2. Red Blood Cell Glycolysis


An average human has 5,000,000 red blood cells (RBC) per microliter of blood. Each RBC contains ~270,000,000 Hemoglobin (Hb), which means there’s roughly 1,000,000,000 Hb/ml.

Structure of Hemoglobin

Hb is a tetramer made up of 2 alpha subunits and 2 beta subunits, each with a similar structure. Each contains a Heme, a porphyrin structure with a molecule of iron (Fe) in its center. Each Heme can bind one molecule of oxygen (O2).


Hb has two different quaternary structures. The first is the deoxygenated conformation, also called the T-State, which has a low affinity for oxygen. The other is the oxygenated conformation called the R-State, which has a high affinity for oxygen.

The switch between these two states allows for the release of O2 in tissues and the upload of O2 in the lungs.

Difference between the T and R States

The R-State is the O2-binding state. In this state, the interfaces between alpha and beta subunits change. In particular, the pocket between the two beta subunits become narrow.

The T-State is the O2-releasing state. Here the Heme adopts a planar structure to release the oxygen.

The site of the last O2 binding has a 100-1000x higher affinity that the first site, a property called cooperative binding.

Graphing the percentage of binding sites versus the partial press of O2 yields an S-curve: as the PP of O2 increases, the number of O2-binding sites beings to accelerate until they plateau, i.e., all sites become occupied.

At low PP, Hb has a very low affinity for O2 with the number of binding sites occupied by O2 growing slowly.

Cooperative binding is responsible for the fast increase in the number of sites occupied by O2 as the PP rises.

Compare this with the binding in Myoglobin, another transporter of O2. Myoglobin is a single polypeptide chain and exhibits no cooperative binding. Its curve is hyperbolic.

Cooperative binding allows for dynamic oxygen binding. That is, the adaptation of O2 delivery system to match the needs in O2 of tissues. At rest, the need is moderate–only a small fraction of bound O2 is given away by Hb. During exercise, Hb will provide much more O2.

Arteries bring oxygen to tissues; veins collect the blood that went through the tissues.

In the graph below, the first two dots on the left (blue then yellow) represents the amount of oxygen left bound to the Hb in the veins–so, after leaving the tissues. During exercise, there’s far less oxygen leftover (as shown in the first blue dot), as it was given away to the tissues. At rest, the difference is far smaller (the difference between the two yellow dots)–not that much was released.

crappy notebook drawing

Variations in the S-Curve

A leftward shift in the S-curve indicates a higher oxygen affinity.

A rightward shift indicates lower oxygen affinity.

pH is a major modulator of these shifts. Two examples:

–in peripheral tissues, oxygen is consumed producing CO2, which reacts with water to form carbonic acid.

CO2 + H2is in equilibrium with H2CO3

–muscle when active releases lactic acid, resulting in an acidification of the blood

As CO2 arrives in the lung, the equilibrium between carbonic acid and CO2 shifts toward CO2 as CO2 is exhaled/eliminated. Thus the pH of the blood in the lungs is higher than the rest of the tissues:  CO2 + H2O is in equilibrium with H2CO3 -> CO2 + H2O

On the other hand, pH in tissues is lower: CO2 + H2O is in equilibrium with H2CO3 -> HCO3 + H+

This is The Bohr Effect:

Higher pH shifts the curve to the left => higher affinity => O2 loading => lungs

Lower pH shifts the curve to the right => lower affinity => O2 dumping => periphery tissue


Back to 2,3-BPG from the last lecture…

T-state: binds 2,3-BPG; R-state, excludes 2,3-BPG

2,3-BPG binds to Hb in its T-state, it forms non-covalent bonds including salt bridges, with residues of different subunits of Hb in its T-state.

The shift of T->R requires breaking these bonds. Thus, 2-3-BPG stabilized Hb in its T-state where Hb has a low affinity. Keeps oxygen flowing to tissues, not stores in Hb.

This is critical to our adaptation to high altitudes with low O2 or in those with emphysema. RBCs produce large quantities of 2,3-BPG to favor oxygenation of tissues.

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