere with disaccharide hydrolysis and absorption

Utilization of Glucose in the Body

• After absorption into the portal blood, glucose passes through the liver before entering systemic circulation
• Liver functions:
  • Withdrawal of carbohydrates from blood:
    • Uptake of hexoses (galactose, fructose) by liver cells and conversion to glucose
    • Conversion of glucose to glycogen for storage (glycogenesis)
    • Oxidation of glucose for energy production (glycolysis)
    • Glucose used for synthesis of other compounds (e.g., fatty acids, certain amino acids)
  • Release of glucose to the blood:
    • Formation of blood glucose from hexoses other than glucose (released from liver cells)
    • Conversion of liver glycogen to blood glucose (glycogenolysis)
    • Formation of blood glucose from non-carbohydrate sources (amino acids, pyruvate, lactate, glycerol, propionyl CoA) (gluconeogenesis)

Utilization of Glucose:

• Oxidation:
  • Energy provision: Oxidation of glucose or glycogen to pyruvate and lactate via the EM pathway (glycolysis) occurs in all tissues.
  • HMP Shunt (Pentose Phosphate Pathway): Alternative glucose oxidation pathway:
    • Not for energy production
    • Provides NADPH for reductive synthesis and pentoses for nucleic acid synthesis
    • Active in specific tissues, not all
  • Uronic Acid Pathway: Alternative glucose oxidation pathway
    • Produces D-glucuronic acid for mucopolysaccharide synthesis and conjugation reactions
• Storage: Excess glucose is converted to glycogen in various tissues (glycogenesis), mainly the liver and skeletal muscle, for future use
• Conversion to Fats: Excess glucose is converted to fatty acids and stored as "triacylglycerol" (TG) in fat depots (lipogenesis)
• Conversion to Other Carbohydrates: Small amounts of glucose are used directly or indirectly in the synthesis of other carbohydrates or derivatives:
  • Ribose and deoxyribose formation
  • Fructose formation from glucose
  • Mannose, fucose, glucosamine, neuraminic acid, galactose, D-glucuronic acid
• Conversion to Amino Acids:

Carbohydrate Metabolism (2): Glycolysis

• Definition: Oxidation of glucose or glycogen to pyruvate and lactate, also called the EM pathway (Embden-Meyerhof pathway)
• Occurs in all cells of the body
• Erythrocytes and nervous tissue rely primarily on glycolysis for energy
• Takes place in the cytosol
• Two phases:
  • Aerobic Phase (with oxygen): Series of ten reactions where oxygen is required to reoxidize NADH formed during the oxidation of glyceraldehyde-3-phosphate. Prepares for oxidative phosphorylation of pyruvate to acetyl CoA, a key fuel for the citric acid cycle.
  • Anaerobic Phase (without oxygen): Glucose converted to pyruvate, which is reduced by NADH to form lactate. Called anaerobic because it occurs without oxygen. Allows ATP production in tissues without mitochondria (e.g., red blood cells) or those oxygen-deprived. Anaerobic glycolysis occurs regardless of oxygen presence.
    • In erythrocytes, glycolysis always ends with pyruvate and lactate.
    • Vigorous skeletal muscle contraction creates relative anaerobiosis, leading to lactic acid production.
    • Oxamate, a lactate dehydrogenase (LDH) inhibitor, competitively inhibits LDH and prevents NADH reoxidation.

Biomedical Importance of Glycolysis

• Energy provision:
• Skeletal muscle: Provides ATP even in the absence of oxygen, enabling muscle survival during anoxic episodes
  • Insulin activates key glycolytic enzymes, favoring glycolysis
  • Glucagon and glucocorticoids inhibit glycolysis and favor gluconeogenesis
• Heart muscle: Adapted for aerobic performance, has relatively low glycolytic activity and poor survival under ischemic conditions
• Cancer therapy: Fast-growing cancer cells have very high glycolysis rates, producing more pyruvate than the TCA cycle can handle. This leads to excessive lactic acid production and local lactic acidosis.
• Hemolytic anemia: Inherited enzyme deficiencies in glycolytic pathway enzymes (e.g., hexokinase, pyruvate kinase) can cause hemolytic anemia.

Explore the intricacies of cellular regulation in metabolic pathways and delve into carbohydrate metabolism. This quiz covers key concepts such as regulatory enzymes, genetic regulation, and classifications of carbohydrates. Test your knowledge on how various factors influence metabolic processes.