Role of 2,3-disphosphoglycerate in RBCs

Biree Andemariam, MD: Matt, I’m going to have you pick up here from what Nirmish [Shah], and Elena [Saah] were saying. Let’s talk about the different pathways, like pyruvate kinase R [PKR] 2,3 DPG [disphosphoglycerate]. What’s the role of ATP [adenosine triphosphate]? What’s the role of 2,3 DPG and hemoglobin oxygen affinity? Is there any interplay, when thinking about biochemistry of PKR and 2,3 DPG? What are your thoughts on that?

Matthew M. Heeney, MD: In the glycolytic pathway, the Embden-Meyerhof-Parnas pathway, the red blood cell gets its energy because, as Elna told us, there’s no nucleus anymore. There are no mitochondria. There’s no other way to get ATP. The red blood cells need that ATP desperately to maintain their membranes and the ionic borders of the membranes and to keep them appropriate and separate.

In this glycolytic pathway, there’s a side shunt, the Rapoport-Luebering shunt, which produces 2,3 DPG. This molecule plays an important role in the normal physiology of the 2,3 DPG. When it’s bound to hemoglobin, it allosterically stabilizes it in the tense conformation. That decreases the hemoglobin affinity for oxygen, as Nirmish described. And so under certain states, 2,3 DPG can be very useful. In stress and by decreasing the amount of 2,3 DPG, you can increase or decrease the oxygen affinity. This is how the body can manage this in certain stress states.

But therapeutically, we can potentially modulate this by increasing the flux through the glycolytic pathway. This produces not only more ATP, which red blood cells may find helpful in times of stress, but also alters that oxygen dissociation curve. In this case, our goal is to shift the curve to the left, and increase oxygen affinity, in a training attempt to try and increase hemoglobin in sustainable monopolies such as sickle cell [disease]. This pathway is now manipulatable. Using a lot of these small molecule allosteric modifiers is potentially a novel way of doing so.

Biree Andemariam, MD: I like your term: manipulatable. That’s a preview of what we’re going to talk about next as we get into unhealthy red blood cells. Thank you.

Transcript edited for clarity