Kyoto, Japan – Researchers at Kyoto University have unlocked a key understanding of how the Na⁺-NQR enzyme, a sodium pump crucial for the respiration of many marine and pathogenic bacteria, functions at a molecular level. The breakthrough, published this week, details how redox reactions – the transfer of electrons – directly drive the transport of sodium ions across cell membranes, a process previously shrouded in mystery.
The Na⁺-NQR enzyme is vital for bacterial survival, powering respiration by moving sodium ions. However, scientists have long struggled to understand the precise mechanism linking the energy released from electron transfer to the actual pumping of sodium. A major hurdle was the inability to visualize the enzyme’s intermediate states – the fleeting structural changes it undergoes during operation.
To overcome this challenge, the Kyoto University team, led by Masatoshi Murai, employed cryo-electron microscopy. Co-first author Moe Ishikawa-Fukuda used this technique to capture multiple structural snapshots of the enzyme as it changed shape during its operational cycle. These images were then combined with molecular dynamics simulations, conducted by co-first author Takehito Seki, to create a comprehensive model of the pump’s activity.
The simulations revealed a dynamic relationship between electron transfer and structural change. As electrons move within the protein, the Na⁺-NQR enzyme physically alters its conformation. These changes, in turn, control a “gate” within the bacterial cell membrane, opening and closing to allow sodium ions to pass through. This coupling of electron flow to mechanical movement is what drives the sodium ion translocation.
“Our study is the first to clearly explain how redox reactions directly drive sodium ion transport at the molecular level, providing a new framework for understanding energy conversion in bacteria,” explained Ishikawa-Fukuda. The research provides a detailed, molecular-level explanation for a process that has been a long-standing question in the field of bioenergetics.
Interestingly, the team also found that a specific inhibitor, korormicin, plays a critical role in stabilizing these intermediate states, making them observable. Korormicin, previously identified by the team, effectively “freezes” the enzyme in key configurations, allowing for detailed structural analysis. This suggests that korormicin could be a valuable tool for further research into the pump’s mechanism.
Seki highlighted the significance of this discovery in the broader context of bioenergetics. “Understanding redox-driven sodium pumping addresses a long-standing question in bioenergetics, revealing a strategy that is fundamentally different from the proton pump found in mammalian mitochondria,” he stated. Mammalian cells rely on proton pumps for energy conversion, while many bacteria utilize sodium pumps like Na⁺-NQR. This difference underscores the diversity of energy-generating strategies in the biological world.
The researchers are now exploring whether the structural states they’ve identified can be targeted to disrupt the pump’s function. This could pave the way for the development of novel antibiotics that target a previously unexplored mechanism in bacteria. By selectively blocking the sodium pump, it may be possible to inhibit bacterial growth without relying on traditional antibiotic targets.
Murai emphasized the long-term implications of the research. “Our goal was to understand how this sodium pump works at a fundamental level,” he said. “Although this is basic research, we hope that clarifying these mechanisms will eventually contribute to the development of new strategies to combat pathogenic bacteria.” The team’s work represents a significant step forward in understanding the intricate machinery of bacterial life and offers a promising avenue for future antibiotic development.
