The Pentose Phosphate Path and PH, Part I – RBCs, G6PD, & GSH

The pentose phosphate pathway (PPP) is a metabolic pathway that parallels glycolysis. In cells, within the cytosol, glucose is converted into glucose 6-phosphate (catalyzed by the enzyme hexokinase), which can then either 1) enter glycolysis (and subsequent glucose oxidation via citric acid cycle) to produce ATP, or 2) enter the PPP. The PPP (diagram below) is primarily an anabolic pathway; the primary purpose being the following: to produce molecules (specifically 5 carbon sugars, and Ribose-5-phosphate) used for fatty acid synthesis, nucleic acid synthesis, and protein synthesis.


However, another important purpose of the PPP is to produce NADPH, a high energy electron carrier. NADPH is generated in the first step of the PPP by the enzyme G6PD. NADPH is utilized by cells to produce glutathione (GSH), a master antioxidant. NADPH does this by reducing GSSG (the oxidized form of GSH) to GSH within cells. One of the most important functions of GSH (and antioxidants in general), is to neutralize reactive oxygen species (ROS) and free radicals. But, aside from the importance of free radical neutralization in the maintenance of health and homeostasis, how is this all related to PH? It is related in one way (the other way will be covered in Part II) via erythrocytes, or Red Blood Cells (RBCs)…

Erythrocytes are the oxygen carriers of the body. Without them, we would not have life. However, they are also the cells of the body that are most subject to oxidative stress (due to the fact that their sole function is to transport oxygen). Since erythrocytes lack mitochondria (and hence cannot derive energy from fatty acids or amino acids, or glucose oxidation), they utilize both glycolysis and PPP for their energy and synthetic needs.

Due to constant exposure to oxidative stress, the erythrocyte is subject to damage via ROS and autoxidation of hemoglobin. And this is why GSH is so important for RBCs. If RBCs do not generate enough GSH, then peroxides can form and, via lipid oxidation, cause damage to the RBC wall thus causing hemolysis. And the most important factor for the maintenance and generation of GSH in RBCs is the PPP, specifically, it is the presence of the enzyme G6PD.

G6PD deficiency leads to hemolytic anemia (as mentioned in the above paragraph, because it leads to lower NADPH levels), and anemia/hemolysis can predispose individuals to developing PH: “The continuous release of free hemoglobin has been linked with the development of pulmonary hypertension (increased pressure over the pulmonary artery); this, in turn, leads to episodes of syncope (fainting), chest pain, and progressive breathlessness. Pulmonary hypertension eventually causes right ventricular heart failure, the symptoms of which are peripheral edema (fluid accumulation in the skin of the legs) and ascites (fluid accumulation in the abdominal cavity).This quote is from wikipedia. A more comprehensive review of how blood/hematologic disorders contribute to PH can be read here.

If anemia/hemolysis does this, perhaps it is also involved in sustaining the PH phenotype in individuals? It is important to note, however, that not all PH patients have hematologic disorders. 

In my opinion, all of this suggests that perhaps GSH supplementation may be beneficial for individuals lacking G6PD enzyme or decreased G6PD activity. It may not be true, but it makes for a strong case…

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