Structures, Synthesis, and Human Nod1 Stimulation of Immunostimulatory Bacterial Peptidoglycan Fragments in the Environment

Bacteria release immunostimulatory compounds to the environment, and one of the stimulants is the ligand of nucleotide-binding oligomerization domain protein 1 (Nod1), an intracellular protein involved in the recognition of the bacterial component peptidoglycans having a diaminopimelic acid (DAP) structure. The polymorphisms of Nod1 have been linked to several inflammatory diseases and allergies that are strongly affected by environmental factors. The present paper summarizes recent results on the isolation and structural elucidation of natural human Nod1 (hNod1) ligands from the Escherichia coli (E. coli) K-12 culture supernatant, the first chemical synthesis of these natural ligands and related PGN fragments structures, and the hNod1 stimulatory activities of the chemically synthesized DAP-type PGN fragments. For structural characterization studies, the 7-(diethylamino)- coumarin-3-carbonyl (DEAC) labeling method was also used to enhance the sensitivity in mass spectrometry studies, in order to observe PGN fragments in a comprehensive manner. The results suggest that DAP-containing bacteria release certain hNod1 ligands to the environment and that these ligands accumulate in the environment and regulate the immune system through Nod1.