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In the human body, carbon dioxide (CO2) is a metabolic waste product of aerobic metabolism. Specifically, two catabolic processes, pyruvate decarboxylation and the Kreb’s cycle, both of which occur in the mitochondria of cells, produce CO2. As a result of these processes, the concentration of CO2 increases proportionally to metabolic activity within tissues, leading to an increased partial pressure of carbon dioxide (Pco2). This pressure gradient drives CO2, a highly lipid-soluble molecule, out of tissues, across cell membranes, and into the blood of systemic capillaries. Once it has diffused into the capillaries, CO2 is transported to the lungs by three mechanisms.

The majority (≈70%) of CO2 is transported to the lungs in the form of bicarbonate (HCO−3), a process known as isohydric transport. Upon entering red blood cells, CO2 rapidly combines with water (H2O) to form carbonic acid (H2CO3) via the reversible enzyme carbonic anhydrase. Just as rapidly as it is produced, carbonic acid releases hydrogen ion (H+) and forms bicarbonate (HCO3−). This reversible reaction is represented below:

CO2 + H2O ←(carbonic anhydrase)→ H2CO3 ←→ HCO3− + H+

The proton released from carbonic acid is buffered by binding to histidine residues on hemoglobin. Simultaneously, the bicarbonate ion diffuses out of the cell in exchange for a chloride ion via a bicarbonate-chloride carrier protein embedded in the membrane of the red blood cell. This exchange of bicarbonate for chloride maintains the electric neutrality within the cell and leads to an increase in chloride within blood cells of the venous system, as well as a decreased concentration of chloride in venous blood, referred to as the chloride shift, or Hamburger shift.

Approximately 23% of CO2 is carried to the lungs, bound to hemoglobin and other plasma proteins. Hemoglobin possesses four N-terminal amino groups, each of which can bind CO2 to form carbaminohemoglobin. During the reaction, a proton is released, which eventually leads to a decrease in the pH of surrounding tissues and concomitant release of O2 from hemoglobin. The reaction is represented by the following equation.

CO2 + Hb−NH2 ←→ H+ + Hb−NH−COO

A small percentage of CO2 binds to amino groups on the polypeptide chains of plasma proteins.

Finally, the remaining 7% of CO2 produced in tissues travels to the lungs dissolved in plasma. A negligible portion of CO2 dissolved in plasma combines with water to form carbonic acid, with immediate release of a proton to form bicarbonate. This reaction is identical to that which occurs in red blood cells. However, it should be noted that carbonic anhydrase is not present in the ...

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