N‐Acyl Amides from Neisseria meningitidis and Their Role in Sphingosine Receptor Signaling. (13th October 2022)

• Record Type: Journal Article
• Authors: Cho, Wooyoung; York, Autumn G.; Wang, Rurun; Wyche, Thomas P.; Piizzi, Grazia; Flavell, Richard A.; Crawford, Jason M.
• Is Part Of: Chembiochem. Volume 23:Number 22(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-10-13
• Subjects: GPCR signaling -- host-microbe interactions -- natural products -- N-acyl amides -- Neisseria; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.202200490
• Languages: English
• ISSNs: 1439-4227

Abstract

Abstract: Neisseria meningitidis is a Gram‐negative opportunistic pathogen that is responsible for causing human diseases with high mortality, such as septicemia and meningitis. The molecular mechanisms N. meningitidis employ to manipulate the immune system, translocate the mucosal and blood‐brain barriers, and exert virulence are largely unknown. Human‐associated bacteria encode a variety of bioactive small molecules with growing evidence for N ‐acyl amides as being important signaling molecules. However, only a small fraction of these metabolites has been identified from the human microbiota thus far. Here, we heterologously expressed an N ‐acyltransferase encoded in the obligate human pathogen N. meningitidis and identified 30 N ‐acyl amides with representative members serving as agonists of the G‐protein coupled receptor (GPCR) S1PR4. During this process, we also characterized two mammalian N ‐acyl amides derived from the bovine medium. Both groups of metabolites suppress anti‐inflammatory interleukin‐10 signaling in human macrophage cell types, but they also suppress the pro‐inflammatory interleukin‐17A + population in TH 17‐differentiated CD4 + T cells. Abstract : This study expands on the biosynthetic and functional diversity of N ‐acyl amides through structural characterization of previously undescribed N ‐acyl amides from bacterial and mammalian origin and functional characterization of such molecules to signal through G‐protein coupled receptor S1PR4, downregulate IL‐10 in a macrophage model, and decrease IL17A + population in TH 17 cells.