Research News

A research team from Cleveland Clinic has shown that a well-known metabolic enzyme called glyceraldehyde-3-phosphate dehydrogenase (GAPDH) performs a second job beyond its textbook role in energy production: transporting iron-rich heme molecules throughout the cell.  

Two recent studies, published in the Journal of Biological Chemistry and Nature Communications, demonstrate how GAPDH loads and unloads this precious cargo, further cementing its role in cellular health and protein function. The findings also answer a long-standing biological question: how does heme get from where it’s made to where it’s needed? 

What is heme? 

Heme is an iron-containing molecule that attaches to certain proteins after they’re made, supplying the iron they need to function. Without heme, iron can’t do its job. Heme is critical to many biological processes, including how blood cells produce hemoglobin, which is the protein that lets our blood transport oxygen throughout our bodies. 

Heme molecules are sticky and toxic and can’t move on their own. Transport proteins are critical to ensuring heme makes it to places inside cells where it’s needed in a safe and efficient manner. 

“Our bodies make red blood cells continuously, and a crazy amount of heme synthesis and transport has to happen within hours to get heme to their hemoglobin,” says study lead author Dennis Stuehr, PhD. “Problems with heme transport or synthesis can be medical emergencies at best and incompatible with life at worst.” 

Redefining GAPDH as a central heme distributor 

Dr. Stuehr’s lab first observed GAPDH’s potential as a heme transporter in 2010, as part of their work studying heme and its role in our biological processes. The discovery was met with skepticism from the field because GAPDH has so many other known functions. 

Dr. Stuehr's two most recent publications map some of the most critical steps of all: transferring the heme molecule to GAPDH from where it was made and taking it off GAPDH at its delivery destination. He compares the processes to loading and unloading a cargo truck. 

“I was skeptical too when we came across GAPDH as a potential heme transporter in 2010, but our follow-up studies now reveal it’s likely the major heme transporter in our cells,” he says. “The field is beginning to show more confidence in our findings. Those that are doubtful have motivated us to expand our work to establish the scope of GAPDH's role in heme distribution within our cells, and exactly how it works at every step of the way.” 

The current publications reveal that once heme is made by our cell mitochondria, they transfer it to GAPDH with the help of proteins called FLVCR1b and TANGO2, the “cargo loaders.” Then, GAPDH goes on to interact with the many cellular proteins that need heme, transferring it with the help of specific "cargo unloaders" like the protein hsp90.  

“For decades, people have been guessing that heme could travel in cells by different pathways. Now that we’ve found the primary path for heme to get to where it is needed in cells, we can move on to asking new questions about other parts of the process and how it’s all regulated,” Dr. Stuehr says. “For example, each of these steps and the identified helper proteins are potential therapeutic targets. Overall, we’re redefining the textbook role for a major metabolic enzyme, with new implications for health and disease. I think that’s kind of cool.”