January 19, 2021

Researchers discover long-sought mechanism behind worst cases of a common blood disorder

G6PD deficiency affects about 400M people worldwide and can pose serious health risks. Uncovering the causes of the most severe cases could finally lead to treatments.

By Nathan Collins

Red blood cells containing enzymes. One, with a bent enzyme, bursts.
The G6PD enzyme plays a crucial role in red blood cells, removing molecules such as hydrogen peroxide from the body. In some cases, mutations can bend the molecule awkwardly, interfering with G6PD's function. In the worst cases, the mutations lead red blood cells to rupture. (Mio Wakatsuki, from protein images by Naoki Horikoshi/SLAC National Accelerator Laboratory)

With a name like glucose-6-phosphate dehydrogenase deficiency, one would think it is a rare and obscure medical condition, but that’s far from the truth. Roughly 400 million people worldwide live with potential of blood disorders due to the enzyme deficiency. While some people are asymptomatic, others suffer from jaundice, ruptured red blood cells and, in the worst cases, kidney failure. 

Now, a team led by researchers at the Department of Energy’s SLAC National Accelerator Laboratory has uncovered the elusive mechanism behind the most severe cases of the disease: a broken chain of amino acids that warps the shape of the condition’s namesake protein, G6PD. The team, led by SLAC Professor Soichi Wakatsuki, report their findings January 18th in Proceedings of the National Academy of Sciences

An essential enzyme

G6PD’s role in our health is hard to overstate. In red blood cells, which deliver oxygen to other cells, the enzyme helps remove more chemically reactive and potentially harmful oxygen molecules, such as hydrogen peroxide, and convert them to water and other more inert byproducts. If the G6PD protein isn’t working properly, red blood cells also stop working properly and can, in the worst cases, rupture. 

“It’s quite an important enzyme in our bodies,” Wakatsuki said.

Still, doctors have mostly been at a loss to treat the disease, especially in the most severe cases, known as Class I. “At the moment the treatment for these patients is blood transfusions,” said Stanford professor Daria Mochly-Rosen, a senior author on the new study. 

Medical researchers have known for decades that upwards of 190 different mutations can lead to some forms of G6PD deficiency, and they also worked out the structure of ordinary G6PD in various forms decades ago. Mochly-Rosen and colleagues have also made strides in identifying drugs that may treat some less-severe forms of the disease, known as Class II and III.

Unfortunately, those drugs do not work for Class I cases, which have proved especially confusing. Most of the mutations that lead to the most severe symptoms were known to occur in areas far away from the active site where it binds to substrate molecules for its enzyme reactions – the usual spot where such mutations would be thought to cause problems. 

A bend in the road

To better understand what was going on, Wakatsuki and colleagues from SLAC, Stanford University, the University of Tsukuba and the University de Concepción – along with a group of Stanford undergraduates and local high school students – started with X-ray crystallography studies of four forms of G6PD associated with the worst G6PD-deficiency symptoms, conducted at Structural Molecular Biology beamlines at SLAC’s Stanford Synchrotron Radiation Lightsource, Lawrence Berkeley National Laboratory’s Advanced Light Source and Argonne National Laboratory’s Advanced Photon Source.

The team found that even though the mutations are far from G6PD’s active site, they break up connections in a chain of amino acids that help stabilize the protein. That has a kind of domino effect on the whole protein molecule: It bends awkwardly, and a molecular arm that should help molecules bind to G6PD’s active site instead wobbles unpredictably around. The team confirmed aspects of those results with a mixture of other techniques, including small angle X-ray scattering at Beam Line 4-2 at SSRL, computer simulations and cryogenic electron microscopy performed at the Stanford-SLAC Cryo-EM Center. 

The results show for the first time how the most severe cases of G6PD deficiency work at the molecular level and could help researchers design new drugs to treat the disease. 

“It’s been some time we’ve been working on this,” Wakatsuki said. “There’s no cure so far, but this could pave the way for new therapeutics.”

Mochly-Rosen agreed. “You can start to imagine what kind of drug you need,” she said. “With Class I, we were stuck until we found this clue.”

The research was supported by grants from the National Institutes of Health and the Japan Society for the Promotion of Science. SSRL, ALS and APS are DOE Office of Science user facilities. The Stanford-SLAC Cryo-EM Center is supported by the National Institutes of Health. The Structural Molecular Biology Program at SSRL is supported by the DOE Office of Science  and by the National Institutes of Health, National Institute of General Medical Sciences.

Citation: Naoki Horikoshi et al., 19 January 2020, Proceedings of the National Academy of Sciences (10.1073/pnas.2022790118)

For questions or comments, contact the SLAC Office of Communications at communications@slac.stanford.edu.


SLAC is a vibrant multiprogram laboratory that explores how the universe works at the biggest, smallest and fastest scales and invents powerful tools used by scientists around the globe. With research spanning particle physics, astrophysics and cosmology, materials, chemistry, bio- and energy sciences and scientific computing, we help solve real-world problems and advance the interests of the nation.

SLAC is operated by Stanford University for the U.S. Department of Energy’s Office of Science. The Office of Science is the single largest supporter of basic research in the physical sciences in the United States and is working to address some of the most pressing challenges of our time.

 

Dig Deeper

Related stories

News Brief

Wheat and other sources of gluten can spell trouble for people with the disease, but new findings could aid the development of first-ever drugs...

Close up of wheat in a field.
News Feature

Researchers figured out how to spray and freeze a cell sample in its natural state in milliseconds, helping them capture basic biological processes in...

These are two images of the same cell at different times during an experiment.
News Feature

Disabling those hinges could be a good strategy for designing vaccines and treatments against a broad range of coronavirus infections.

A 3D image of a round, spiky coronavirus with inset showing how far its spikes can bend.
News Brief

Wheat and other sources of gluten can spell trouble for people with the disease, but new findings could aid the development of first-ever drugs...

Close up of wheat in a field.
News Feature

Researchers figured out how to spray and freeze a cell sample in its natural state in milliseconds, helping them capture basic biological processes in...

These are two images of the same cell at different times during an experiment.
News Feature

Disabling those hinges could be a good strategy for designing vaccines and treatments against a broad range of coronavirus infections.

A 3D image of a round, spiky coronavirus with inset showing how far its spikes can bend.
News Feature

Scientists developed a new method to unlock the secrets of RNA. The implications are wide-reaching, from better understanding diseases to designing new therapeutics. 

CXI hutch
News Feature

Peter Dahlberg has combined two complex imaging techniques into one. The 2021 Panofsky Fellow adds cryo-ET and biosensors to fluorescence microscopy to give context...

A green, red and blue outline encloses small yellow dots and orange circles, representing parts of a cell.
Press Release

With up to a million X-ray flashes per second, 8,000 times more than its predecessor, it transforms the ability of scientists to explore atomic-scale...

LCLS-II first light