Metabolic Pathways in Cellular Respiration

Why This Matters

Cellular respiration isn't just a single pathway—it's an integrated network of reactions that demonstrates how cells extract, store, and transfer energy. You're being tested on your understanding of redox chemistry, enzyme regulation, compartmentalization, and energy coupling. The exam expects you to connect these pathways conceptually: why does glycolysis happen in the cytoplasm while the citric acid cycle occurs in the mitochondrial matrix? How do electron carriers link catabolic pathways to ATP synthesis? These are the questions that separate memorization from mastery.

Each pathway in this guide illustrates fundamental biochemical principles: substrate-level vs. oxidative phosphorylation, anabolic vs. catabolic reactions, and metabolic regulation in response to energy status. Don't just memorize the steps—know what concept each pathway demonstrates and how they interconnect. When you can explain why pyruvate must be converted to acetyl-CoA before entering the citric acid cycle, or why NADPH and NADH serve different cellular roles, you're thinking like a biochemist.

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Energy-Extracting Pathways: Breaking Down Fuel

These pathways share a common purpose: oxidizing carbon-based fuels to capture energy in electron carriers (NADH, $FADH_2$) and ATP. The progressive oxidation of carbon from glucose to $CO_2$ releases free energy that drives ATP synthesis.

Glycolysis

• Occurs in the cytoplasm—this ancient pathway requires no oxygen and is conserved across all domains of life
• Net yield of 2 ATP and 2 NADH per glucose via substrate-level phosphorylation; the energy investment phase consumes 2 ATP before the payoff phase generates 4
• Produces two pyruvate molecules—the fate of pyruvate depends on oxygen availability (aerobic → mitochondria; anaerobic → fermentation)

Pyruvate Decarboxylation

• Links glycolysis to the citric acid cycle—this irreversible reaction commits carbon to complete oxidation
• Produces acetyl-CoA, $CO_2$, and NADH in the mitochondrial matrix; the pyruvate dehydrogenase complex catalyzes this oxidative decarboxylation
• Regulated by energy status—high ATP and NADH inhibit the complex, preventing unnecessary fuel oxidation

Citric Acid Cycle (Krebs Cycle)

• Completes glucose oxidation in the mitochondrial matrix, releasing the remaining carbons as $CO_2$
• Yields 3 NADH, 1 $FADH_2$, and 1 GTP per acetyl-CoA; these electron carriers are the primary energy output
• Functions as a metabolic hub—intermediates like $\alpha$-ketoglutarate and oxaloacetate connect to amino acid and biosynthetic pathways

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Oxidative Phosphorylation: Harvesting Electron Energy

The electron transport chain and ATP synthase work together to convert the energy stored in NADH and $FADH_2$ into ATP. The chemiosmotic theory explains how electron flow creates a proton gradient that drives ATP synthesis.

Electron Transport Chain

• Located in the inner mitochondrial membrane—four protein complexes (I-IV) transfer electrons through a series of redox reactions
• Creates a proton gradient by pumping $H^+$ from the matrix to the intermembrane space; this electrochemical gradient stores potential energy
• Oxygen is the final electron acceptor—its high electronegativity drives the entire chain forward, forming $H_2O$

Oxidative Phosphorylation

• Couples electron transport to ATP synthesis—the proton-motive force drives $H^+$ through ATP synthase
• ATP synthase (Complex V) catalyzes $ADP + P_i \rightarrow ATP$ as protons flow down their gradient back into the matrix
• Generates approximately 28-34 ATP per glucose—this accounts for ~90% of ATP from complete glucose oxidation

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Alternative Fuel Pathways: Beyond Glucose

Cells don't rely on glucose alone. These pathways demonstrate metabolic flexibility—the ability to oxidize different fuel sources depending on availability and tissue needs.

Beta-Oxidation of Fatty Acids

• Breaks fatty acids into acetyl-CoA units in the mitochondrial matrix through repeated four-step cycles
• Produces NADH and $FADH_2$ with each cycle—a 16-carbon palmitate yields 106 ATP, far more than glucose
• Primary fuel during fasting and endurance exercise—adipose tissue releases fatty acids when glucose is scarce

Amino Acid Catabolism

• Deamination removes the amino group as ammonia (converted to urea in the liver for excretion)
• Carbon skeletons enter central metabolism—glucogenic amino acids → pyruvate or citric acid cycle intermediates; ketogenic amino acids → acetyl-CoA
• Significant energy source during starvation—muscle protein breakdown provides gluconeogenic precursors

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Biosynthetic and Storage Pathways: Building and Saving

Not all metabolism is catabolic. These pathways synthesize glucose, store energy, or produce essential biosynthetic precursors. Anabolic pathways consume ATP and reducing equivalents rather than producing them.

Gluconeogenesis

• Synthesizes glucose from non-carbohydrate precursors (lactate, glycerol, glucogenic amino acids) primarily in the liver
• Bypasses three irreversible glycolytic reactions using unique enzymes: pyruvate carboxylase, PEP carboxykinase, fructose-1,6-bisphosphatase, and glucose-6-phosphatase
• Consumes 4 ATP and 2 GTP per glucose—this energy cost ensures glycolysis and gluconeogenesis don't run simultaneously (futile cycling)

Glycogen Metabolism

• Glycogenesis stores glucose as glycogen; glycogenolysis releases glucose-1-phosphate for energy needs
• Liver glycogen maintains blood glucose; muscle glycogen fuels local contraction—different tissue functions reflect different regulatory mechanisms
• Hormonally regulated—insulin promotes storage; glucagon and epinephrine promote breakdown through cAMP signaling cascades

Pentose Phosphate Pathway

• Generates NADPH for reductive biosynthesis (fatty acid synthesis, cholesterol synthesis, glutathione reduction)
• Produces ribose-5-phosphate for nucleotide and nucleic acid synthesis—essential for dividing cells
• Operates in oxidative and non-oxidative phases—cells can adjust flux based on whether they need NADPH, ribose, or both

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Quick Reference Table

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Self-Check Questions

1. Which two pathways both produce acetyl-CoA for entry into the citric acid cycle, and how do their ATP yields compare?

2. Explain why glycolysis and gluconeogenesis cannot operate simultaneously at full capacity—what regulatory mechanisms prevent this futile cycle?

3. Compare the roles of NADH and NADPH in cellular metabolism. Why do cells maintain separate pools of these electron carriers?

4. If the electron transport chain is inhibited but glycolysis continues, what happens to pyruvate and why? Which pathway would increase in activity?

5. A patient is fasting for 48 hours. Describe which metabolic pathways are upregulated in the liver and muscle, and explain how hormonal signals coordinate this response. (FRQ-style: integrate multiple pathways)