Macrophage-targeting oligopeptides from Mortierella alpina. Issue 31 (21st July 2022)

• Record Type: Journal Article
• Authors: Wurlitzer, Jacob M.; Stanišić, Aleksa; Ziethe, Sebastian; Jordan, Paul M.; Günther, Kerstin; Werz, Oliver; Kries, Hajo; Gressler, Markus
• Is Part Of: Chemical science. Volume 13:Issue 31(2022)
• Page Start: 9091
• Page End: 9101
• Publication Date: 2022-07-21
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/d2sc00860b
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : Specificity profiling of a nonribosomal peptide synthetase of an early diverging fungus revealed high substrate flexibility. Feeding studies with click-functionalised amino acids enabled the production of fluorescent peptides targeting macrophages. Abstract : The realm of natural products of early diverging fungi such as Mortierella species is largely unexplored. Herein, the nonribosomal peptide synthetase (NRPS) MalA catalysing the biosynthesis of the surface-active biosurfactants, malpinins, has been identified and biochemically characterised. The investigation of the substrate specificity of respective adenylation (A) domains indicated a substrate-tolerant enzyme with an unusual, inactive C-terminal NRPS module. Specificity-based precursor-directed biosynthesis yielded 20 new congeners produced by a single enzyme. Moreover, MalA incorporates artificial, click-functionalised amino acids which allowed postbiosynthetic coupling to a fluorophore. The fluorescent malpinin conjugate penetrates mammalian cell membranes via an phagocytosis-mediated mechanism, suggesting Mortierella oligopeptides as carrier peptides for directed cell targeting. The current study demonstrates substrate-specificity testing as a powerful tool to identify flexible NRPS modules and highlights basal fungi as reservoir for chemically tractable compounds in pharmaceutical applications.