24.2 Carbohydrate Metabolism

Glycolysis and the Krebs Cycle

Glucose is the cell's primary fuel, and breaking it down is how your body extracts usable energy in the form of ATP. This process happens in stages: glycolysis splits glucose in the cytoplasm, and then the Krebs cycle finishes the job inside the mitochondria. Each stage also generates electron carriers (NADH and $FADH_2$) that feed into the electron transport chain later.

Steps and outcomes of glycolysis

Glycolysis is a 10-step pathway that occurs in the cytoplasm and does not require oxygen. It splits one 6-carbon glucose molecule into two 3-carbon pyruvate molecules. Here's how the key steps break down:

Energy investment phase (steps 1–4): The cell spends 2 ATP to get the process going.

1. Hexokinase phosphorylates glucose, forming glucose-6-phosphate (costs 1 ATP).
2. Glucose-6-phosphate is rearranged into fructose-6-phosphate.
3. Phosphofructokinase (PFK) phosphorylates fructose-6-phosphate, forming fructose-1,6-bisphosphate (costs 1 ATP). PFK is the major rate-limiting enzyme of glycolysis.
4. Fructose-1,6-bisphosphate is split into two 3-carbon molecules: glyceraldehyde-3-phosphate (G3P) and dihydroxyacetone phosphate (DHAP). DHAP is converted to G3P, so from here on, every reaction happens twice per glucose.

Energy payoff phase (steps 5–10): The cell earns back 4 ATP and 2 NADH.

1. G3P is oxidized and phosphorylated, producing 1,3-bisphosphoglycerate and reducing $NAD^+$ to NADH.
2. 1,3-bisphosphoglycerate transfers a phosphate to ADP, generating ATP and forming 3-phosphoglycerate (×2 = 2 ATP).
3. 3-phosphoglycerate is rearranged to 2-phosphoglycerate.
4. 2-phosphoglycerate is dehydrated to phosphoenolpyruvate (PEP).
5. Pyruvate kinase transfers PEP's phosphate to ADP, generating ATP and forming pyruvate (×2 = 2 ATP).

Pyruvate in the Krebs cycle

Before entering the Krebs cycle, pyruvate must cross into the mitochondrial matrix and be converted to acetyl-CoA. This is a critical linking step.

Pyruvate dehydrogenase complex removes one carbon (released as $CO_2$), oxidizes the remaining 2-carbon fragment, and attaches it to coenzyme A. This produces 1 NADH per pyruvate. Since each glucose yields 2 pyruvates, this step generates 2 NADH and 2 $CO_2$ total.

The Krebs cycle (also called the citric acid cycle) then processes each acetyl-CoA through eight reactions:

1. Acetyl-CoA (2C) combines with oxaloacetate (4C) to form citrate (6C).
2. Citrate is rearranged to isocitrate.
3. Isocitrate is oxidized to $\alpha$-ketoglutarate (5C), releasing $CO_2$ and generating 1 NADH.
4. $\alpha$-ketoglutarate is oxidized to succinyl-CoA (4C), releasing $CO_2$ and generating 1 NADH.
5. Succinyl-CoA is converted to succinate, generating 1 GTP (which is equivalent to 1 ATP).
6. Succinate is oxidized to fumarate, generating 1 $FADH_2$.
7. Fumarate is hydrated to malate.
8. Malate is oxidized to oxaloacetate, generating 1 NADH. Oxaloacetate is now ready to accept another acetyl-CoA, and the cycle repeats.

Notice that the Krebs cycle itself produces very little ATP directly. Its main job is loading up electron carriers (NADH and $FADH_2$) for the next stage.

Electron Transport Chain and ATP Synthesis

This is where the big ATP payoff happens. The electron transport chain (ETC) sits in the inner mitochondrial membrane and uses the electrons stored in NADH and $FADH_2$ to build a proton gradient that drives ATP production.

Electron flow in cellular respiration

1. Complex I accepts electrons from NADH (oxidizing it back to $NAD^+$) and pumps $H^+$ ions from the matrix into the intermembrane space.
2. Complex II accepts electrons from $FADH_2$ (oxidizing it back to FAD). Complex II does not pump protons, which is why $FADH_2$ yields less ATP than NADH.
3. Both complexes pass electrons to ubiquinone (coenzyme Q), a mobile carrier that shuttles them to Complex III.
4. Complex III passes electrons to cytochrome c (another mobile carrier) and pumps more $H^+$ into the intermembrane space.
5. Complex IV transfers electrons to the final electron acceptor: molecular oxygen ($O_2$). Oxygen combines with electrons and $H^+$ to form water ($H_2O$). This is why you need to breathe.

Each transfer is a redox reaction, and the energy released at Complexes I, III, and IV is used to pump protons. The result is a high concentration of $H^+$ in the intermembrane space relative to the matrix.

Mechanism of oxidative phosphorylation

The proton gradient created by the ETC stores potential energy, much like water behind a dam. This process of using the gradient to make ATP is called chemiosmotic coupling.

• $H^+$ ions flow back into the matrix through ATP synthase, a channel-like enzyme embedded in the inner mitochondrial membrane.
• The flow of protons causes ATP synthase to physically rotate, which drives conformational changes that catalyze the phosphorylation of ADP to ATP.
• This is called oxidative phosphorylation because the ATP production depends on the oxidation of electron carriers by the ETC.

Total ATP from one glucose (approximate):

The 10 NADH come from: 2 in glycolysis, 2 from pyruvate dehydrogenase, and 6 from the Krebs cycle. The 2 $FADH_2$ come from the Krebs cycle. The range of 30–32 depends on which shuttle system transports cytoplasmic NADH into the mitochondria.

Gluconeogenesis

When blood glucose drops (during fasting, prolonged exercise, or stress), your body can't just wait around. Gluconeogenesis is the synthesis of new glucose from non-carbohydrate precursors. It occurs primarily in the liver, with minor contributions from the kidneys.

Glucose production via gluconeogenesis

Gluconeogenesis largely runs glycolysis in reverse, but three glycolytic steps are irreversible, so the cell uses different enzymes to bypass them:

1. Pyruvate carboxylase converts pyruvate to oxaloacetate (bypasses pyruvate kinase, step 1 of 2).
2. PEP carboxykinase converts oxaloacetate to phosphoenolpyruvate (PEP) (bypasses pyruvate kinase, step 2 of 2).
3. Fructose-1,6-bisphosphatase converts fructose-1,6-bisphosphate to fructose-6-phosphate (bypasses PFK).
4. Glucose-6-phosphatase removes the phosphate from glucose-6-phosphate, releasing free glucose into the blood (bypasses hexokinase).

The remaining steps between these bypasses simply use the reversible glycolytic enzymes running in the opposite direction.

Key substrates that feed into gluconeogenesis:

• Lactate from anaerobic glycolysis in skeletal muscle (converted back to pyruvate via lactate dehydrogenase; this is the Cori cycle)
• Glycerol from triglyceride breakdown in adipose tissue (enters the pathway as DHAP)
• Glucogenic amino acids from protein catabolism (converted to pyruvate or Krebs cycle intermediates)

Additional Carbohydrate Metabolism Pathways

Glycogen metabolism

Your body stores glucose as glycogen, a branched polysaccharide found mainly in the liver and skeletal muscle.

• Glycogenesis is the synthesis of glycogen from glucose. When blood glucose is high (after a meal), insulin promotes glycogenesis so excess glucose gets stored rather than wasted.
• Glycogenolysis is the breakdown of glycogen back to glucose-1-phosphate, which is then converted to glucose-6-phosphate for use in glycolysis (muscle) or released as free glucose into the blood (liver). Glucagon and epinephrine stimulate glycogenolysis.

Alternative glucose metabolism

The pentose phosphate pathway (PPP) is a branching route off glycolysis that diverts glucose-6-phosphate for two purposes:

• Produces NADPH, which is used for fatty acid synthesis and other anabolic reactions, as well as for protecting cells against oxidative damage.
• Produces ribose-5-phosphate, the sugar backbone needed to build nucleotides (for DNA and RNA synthesis).

Metabolic regulation

Carbohydrate metabolism doesn't run at a constant rate. It's tightly controlled at two levels:

• Allosteric regulation provides rapid, local control. For example, phosphofructokinase (PFK) is inhibited by ATP (signaling plenty of energy) and activated by AMP (signaling low energy). This makes PFK a key control point for glycolysis.
• Hormonal regulation coordinates metabolism across the whole body. Insulin signals the fed state and promotes glycolysis, glycogenesis, and glucose uptake. Glucagon signals the fasted state and promotes glycogenolysis and gluconeogenesis. These two hormones work in opposition to keep blood glucose within a normal range.