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 gonoccocal 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 < .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.
Similar content being viewed by others
References
Fleming, T. J., D. E. Wallsmith & R. S. Rosenthal (1986) Arthropathic properties of gonococcal peptidoglycan fragments: implications for the pathogenesis of disseminated gonococcal disease. Infect. Immun. 52:600–608
Krueger, J. M., D. Davenne, J. Walter, S. Shoham, S. L. Kubillus, R. S. Rosenthal, S. A. Martin & K. Biemann (1986) Bacterial peptidoglycans as modulators of sleep: II. Effects of muramyl peptides on the structure of rabbit sleep. Brain Res. 403:258–266
Krueger, J. M., M. L. Karnovsky, S. A. Martin, J. R. Pappenheimer, J. Walter & K. Biemann (1984) Peptidoglycans as promoters of slow-wave sleep: II. Somnogenic and pyrogenic activities of some naturally occurring muramyl peptides; correlations with mass spectrometric structure determination. J. Biol. Chem. 259:12659–12662
Krueger, J. M., J. R. Pappenheimer & M. L. Karnovsky (1982) The composition of sleep-promoting factor isolated from human urine. J. Biol. Chem. 257:1664–1669.
Krueger, J. M., J. R. Pappenheimer & M. L. Karnovsky (1982a) Sleep-promoting effects of muramyl peptides. Proc. Natl. Acad. Sci., USA 79:6102–6106
Martin, S. A., M. L. Karnovsky, J. M. Krueger, J. R. Pappenheimer & K. Biemann (1984) Peptidoglycans as promoters of slow-wave sleep. I. Structure of the sleep-promoting factor isolated from human urine. J. Biol. Chem. 259:12652–12658
Melly, M. A., Z. A. McGee & R. S. Rosenthal (1984) Ability of monomeric peptidoglycan fragments from Neisseria gonorrhoeae to damage human fallopian tube mucosa. J. Infect. Dis. 149:378–386
Pappenheimer, J. R., G. Koski, V. Fenel, M. L. Karnovsky & J. Krueger (1975) Extraction of sleep-promoting factor S from cerebrospinal fluid and from brains of sleep-deprived animals. J. Neurophysiol. 38:1299–1311
Rosenthal, R. S. (1979) Release of soluble peptidoglycan from growing gonococci: hexaminidase and amidase activities. Infect. Immun. 24:869–878
Rosenthal, R. S., W. J. Folkening, D. R. Miller & S. C. Swim (1983) Resistance of O-acetylated gonococcal peptidoglycan to human peptidoglycan-degrading enzymes. Infect. Immun. 40:903–911
Sinha, R. K. & R. S. Rosenthal (1980) Release of soluble peptidoglycan from growing gonococci: demonstration of anhydro-muramyl-containing fragments. Infect. Immun. 29:914–925
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Rosenthal, R.S., Krueger, J.M. Promotion of sleep by gonococcal peptidoglycan fragments. Structural requirements for the somnogenic activity. Antonie van Leeuwenhoek 53, 523–532 (1987). https://doi.org/10.1007/BF00415512
Issue Date:
DOI: https://doi.org/10.1007/BF00415512