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Macrophage-targeting oligopeptides from Mortierella alpina
Jacob M Wurlitzer1, Aleksa Stanišić2, Sebastian Ziethe1
1Department Pharmaceutical Microbiology at the Leibniz Institute for Natural Product Research and Infection Biology (Hans-Knöll-Institute), Friedrich-Schiller-University Winzerlaer Strasse 2 Jena 07745 Germany markus.gressler@leibniz-hki.de.
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.
Insights
Researchers identified the enzyme MalA, which produces malpinins, novel biosurfactants from fungi. This enzyme can create new compounds and be used for drug delivery applications.
Area of Science:
- Biochemistry
- Mycology
- Natural Products Chemistry
Background:
- Early diverging fungi, like *Mortierella* species, are a largely unexplored source of novel natural products.
- Nonribosomal peptide synthetases (NRPS) are key enzymes in the biosynthesis of complex microbial metabolites.
Purpose of the Study:
- To identify and characterize the NRPS enzyme MalA responsible for malpinin biosynthesis in *Mortierella* species.
- To explore the substrate specificity and biosynthetic potential of MalA for generating novel compounds.
- To investigate the potential of malpinins as carrier peptides for drug delivery.
Main Methods:
- Biochemical characterization of the NRPS enzyme MalA.
- Substrate specificity analysis of adenylation (A) domains.
- Precursor-directed biosynthesis to generate malpinin congeners.
- Postbiosynthetic modification with a fluorophore for cell imaging.
Main Results:
- Identification and biochemical characterization of MalA, a NRPS catalyzing malpinin production.
- MalA demonstrated substrate tolerance and produced 20 new malpinin congeners via precursor-directed biosynthesis.
- MalA incorporated artificial amino acids, enabling fluorescent labeling of malpinins.
- Fluorescent malpinins were shown to penetrate mammalian cells via phagocytosis, suggesting potential as carrier peptides.
Conclusions:
- Substrate-specificity testing is effective for identifying flexible NRPS modules.
- Basal fungi represent a valuable resource for discovering chemically tractable compounds for pharmaceutical applications.
- Malpinins derived from *Mortierella* species show promise for targeted cell delivery applications.
