title: Acyl Histidines: New N-Acyl Amides from Legionella pneumophila.
abstract: Legionella pneumophila, the causative agent of Legionnaires' disease, is a Gram-negative gammaproteobacterial pathogen that infects and intracellularly replicates in human macrophages and a variety of protozoa. L. pneumophila encodes an orphan biosynthetic gene cluster (BGC) that contains isocyanide-associated biosynthetic genes and is upregulated during infection. Because isocyanide-functionalized metabolites are known to harbor invertebrate innate immunosuppressive activities in bacterial pathogen-insect interactions, we used pathway-targeted molecular networking and tetrazine-based chemoseletive ligation chemistry to characterize the metabolites from the orphan pathway in L. pneumophila. We also assessed their intracellular growth contributions in an amoeba and in murine bone-marrow-derived macrophages. Unexpectedly, two distinct groups of aromatic amino acid-derived metabolites were identified from the pathway, including a known tyrosine-derived isocyanide and a family of new N-acyl-l-histidine metabolites.
authors.affiliation: Interdiscplinary Nanoscience Center, Aarhus University, Gustav Wieds Vej 14, 8000, Aarhus C, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tørring
authors.affiliation: Department of Microbial Pathogenesis, Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA.
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: Shames
authors.affiliation: Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT, 06511, USA.|Chemical Biology Institute, Yale University, 600 West Campus Drive, West Haven, CT, 06516, USA.
authors.forename: Wooyoung
authors.initials: W
authors.lastname: Cho
authors.affiliation: Department of Microbial Pathogenesis, Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA.
authors.forename: Craig R
authors.initials: CR
authors.lastname: Roy
authors.affiliation: Department of Microbial Pathogenesis, Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA.|Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT, 06511, USA.|Chemical Biology Institute, Yale University, 600 West Campus Drive, West Haven, CT, 06516, USA.
authors.forename: Jason M
authors.identifier: 0000-0002-7583-1242
authors.initials: JM
authors.lastname: Crawford
mesh_terms: D048248:Acanthamoeba castellanii / Q000382:microbiology; D000577:Amides / Q000378:metabolism*; D000818:Animals; D006639:Histidine / Q000031:analogs & derivatives* / Q000096:biosynthesis*; D016952:Legionella pneumophila / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D015335:Molecular Probes / Q000737:chemistry; D005810:Multigene Family; D011725:Pyridines / Q000737:chemistry
chemical_list: C000622613:3,6-di-2-pyridyl-1,2,4,5-tetrazine; D000577:Amides; D015335:Molecular Probes; D011725:Pyridines; D006639:Histidine
keywords: legionellosis; metabolomics; natural product; pneumonia; secondary metabolism