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.