9RO8

Pantoea ananatis encodes an antibacterial and anti-eukaryotic human CD38 homologue T6SS ADP-ribosyl cyclase polymorphic toxin

Summary for 9RO8

• Entry DOI: 10.2210/pdb9ro8/pdb
• Descriptor: ADP-ribosylcyclase toxin (2 entities in total)
• Functional Keywords: secreted toxin, adp-ribosylcyclase, cd38, adp-ribosylhydrolase, type vi secretion system, polymorphic toxin, toxin
• Biological source: Pantoea ananatis LMG 20103
• Total number of polymer chains: 2
• Total formula weight: 32846.54

Authors

Martinkus, J.,Terradot, L.,Jurenas, D.,Cascales, E. (deposition date: 2025-06-20, release date: 2025-10-01, Last modification date: 2025-11-12)

Primary citation

Martinkus, J.,Terradot, L.,Jurenas, D.,Cascales, E.
Widespread deployment of the human CD38 ADP-ribosyl cyclase fold in antibacterial and anti-eukaryotic polymorphic toxins.
J.Biol.Chem., 301:110775-110775, 2025

PubMed Abstract: Bacterial polymorphic toxins are modular weapons that mediate inter-microbial competition and host interactions by delivering diverse cytotoxic domains through specialized secretion systems. Here, we identify and characterize a novel toxin domain in Pantoea ananatis that displays remarkable structural and functional conservation with the human enzyme CD38. This bacterial toxin, fused to a type VI secretion system (T6SS) PAAR domain, harbors a C-terminal ADP-ribosyl cyclase (ARC) domain that hydrolyzes NAD and NADPin vitro and in vivo, leading to growth inhibition in both bacterial and eukaryotic cells. The 1.6-Å resolution structure of ARC reveals that it adopts a globular fold nearly identical to the human CD38 ADP ribosyl cyclase, with key catalytic residues conserved. Comparative genomics reveals that CD38-like ARC domains are widespread in bacteria, fused to diverse delivery modules including T6SS, T7SS, and CDI systems. Functional assays demonstrate that these domains act as NAD-depleting toxins, with cross-immunity observed between non-cognate toxin-immunity pairs. Taken together, our findings identify a bacterial NAD hydrolase fold with strong similarity to human CD38 and define a novel class of metabolic toxins, expanding the functional scope of polymorphic effectors and illustrating how enzymes can be co-opted for microbial warfare.

PubMed: 41022325
DOI: 10.1016/j.jbc.2025.110775

Experimental method

X-RAY DIFFRACTION (1.59 Å)