biostudies-literatureColautti JU.S. Department of EnergyInstitute of Infection and ImmunityBurroughs Wellcome FundOffice of ScienceBrookhaven National LaboratoryCanadian Institutes of Health Research110491https://www.ebi.ac.uk/biostudies/studies/S-EPMC12356396biostudies-literatureUnknown301(8)In metazoans, enzymes belonging to the bifunctional ADP-ribosyl cyclase/cyclic ADP-ribose (cADPr) hydrolase family regulate diverse cellular processes by synthesizing and hydrolyzing the intracellular second messenger cADPr, derived from the electron carrier NAD⁺. However, bacterial enzymes belonging to this family have not been characterized. Here, we identify a bacterial ADP-ribosyl cyclase that is associated with the type VII secretion system and functions as an antibacterial toxin. This enzyme, which we name Tac1, inhibits bacterial growth by rapidly hydrolyzing NAD⁺ and NADP⁺. We determine the X-ray crystal structure of Tac1 to a resolution of 1.4 Å, which reveals that this protein adopts the core catalytic fold of metazoan ADP-ribosyl cyclase enzymes The Journal of biological chemistryAntibacterial ADP-ribosyl cyclase toxins inhibit bacterial growth by rapidly depleting NAD(P)<sup/>.PMC12356396DE-SC0012704PJT-173486Kim YColautti JWhitney JCfalseAntibacterial ADP-ribosyl cyclase toxins inhibit bacterial growth by rapidly depleting NAD(P)<sup/>.In metazoans, enzymes belonging to the bifunctional ADP-ribosyl cyclase/cyclic ADP-ribose (cADPr) hydrolase family regulate diverse cellular processes by synthesizing and hydrolyzing the intracellular second messenger cADPr, derived from the electron carrier NAD⁺. However, bacterial enzymes belonging to this family have not been characterized. Here, we identify a bacterial ADP-ribosyl cyclase that is associated with the type VII secretion system and functions as an antibacterial toxin. This enzyme, which we name Tac1, inhibits bacterial growth by rapidly hydrolyzing NAD⁺ and NADP⁺. We determine the X-ray crystal structure of Tac1 to a resolution of 1.4 Å, which reveals that this protein adopts the core catalytic fold of metazoan ADP-ribosyl cyclase enzymes 2025-01-01T00:00:00Z2025 Aug2026-05-29T16:32:06.44Z2026-04-08T05:25:01.263ZS-EPMC123563964068084210.1016/j.jbc.2025.110491