Macrophage-targeting oligopeptides from Mortierella alpina

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 inve...

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Bibliographic Details
Published in:Chemical science (Cambridge) 2022-08, Vol.13 (31), p.9091-9101
Main Authors: Wurlitzer, Jacob M., Stanišić, Aleksa, Ziethe, Sebastian, Jordan, Paul M., Günther, Kerstin, Werz, Oliver, Kries, Hajo, Gressler, Markus
Format: Article
Language:English
Subjects:
Amino acids
Biosynthesis
Cell membranes
Chemistry
Congeners
Fluorescence
Fungi
Modules
Natural products
Peptides
Substrates
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Summary: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.
ISSN:2041-6520
2041-6539
DOI:10.1039/d2sc00860b