Glucose metabolism begins in the cytosol and is completed in mitochondria

All cells in the body are able to use glucose as fuel to produce ATP. The first step in glucose oxidation occurs in the cytosol with the process of glycolysis (or the glycolytic pathway), which does not require oxygen.

Glycolysis means to break apart glucose, and it splits the six-carbon glucose molecule into two 3-carbon molecules of pyruvate, with a net gain of two ATP and the production of two reduced coenzymes. The final steps in glucose oxidation occur in mitochondria. When there is adequate oxygen, pyruvate is transported into mitochondria, where the aerobic (oxygen-dependent) oxidation of pyruvate to carbon dioxide (CO₂) and water completes the oxidation of glucose.

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Glycolysis is a universal process that allows every cell in the body to extract energy from carbohydrates.

Glycolysis occurs in two phases, an energy investment phase and an energy payoff phase. During the first phase, glucose is rearranged into fructose, and energy is invested as phosphates from two ATP molecules are transferred to the sugar molecule to make it more reactive. The doubly phosphorylated fructose can then be split into two 3-carbon phosphate-containing molecules.

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Glycolysis is the metabolic pathway by which all cells can produce ATP by breaking down glucose to pyruvate. Glycolysis occurs in the cytosol of the cell and does not require oxygen.

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In the energy payoff phase of glycolysis, energy is harvested as these phosphorylated three-carbon molecules are oxidized to form two molecules of pyruvate. During this phase of glycolysis four ATP are produced. Since two ATP were used during the energy investment phase there is a net yield of two ATP.

In addition, two coenzymes (NAD⁺) are reduced (to NADH) as they acquire high-energy electrons (along with a positively charged hydrogen ion). When sufficient oxygen is present these high-energy electrons will be transferred to the ETC in mitochondria.

Sufficient oxygen availability also allows pyruvate to enter mitochondria where its oxidation can be completed. The aerobic oxidation of pyruvate is responsible for generating the majority of ATP that is derived from glucose metabolism. However, for pyruvate to enter the next major pathway of energy metabolism (the citric acid cycle), it must first be transformed into a two-carbon molecule in a reaction catalyzed by the enzyme pyruvate dehydrogenase. This is step 3 in the Cellular Respiration illustration following.

Coenzyme A attaches to pyruvate, which allows a CO₂ to be released. This produces the two-carbon acetyl-coenzyme A molecule (acetyl-CoA) and a reduced coenzyme (NADH). (The release of CO₂ at this step is directly dependent on a coenzyme synthesized from thiamin. A similar thiamin-dependent CO₂-producing reaction also occurs approximately midway through the citric acid cycle.)

The final step in the oxidation of glucose involves entry of acetyl-CoA into the mitochondrial pathway called the citric acid cycle (step 4 in the Cellular Respiration illustration following). This pathway is also commonly referred to by two other names: the tricarboxylic acid (TCA) cycle and the Krebs cycle (after the scientist who first described it).

In the citric acid cycle, acetyl-CoA is oxidized to produce two molecules of CO₂, four reduced coenzymes (three NADH and one FADH₂), and a GTP, which is an ATP-like molecule that is energetically equivalent to producing ATP (step 5 in the Cellular Respiration illustration).

The citric acid cycle not only completes the oxidation of glucose, it is also the final oxidative pathway for fatty acids and amino acids. Fatty acids also enter the citric acid cycle as acetyl-CoA, while amino acids enter at several different points along the pathway.

At the completion of the citric acid cycle the oxidation of glucose has yielded 12 reduced coenzymes: two from glycolysis, two from the oxidation of two molecules of pyruvate to acetyl-CoA, and eight from the oxidation of two molecules of acetyl-CoA to CO₂ in the citric acid cycle. With the completion of glucose oxidation in the citric acid cycle the majority of the chemical bond energy originally present is now conserved in the high-energy electrons carried by these reduced coenzymes.

To use the energy conserved in reduced coenzymes, they transfer their high-energy electrons to the ETC embedded in the inner-mitochondrial membrane. As electrons move down the ETC they gradually lose energy, which is captured, and can then be used to synthesize the majority of ATP that is produced by the metabolism of glucose (steps 6 and 7 in the Cellular Respiration illustration following).

The transfer of electrons from reduced coenzymes to the ETC is also critically important because it returns the coenzymes to their oxidized form, which allows them to continue participating in the oxidation of metabolic fuels. If the electron transfer did not occur reduced coenzymes would accumulate, and oxidized coenzymes would become depleted. With an inadequate number of coenzymes available to accept electrons from fuels as they are oxidized, oxidation would slow dramatically and eventually stop.

At the end of the ETC, electrons combine with oxygen and positively charged hydrogen ions to form water (step 8 in the Cellular Respiration illustration following).

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Cellular Respiration is the process by which the energy stored in fuels is transferred to ATP through a series of enzyme-catalyzed reactions. Aerobic respiration requires oxygen and occurs in mitochondria, where fatty acids and pyruvate are broken down to carbon dioxide and water.

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The complete aerobic oxidation of one molecule of glucose produces a total of 32 molecules of ATP from three different sources. Glycolysis produces a net yield of two ATP. Two ATP (GTP) are produced by the citric acid cycle, and 28 ATP are produced from the energy captured by the transport of electrons down the ETC. Since both the citric acid cycle and the ETC are aerobic pathways, 30 of the maximum 32 ATP produced by glucose oxidation are produced in an oxygen-dependent manner.

Under some circumstances glycolysis produces pyruvate and reduced coenzymes faster than the aerobic pathways in mitochondria can process them. This may occur when glycolysis metabolizes glucose at very rapid rates to meet high energy demands, or if the activity of the ETC is slowed because of limited oxygen availability. See the Aerobic Versus Anaerobic Glycolysis illustration.

In these circumstances an alternative means to return reduced coenzymes (NADH) in the cytosol to their oxidized form (NAD⁺) must be used so that glycolysis can continue to provide ATP. This is accomplished by pyruvate functioning as an alternative hydrogen atom acceptor (both the electron and the positively charged hydrogen ion). Reduced coenzymes can transfer their hydrogen atom to pyruvate, transforming it to lactate. This quickly regenerates oxidized coenzymes that can then participate in another round of glycolysis.