2. Red Blood Cell Glycolysis

Red Blood Cells

Image from http://physicsworld.com
Image from http://physicsworld.com

Red Blood Cells (RBC) transport/deliver oxygen to other tissues. A third of their volume is occupied by Hemoglobin (Hb). Their lack of intercellular organelles (nuclei, mitochondria) serves to maximize the transfer of oxygen to other tissues. It also allows for cellular deformation as the they navigate narrow capillaries.  This is an example of physiological adaptation.

RBCs rely solely on glycolysis for their supply of ATP.  Since RBCs transport oxygen, it would be unfavorable for them to be also consuming it, as would be required were they to run the Citric Acid Cycle and the Electron Transport Chain.

After glycolysis, the resulting pyruvate is instead fermented into lactate. If lactate (a.k.a., lactic acid) accumulates in the cell of a RBC, it’ll acidify the cytoplasm, affecting the function of the Hemoglobin. And so it’s exported out of the cell to the liver (muscles also do this).

Inside the liver, lactate is anabolized back into glucose via gluconeogenesis, which is a pathway that runs essentially glycolysis in reverse (with several notable exceptions, explained in later sections). It has a very high energy cost though: 6 ATP for every pair of lactate converted to glycolysis.

This metabolic loop of RBC/muscle fermentation <–> gluconeogenesis is called The Cori Cycle.

A few examples of how glycolysis promote RBC function and survival…

The Rapoport-Luebering Shunt (RLS)

In RBCs, glycolysis has multiple functions. Aside from producing ATP, some glycolysis intermediates contribute to the regulation of Hemoglobin and RBC function. The RLS is an example of this.

During Step 6, when 1,3-biphosphoglycerate is converted into 3-phosphoglycerate, a reaction that produces ATP, the RLS diverts the 1-3-BPG via a mutase enzyme to 2,3-biphosphoglycerate (2,3-BPG) and the synthesis of ATP is bypassed.

In most tissues, there are traces of 2,3-BPG, but in RBCs it’s very high. As it turns out, 2,3-BPG has an important function in the release of oxygen from Hemoglobin (this is covered in detail shortly). Thus, its benefits trump the need for ATP.

How NADH Maintains Reduced Iron in RBCs

Hemoglobin

In Step 5 (G3P -> 1,3-BPG), there is a release of NADH from NAD+. This NADH is used to maintain hemoglobin-bound iron in its normal ferrous state, Iron (II). Hemoglobin uses reduced iron to carry oxygen. But reactive oxygen species will oxidize the iron-bound Hb to put Hb into the oxidized Iron (III) or ferric state, also known as methemoglobin, which results in a loss of RBC function since it can not bind to oxygen. Because of this, Hb needs to be constantly reduced.

This is balanced by a small hemoprotein called cytochrome b5. When NADH reacts with (and reduces) the enzyme cytochrome b5 reductase, the enzyme is activated, allowing it to catalyze the reduction of cytochrome b5. The reduced cytochrome b5 then forces the reduction of the methemoglobin back to Hb: Ferric => Ferrous. This also regenerates the NAD+.

NADH Fe
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Hexose Monophosphate Shunt

This occurs in Step 2 when G6P is converted into F6P. Instead, the G6P is converted into Hexose Monophosphate (HMP), a reaction that converts NADP+ to NADPH. From there, the HMP rejoins subsequent steps at 3, 4 or 5.

The HMP protects against reactive oxygen species (ROS) by diverting G6P into other hexomonophosphates.

It is during the reduction of NADP+ that a protein called glutathione is oxidized. This, in turns, destroys the ROS.

HMP
copyright harvardx.org

The HMP shunt is not unique to RBCs, but it occurs to a high extent there. The lifespan of RBCs correlates with the activity of Glucose-6-Phosphatedehydrogenase, an enzyme that catalyzes the last step in the synthesis of HMPs. As this activity decreases so rises the amount of ROS, which leads to the death of the cell.

Bottom-line: the unique features of glycolysis promote RBC function and survival.

 

 

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