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

Cryo-EM structures reveal a novel substrate channeling pathway in Paracoccus TMAO demethylase, linking TMAO degradation to formaldehyde transfer via a tunnel.

• Why it matters: Understanding how unstable intermediates like formaldehyde are managed is crucial for insights into metabolic efficiency and detoxification processes, which remain poorly characterized in this enzyme.
• What they did: The study used cryo-EM to determine structures of TDM in different states, combined with biochemical and molecular dynamics analyses, to identify a tunnel guiding formaldehyde from the catalytic core to a tetrahydrofolate-binding site.
• The result: This bifunctional enzyme unites TMAO demethylation with one-carbon transfer, offering a mechanistic basis for its role in enhancing metabolic efficiency and detoxification.