title: Promotion of sleep by gonococcal peptidoglycan fragments. Structural requirements for the somnogenic activity.
abstract: We exploited an extensive inventory of gonococcal peptidoglycan (PG) fragments to define the essential structural determinants of PG-mediated sleep-promoting activity in a rabbit sleep model. PG fragments, purified using reverse phase HPLC and structurally defined by fast atom bombardment mass-spectrometry, were administered intracerebroventricularly and the duration of specific sleep stages was determined electroencephalographically. Of the compounds tested, the principal naturally occurring sleep factor isolated from sleep-deprived animals (N-acetylglucosaminyl-[NAG]-1,6-anhydro-N-acetylmuramyl [anh.NAM]-alanyl-glutamyl-diaminopimelyl-alanine), the structurally identical PG monomer derived from gonococci, and individual analogs of the gonococcal compound which lacked the NAG residue or contained an additional alanine at the C-terminus possessed maximal potency; as little as 1 pmol of these anh.NAM-containing monomers induced excess slow wave sleep (p less than .05). In fact, each of five different anh.NAM-containing disaccharide peptides tested was somnogenic at 10 pmol or less, but none of a matched set of analogous PG monomers, differing only in replacement of anh.NAM by a hydrated NAM residue, was somnogenic at this dose. Together, these data suggested that the anh.NAM end, but not the NAG moiety, is a crucial structural determinant of gonococcal PG-mediated somnogenic activity. The somnogenic activity of anh.NAM-containing fragments was also modulated (albeit to a lesser extent) by the length and composition of the peptide side chain. On a much broader basis, the data also help raise the intriguing hypothesis that bacterial products may serve as natural regulators of nervous system function in higher animals.
mesh_terms: D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D004569:Electroencephalography; D008297:Male; D013058:Mass Spectrometry; D009344:Neisseria gonorrhoeae; D010446:Peptide Fragments / Q000032:analysis / Q000494:pharmacology*; D010457:Peptidoglycan / Q000032:analysis / Q000494:pharmacology*; D011817:Rabbits; D012890:Sleep / Q000187:drug effects*
chemical_list: D010446:Peptide Fragments; D010457:Peptidoglycan