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Somnogenic activity of O-acetylated and dimeric muramyl peptides
L Johannsen1, R S Rosenthal, S A Martin
1Department of Physiology and Biophysics, University of Tennessee, Memphis 38163.
Abstract:
Slow-wave sleep-promoting factors in brain and urine were identified as muramyl peptides (MPs), the building blocks of bacterial cell wall peptidoglycan. In this study, structural variations of MPs that occur naturally in bacterial peptidoglycan were investigated for somnogenic activity. Monomeric and dimeric MPs were isolated and purified from Neisseria gonorrhoeae and Actinomadura sp. strain R39. The structures of these MPs were verified by fast atom bombardment mass spectroscopy and tandem mass spectroscopy. After intracerebroventricular administration of MPs, electroencephalograms and brain temperatures of rabbits were recorded for 6 h and were analyzed to determine durations of slow-wave sleep, rapid-eye-movement sleep, and wakefulness. The 6-O acetylation of muramic acid enhanced the somnogenic effects of certain monomeric MPs relative to their non-O-acetylated (but otherwise identical) counterparts. Two monomeric MPs containing an unsubstituted amide (i.e., Iso-Gln) were inactive, thus confirming previous results showing that amidation of a variety of MPs can block somnogenic activity. Two peptide-cross-linked MP dimers tested had no effect on slow-wave sleep, although a third peptide-cross-linked MP containing a 1,6-anhydro muramyl end on one of its monomeric subunits, a structure that enhances somnogenic potency of un-cross-linked monomers, was somnogenic. Two dimers connected by glycosidic bonds and containing an Iso-Gln moiety were inactive. Two other glycosidically linked dimers that also contained an Iso-Gln moiety, but were of lower molecular weight, were somnogenic. In summary, 6-O acetylation of muramic acid in somnogenic MPs enhances activity, and as a class, peptide-linked dimeric MPs tend to be less active than their constituent monomers.
Insights
Structural variations of muramyl peptides (MPs), key components of bacterial cell walls, were examined for their sleep-promoting effects. Certain modifications, like 6-O acetylation, enhanced sleep activity, while others, such as amidation, reduced it.
Area of Science:
- Neuroscience
- Sleep Research
- Microbiology
Background:
- Muramyl peptides (MPs), derived from bacterial cell walls, are known sleep-promoting factors.
- Understanding the structure-activity relationship of MPs is crucial for sleep research.
Purpose of the Study:
- To investigate the somnogenic activity of naturally occurring structural variations of muramyl peptides (MPs).
- To determine how specific structural modifications influence the sleep-promoting effects of MPs.
Main Methods:
- Isolation and purification of monomeric and dimeric MPs from bacterial sources (Neisseria gonorrhoeae, Actinomadura sp. R39).
- Structural verification using mass spectrometry (FAB-MS, MS/MS).
- Intracerebroventricular administration of MPs to rabbits, followed by EEG and brain temperature monitoring to assess sleep-wake states.
Main Results:
- 6-O acetylation of muramic acid in MPs enhanced their somnogenic activity.
- Monomeric MPs with unsubstituted amides (Iso-Gln) were inactive, confirming amidation blocks activity.
- Peptide-linked dimeric MPs were generally less active than their monomeric counterparts, with one exception containing a 1,6-anhydro muramyl end.
- Glycosidically linked dimers containing Iso-Gln were inactive, except for lower molecular weight variants which were somnogenic.
Conclusions:
- Specific structural features of muramyl peptides significantly modulate their sleep-promoting (somnogenic) activity.
- 6-O acetylation enhances somnogenic potency, while amidation generally abolishes it.
- Dimeric MPs show varied activity depending on their linkage and substructure, with peptide-linked dimers often less potent than monomers.