Scientists uncover how cells pump protons to convert oxygen into energy, solving decades-old mystery
Researchers have uncovered the molecular mechanism by which cells convert oxygen into usable energy. The study identifies how a copper–tyrosine radical directly drives proton pumping, resolving a decades-old question in biology.
Every breath we take fuels one of the most fundamental processes in biology: the conversion of oxygen into cellular energy. This process is carried out by heme–copper oxidases, enzymes that reduce oxygen to water while pumping protons across membranes to generate the gradient required for ATP synthesis, the energy currency of life.
Although this proton pumping process was discovered more than 40 years ago, how it works at the molecular level has remained elusive.
In 2021, the research team led by Prof. Edward I. Solomon at Stanford University reported a major breakthrough in Science, where they experimentally characterized a key intermediate known as the PM state. That study revealed how oxygen–oxygen bond cleavage occurs at the enzyme’s active site, showing that the intermediate contains an iron(IV)-oxo center magnetically coupled to a copper ion and a tyrosyl radical. This established the electronic structure responsible for initiating the oxygen reduction reaction and opened the door to molecular-level understanding of how proton pumping might be coupled to oxygen reduction.
Now, in a new study that will appear in the Proceedings of the National Academy of Sciences on 29 June 2026, the researchers have completed that picture by identifying how proton pumping is directly controlled.
The team focused on the critical intermediate, known as the F state, formed during the first proton pumping step. Using advanced site-selective spectroscopic techniques, magnetic circular dichroism to study the heme-iron center and copper K-edge x-ray absorption spectroscopy to study the copper/tyrosine center, they discovered that the enzyme’s active site features an electron-delocalized radical shared between a copper center and a uniquely crosslinked tyrosine residue.
This delocalized radical provides the missing link: it directly controls proton movement across a membrane to generate the potential for ATP synthesis.
“We were able to directly observe how the active site redistributes electrons in a way that enables proton pumping,” said Dr. Anex Jose, lead author of the study. “This allows us to connect oxygen chemistry to energy conversion at a fundamental level.”
“This work builds on our earlier Science study and completes the molecular description of how these enzymes function,” said Professor Edward I. Solomon, the corresponding author. “We now see how the enzyme couples oxygen reduction to proton pumping through a unified radical generating mechanism.”
Importantly, the researchers found that this copper–tyrosine radical character is regenerated throughout all proton pumping intermediates, establishing a consistent mechanism across the enzyme’s full catalytic cycle.
Together, these studies provide a comprehensive molecular framework for understanding how aerobic organisms convert oxygen into usable energy, one of the central processes of life.
Beyond advancing fundamental bioenergetics, these findings inform the design of bio-inspired catalysts for energy conversion and storage technologies.
Journal: Proceedings of the National Academy of Sciences
Related prior work: Jose et al., Science (2021): DOI: 10.1126/science.abh3209
Acknowledgments: The authors acknowledge the National Institutes of Health (NIH) Grant R01DK031450 to Prof. Edward I. Solomon, the Stanford Research Computing Center for providing computational resources and the Stanford Synchrotron Radiation Lightsource (SSRL), SLAC National Accelerator Laboratory, supported by the U.S. Department of Energy (DOE), Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515 for x-ray absorption spectroscopy experiments
