Cobamide Scavenging and Import via a Multiprotein Extracellular Relay in Bacteroides thetaiotaomicron.

Cobamides, the structurally diverse family of cobalt-containing cofactors, are required by most bacteria yet synthesized by a subset of prokaryotes, making cobamide acquisition a major determinant of microbial fitness. Bacteroides thetaiotaomicron, an abundant commensal of the human gut, is auxotrophic for cobamides and relies on environmental scavenging to support its metabolism. To meet this demand in a competitive and diverse cobamide environment of the gut, B. thetaiotaomicron employs a B₁₂-uptake (Btu) system that extends far beyond the well-studied Escherichia coli Btu system. Rather than relying on a single outer membrane (OM) transporter, B. thetaiotaomicron deploys a multiprotein extracellular relay in which surface-exposed BtuJ lipoproteins capture cobamides extracellularly and transfer them to BtuH and BtuG lipoproteins at the OM. BtuG forms a stable complex with the TonB-dependent transporter BtuB, coupling cobamide capture to periplasmic translocation, and the inner membrane BtuFCD complex completes cytoplasmic delivery. BtuJ-enriched OM vesicles further extend cobamide capture into the extracellular environment, and cobamide-dependent riboswitches couple Btu protein expression to the availability and chemical identity of intracellular cobamides. We review the structural and mechanistic evidence for each stage of this relay, propose a model for cobamide import, and identify outstanding questions that will illuminate cobamide scavenging across gut bacteria.

© 2026 The Author(s). ChemBioChem published by Wiley‐VCH GmbH.