Bifunctional architecture enables substrate catalysis and channeling in Paracoccus TMAO demethylase.

Cryo-EM structures reveal a bifunctional TDM enzyme with a novel channeling pathway that guides formaldehyde to a remote tetrahydrofolate site, enhancing metabolic efficiency.

• Why it matters: Understanding how unstable intermediates like formaldehyde are managed is crucial for insights into detoxification and metabolic regulation, yet this process has been poorly understood.
• What they did: The study used cryo-EM to determine structures of TDM in different states, combined with biochemical and molecular dynamics analyses, identifying a tunnel that directs formaldehyde to a tetrahydrofolate-binding site.
• The result: This bifunctional architecture explains how TDM couples TMAO demethylation with one-carbon transfer, improving efficiency and detoxification, and broadening understanding of enzyme substrate channeling mechanisms.