Major Metabolic Pathways

Why This Matters

Understanding metabolic pathways isn't just about memorizing enzyme names—it's about seeing how your body orchestrates an incredibly complex energy economy. These pathways answer fundamental questions you'll encounter throughout Advanced Nutrition: How do cells extract energy from food? Why can the brain use ketones but not fatty acids directly? What happens metabolically during fasting versus the fed state? Every clinical nutrition scenario, from diabetes management to sports nutrition to metabolic disorders, traces back to these core pathways.

You're being tested on your ability to connect pathway function to nutritional states, hormonal regulation, and tissue-specific metabolism. The exam will ask you to predict what happens when a pathway is blocked, why certain tissues prefer specific fuels, and how pathways interconnect during different physiological conditions. Don't just memorize the steps—know where each pathway occurs, what regulates it, and why it matters for human nutrition and health.

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Energy-Producing Pathways: Breaking Down Fuel

These pathways extract energy from macronutrients by systematically oxidizing carbon bonds. The key principle: electrons are harvested from fuel molecules and ultimately transferred to oxygen, with the energy released captured as ATP.

Glycolysis

• Glucose → 2 pyruvate—occurs in the cytoplasm of all cells, producing a net gain of 2 ATP and 2 NADH per glucose molecule
• Anaerobic capability—doesn't require oxygen, making it essential for red blood cells (which lack mitochondria) and during intense exercise
• Rate-limiting enzyme: phosphofructokinase (PFK-1)—inhibited by ATP and citrate, activated by AMP and fructose-2,6-bisphosphate

Citric Acid Cycle (Krebs Cycle)

• Acetyl-CoA oxidation hub—located in the mitochondrial matrix, produces 3 NADH, 1 $FADH_2$, and 1 GTP per turn
• Central metabolic crossroads—accepts carbon skeletons from carbohydrates, fats, and proteins for complete oxidation
• Regulated by energy charge—isocitrate dehydrogenase and α-ketoglutarate dehydrogenase are inhibited by NADH and ATP

Electron Transport Chain and Oxidative Phosphorylation

• ATP powerhouse—generates approximately 30-32 ATP per glucose via the proton gradient across the inner mitochondrial membrane
• $O_2$ as final electron acceptor—explains why we need to breathe; without oxygen, the chain backs up and ATP production halts
• ATP synthase mechanism—protons flow through this enzyme complex, driving the phosphorylation of ADP to ATP (chemiosmotic coupling)

Fatty Acid Oxidation (Beta-oxidation)

• Mitochondrial pathway—breaks fatty acids into 2-carbon acetyl-CoA units, each cycle producing 1 NADH, 1 $FADH_2$, and 1 acetyl-CoA
• High ATP yield—a 16-carbon palmitate generates approximately 106 ATP, making fat the most energy-dense fuel
• Carnitine shuttle required—long-chain fatty acids need carnitine palmitoyltransferase I (CPT-I) to enter mitochondria, a key regulatory point

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Glucose Homeostasis Pathways: Maintaining Blood Sugar

These pathways ensure blood glucose stays within a narrow range regardless of feeding state. The liver acts as the glucose thermostat, storing excess glucose after meals and releasing it during fasting.

Gluconeogenesis

• Makes glucose from non-carbohydrate sources—lactate, glycerol, and glucogenic amino acids are converted to glucose primarily in the liver and kidneys
• Bypasses irreversible glycolytic steps—key enzymes include pyruvate carboxylase, PEPCK, and glucose-6-phosphatase
• Fasting survival mechanism—maintains blood glucose for glucose-dependent tissues (brain, RBCs) when dietary carbohydrate is unavailable

Glycogenesis and Glycogenolysis

• Glycogenesis stores glucose as glycogen—activated by insulin in the fed state, primarily in liver (~100g capacity) and muscle (~400g capacity)
• Glycogenolysis releases glucose—glucagon and epinephrine activate glycogen phosphorylase to mobilize stored glucose
• Tissue-specific function—liver glycogen maintains blood glucose; muscle glycogen fuels local contraction (muscle lacks glucose-6-phosphatase)

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Alternative Fuel Pathways: Adapting to Metabolic Stress

When glucose is scarce or energy demands shift, these pathways provide alternative fuels and metabolic flexibility. This is where nutritional state dramatically influences which pathways dominate.

Ketogenesis

• Produces ketone bodies from excess acetyl-CoA—occurs in liver mitochondria when acetyl-CoA exceeds citric acid cycle capacity
• Three ketone bodies: acetoacetate, β-hydroxybutyrate, acetone—the first two serve as fuel; acetone is exhaled (fruity breath in ketoacidosis)
• Brain's alternative fuel—unlike fatty acids, ketones cross the blood-brain barrier, providing up to 70% of brain energy during prolonged fasting

Pentose Phosphate Pathway

• Parallel to glycolysis in the cytoplasm—generates NADPH for biosynthesis and antioxidant defense, plus ribose-5-phosphate for nucleotides
• Two phases: oxidative and non-oxidative—oxidative phase produces NADPH; non-oxidative phase interconverts sugars based on cellular needs
• Critical for RBC protection—NADPH maintains reduced glutathione; G6PD deficiency causes hemolytic anemia when oxidative stress increases

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Biosynthetic Pathways: Building Cellular Components

These anabolic pathways use energy and precursors to synthesize molecules the body needs. They're typically active in the fed state when energy and substrates are abundant.

Fatty Acid Synthesis

• Cytoplasmic pathway—converts acetyl-CoA into fatty acids using NADPH from the pentose phosphate pathway
• Key enzyme: acetyl-CoA carboxylase (ACC)—produces malonyl-CoA, the committed step; activated by insulin, inhibited by glucagon and AMPK
• Fatty acid synthase complex—adds 2-carbon units to growing chain; primarily produces palmitate (16:0) as the end product

Cholesterol Biosynthesis

• Multi-step pathway in liver cytoplasm and ER—converts acetyl-CoA → mevalonate → squalene → cholesterol
• Rate-limiting enzyme: HMG-CoA reductase—target of statin drugs; inhibited by cholesterol (feedback inhibition) and glucagon
• Essential functions—cell membrane fluidity, precursor for bile acids, vitamin D, and steroid hormones

Purine and Pyrimidine Metabolism

• De novo synthesis vs. salvage pathways—cells can build nucleotides from scratch or recycle bases from nucleic acid breakdown
• Purines (adenine, guanine)—degraded to uric acid in humans; elevated levels cause gout
• Pyrimidines (cytosine, thymine, uracil)—degraded to $CO_2$, $NH_3$, and water; less clinically problematic than purine accumulation

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Nitrogen Handling Pathways: Processing Protein

Amino acid metabolism generates toxic ammonia that must be safely eliminated. The urea cycle is the liver's solution to this nitrogen disposal problem.

Urea Cycle

• Converts toxic ammonia to urea—occurs in liver mitochondria and cytoplasm; urea is water-soluble and excreted by kidneys
• Key enzymes: carbamoyl phosphate synthetase I (CPS I) and arginase—CPS I is the rate-limiting step, activated by N-acetylglutamate
• Links to citric acid cycle—fumarate produced in urea cycle enters TCA cycle (the "bicycle" concept)

Amino Acid Metabolism

• Transamination transfers amino groups—aminotransferases (ALT, AST) shuffle nitrogen between amino acids; elevated in liver damage
• Deamination removes amino groups—releases ammonia for urea synthesis; glutamate dehydrogenase is key
• Metabolic fates vary—amino acids are glucogenic (→ glucose), ketogenic (→ ketones), or both; leucine and lysine are purely ketogenic

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Plant-Based Energy Capture: Photosynthesis

While not a human metabolic pathway, photosynthesis is the ultimate source of the chemical energy in our food. Understanding this pathway completes the picture of biological energy flow.

Photosynthesis (Calvin Cycle and Light Reactions)

• Light reactions capture solar energy—occur in thylakoid membranes, producing ATP and NADPH while splitting water to release $O_2$
• Calvin Cycle fixes carbon—uses ATP and NADPH to convert $CO_2$ into glucose in the chloroplast stroma
• Foundation of food chains—all dietary carbohydrates, fats, and proteins ultimately trace back to photosynthetic carbon fixation

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Quick Reference Table

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Self-Check Questions

1. Which two pathways both produce acetyl-CoA, and how do their contributions differ during fasting versus the fed state?

2. A patient has a deficiency in carnitine palmitoyltransferase I (CPT-I). Which pathway is directly impaired, and what compensatory pathway would you expect to be upregulated?

3. Compare and contrast gluconeogenesis and glycogenolysis: When does each predominate, and why can muscle glycogenolysis not directly contribute to blood glucose?

4. If an FRQ asks you to explain how the body maintains brain function during a 48-hour fast, which three pathways would you discuss and in what sequence?

5. Both fatty acid synthesis and cholesterol biosynthesis require NADPH. Which pathway supplies this NADPH, and what other critical function does this pathway serve?