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Carbohydrate Metabolism and Glycolysis

Core Metabolism: Carbohydrate Metabolism

  • Focusing on carbohydrate metabolism, particularly glycolysis and gluconeogenesis.
  • Amino acid catabolism connects with these pathways, with some amino acids breaking down into intermediates or acting as substrates.
  • Emphasis on a deeper look into the reactions of core metabolism compared to the overview of individual amino acid pathways.

Overview of Carbohydrate Catabolism

  • Stage One: Polysaccharides broken down into simple sugars, with glucose as the model sugar.
  • Other sugars consumed in the diet also feed into these pathways.
  • Glycolysis: Represented as a series of reactions generating energy.
  • Anaerobic Fermentation: Occurs when stage three of catabolism can't function, making glycolysis a major energy-yielding pathway.
  • Glycogenesis: The reciprocal pathway of glycolysis, with many reactions simply reversed.
  • Stage Three: Similar regardless of the starting energy-yielding nutrient.

Further Topics

  • Ruminant fermentation.
  • Storage polysaccharides, particularly glycogen.
  • Anaerobic metabolism/fermentation.
  • Secondary pathways in carbohydrate metabolism.

Stage One of Catabolism: Breakdown into Simple Sugars

  • Amylases from saliva and pancreas break down carbohydrates into simple sugars.
  • Glucose is the model sugar, but many others exist.

Absorption Across Gastrointestinal Epithelium

  • Transport across the epithelial apical membrane occurs against the concentration gradient via co-transport with sodium.
  • Sodium-potassium pump establishes sodium gradients.
  • Glucose moves with its concentration gradient through the basal surface via passive transport.
  • Both active and passive transport are facilitated by carrier proteins.
  • Carrier proteins change conformation upon binding to glucose to facilitate transport across the membrane.

Glycolysis: A Central Pathway

  • Glycolysis is one of the potential fates of glucose once inside cells.
  • The first step in glycolysis is a key junction point for other pathways like glycogen synthesis.
  • 10 steps seem complex, but it can be broken down.

Three Phases of Glycolysis

  • Steps 1-3: Inputting energy (2 ATP molecules) to form fructose 1,6-bisphosphate, creating bilateral symmetry.
  • Steps 4-5: Cleavage of the six-carbon sugar into two three-carbon sugars.
  • Steps 6-10: Harvesting energy, releasing 4 ATP molecules and 2 NADH molecules. Net release of energy.
  • Goes from a six-carbon sugar to two three-carbon pyruvate molecules.

Glycolysis Reactions

  • Step 1: Glucose to glucose-6-phosphate via hexokinase, using 1 ATP.
    • Irreversible and key regulatory step.
    • Glucose-6-phosphate locks glucose in the cell and is a branch point for other pathways.
  • Step 2: Glucose-6-phosphate to fructose-6-phosphate via phosphoglucose isomerase (bond rearrangement).
    • Reversible reaction.
  • Step 3: Fructose-6-phosphate to fructose-1,6-bisphosphate via phosphofructokinase, using 1 ATP.
    • Irreversible and key regulatory step.
  • Step 4: Fructose-1,6-bisphosphate is cleaved into dihydroxyacetone phosphate and glyceraldehyde-3-phosphate.
    • Reversible reaction.
  • Step 5: Dihydroxyacetone phosphate converted to glyceraldehyde-3-phosphate via isomerase.
  • Steps 6-10: Energy harvesting, leading to the release of ATP.
  • Reversible reactions except for steps 1, 3, and 10, the key regulatory steps.

Entry Points and Branching

  • Glycolysis serves as a point of entry for other molecules and a branching point for biosynthesis.

Summary of Glycolysis

  • Net products: 2 molecules of pyruvate, 2 ATP, and 2 NADH.
  • Other sugars feed into glycolysis at different stages.

Regulation of Glycolysis

  • Key Regulatory Enzymes: Hexokinase, phosphofructokinase, and pyruvate kinase (steps 1, 3, and 10).
  • Feedback Inhibition:
    • Hexokinase inhibited by glucose-6-phosphate.
    • Phosphofructokinase inhibited by ATP and citrate; stimulated by fructose-6-phosphate.
    • Pyruvate kinase inhibited by ATP and alanine.
  • Low ATP promotes glycolysis; high ATP inhibits it.

Gluconeogenesis: Synthesis of Glucose

  • Synthesis of glucose from non-carbohydrate precursors.
  • Important for maintaining blood glucose concentration due to glucose dependency of the brain and other tissues.
  • Glycogen stores last only about a day.
  • Gluconeogenesis, along with glycolysis, regulates blood glucose concentration.

Gluconeogenesis Process

  • Reverse of glycolysis, primarily from the bottom up.
  • Same intermediates, but different enzymes at key regulatory steps (equivalent to steps 1, 3, and 10 of glycolysis).
  • An extra step: pyruvate to oxaloacetate.
  • Substrates include pyruvate, some amino acids, and glycerol.

Similarities and Differences Between Glycolysis and Gluconeogenesis

  • Central pathways of metabolism.
  • Seven reversible reactions are the same.
  • Three irreversible steps are different, with different enzymes.
  • Tissue specificity can differ.

Distribution of Metabolic Work

  • Example: Glycolysis in skeletal muscle during exercise, while gluconeogenesis occurs in the liver to replenish blood glucose.

Futile Cycles

  • Energy disparity between glycolysis and gluconeogenesis leads to energy loss as heat.
  • Used in specific cells under specific circumstances, like waking from hibernation or warming up flight muscles in insects.

Regulatory Steps in Gluconeogenesis

  • Different enzymes catalyze the key regulatory steps: glucose-6-phosphatase, fructose-1,6-bisphosphatase, phosphoenolpyruvate carboxykinase, and pyruvate carboxylase.

Reciprocal Regulation

  • Glycolysis and gluconeogenesis, as well as glycogen biosynthesis and glycogen degradation, are reciprocally regulated.
  • Only one pathway can occur in a cell at any one time.

Secondary Pathways in Carbohydrate Metabolism: Anaerobic Fermentation

  • Under normal conditions, pyruvate is transported to the mitochondria, oxidized to acetyl CoA, and enters the citric acid cycle.
  • When molecular oxygen is limited (e.g., during exercise), the electron transport chain downregulates, and pyruvate enters a different pathway in the cytoplasm.
  • Pyruvate is converted to lactate.
  • Anaerobic fermentation regenerates NAD^+, allowing glycolysis to continue.
  • Glycolysis becomes the major ATP-yielding pathway.

Lactate and Its Implications

  • Lactate can be distributed via circulation to other cells.
  • Liver cells can take up lactate and convert it back to pyruvate for gluconeogenesis.
  • Excessive lactate buildup can change pH and lead to clinical syndromes like exertional rhabdomyolysis.

Anaerobic Fermentation in Other Organisms

  • Yeast ferments pyruvate to ethanol.
  • Other fermentation processes produce lactic acid for soy sauce, yogurt, and cheese.

Secondary Pathways: Pentose Phosphate Pathway

  • Two Roles: Generate intermediates and produce ribose phosphate for nucleotide biosynthesis.
  • Produces NADPH, which is involved in biosynthetic pathways.
  • Starts with glucose-6-phosphate.
  • End products are NADPH and ribulose-5-phosphate, which is converted to ribose-5-phosphate.

Sorbitol Pathway

  • Occurs in certain tissues (testes, pancreas, brain, lens of the eye).
  • Formation of fructose from glucose.
  • Becomes important when normal metabolism is disrupted, such as in diabetes mellitus type one.

Disruptions of the Sorbitol Pathway

  • High blood glucose leads to cells trying to get rid of excess glucose.
  • Cells convert excess glucose to sorbitol.
  • In the lens of the eye, excess sorbitol production changes osmotic potential.
  • Proteins precipitate out, forming cataracts.