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.

Synthesis of N-acyl amide natural products using a versatile adenylating biocatalyst

“…The N -C12- l -histidine derivative can be chemically synthesised using the coupling of the acid chloride with l -histidine31 or from a His-loaded Wang resin (for the C6, C8 and C10 l -His versions) 30. We used the acid chloride method and the NMR and MS analysis of our isolated product is consistent with published data, although we noted technical issues with solvent solubility (Fig.…”

“…We picked enthanolamine and benzylamine, as well as amino acids to test whether the enzyme could be used to generate the corresponding N -acyl amino acid secondary amides. We focussed on l - and d -histidine for three reasons; firstly, to prepare the N -acyl histidine targets which have recently been discovered in L. pneumophila , a human pathogen 30. These metabolites are upregulated during the L. pneumophila infection cycle and could regulate human signalling pathways, analogously to other identified acyl amides.…”

An Ugi-like Biosynthetic Pathway Encodes Bombesin Receptor Subtype-3 Agonists

“…Isocyanide-containing compounds are a unique family of compounds, as they are the only stable molecules with a formally divalent carbon . Since the first terrestrial isocyanide xanthocillin was identified in Penicillium notatum in 1950, ∼400 natural products bearing this functionality have been characterized predominately from marine invertebrates, although they are sometimes isolated as their N -formamide (e.g., 2 ) or isothiocyanate degradation products. − Natural isocyanides can be identified via their chemoselective reaction with tetrazine probes in biological media …”

“…10−12 Natural isocyanides can be identified via their chemoselective reaction with tetrazine probes in biological media. 13 There are two established proposals for isocyanide biosynthesis. In the first route, IsnA-type enzymes are thought to excise the C2 carbon of ribulose-5-phosphate and transfer it onto the amine of an amino acid precursor.…”

Metabolomics in Sepsis and Its Impact on Public Health

“…The utility of metabolomics in sepsis also lies with the identification of metabolites from certain pathways in bacteria that could reveal potential antimicrobial targets, thus changing not only the diagnostic but also the therapeutic landscape [90]. A recent study used quantitative 1H-NMR spectroscopy to study the effects of 5 antibiotic classes to the metabolic response of E. coli cultures.…”