Bacterial MbtH-like proteins stimulate nonribosomal peptide synthetase-derived secondary metabolism in the filamentous fungi

Zwahlen, R., Pohl, C., Bovenberg, R. A. L. & Driessen, A. J. M., Sep-2019, In : ACS Synthetic Biology. 8, 8, p. 1776-1787 12 p.

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Filamentous fungi are known producers of bioactive natural products, low molecular weight molecules that arise from secondary metabolism. MbtH-like proteins (MLPs) are small (~10 kDa) proteins, which associate non-covalently with adenylation domains of some bacterial nonribosomal peptide synthetases (NRPS). MLPs promote the folding, stability, and activity of NRPS enzymes. MLPs are highly conserved amongst a wide range of bacteria, however, they are absent from all fungal species sequenced to date. We analyzed the interaction potential of bacterial MLPs with eukaryotic NRPS enzymes first using crystal structures, with results suggesting a conservation of the interaction surface. Subsequently, we transformed five MLPs into Penicillium chrysogenum strains and analyzed changes in NRPS-derived metabolite profiles. Three of the five transformed MLPs increased the rate of nonribosomal peptide formation and elevated the concentrations of intermediate and final products of the penicillin, roquefortine, chrysogine and fungisporin biosynthetic pathways. Our results suggest that even though MLPs are not found in the fungal domain of life, they can be used in fungal hosts as a tool for natural product discovery and biotechnological production.

Original languageEnglish
Pages (from-to)1776-1787
Number of pages12
JournalACS Synthetic Biology
Issue number8
Early online date8-Jul-2019
Publication statusPublished - Sep-2019


  • MbtH-like protein, nonribosomal peptide synthetases, Penicillium chrysogenum, secondary metabolism, fungal natural products, GENE-CLUSTER, SORBICILLIN BIOSYNTHESIS, PENICILLIUM, DOMAIN, GENOME, IDENTIFICATION, EXPRESSION, SEQUENCE, ENTEROBACTIN, ADENYLATION

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