Biosynthesis of a Novel Diketopiperazine Aspkyncin Incorporating a Kynurenine Unit from <i>Aspergillus aculeatus</i>
The simplest cyclo-peptides, also known as diketopiperazines (DKPs), are widespread in nature. The growing interest in these simplest cyclo-peptides is driven by their significant potential for therapeutic applications. In this study, we identified a biosynthetic gene cluster from <i>Aspergill...
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| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-02-01
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| Series: | Journal of Fungi |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2309-608X/11/3/171 |
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| Summary: | The simplest cyclo-peptides, also known as diketopiperazines (DKPs), are widespread in nature. The growing interest in these simplest cyclo-peptides is driven by their significant potential for therapeutic applications. In this study, we identified a biosynthetic gene cluster from <i>Aspergillus aculeatus</i> CRI323-04 through genome mining and heterologous expression in <i>Aspergillus nidulans</i>. The two core genes, <i>aacA</i> and <i>aacB</i>, within the gene cluster were characterized for their role in the biossoynthesis of aspkyncin, a novel DKP compound that incorporates a <span style="font-variant: small-caps;">l</span>-kynurenine (<span style="font-variant: small-caps;">l</span>-Kyn) unit. Furthermore, we successfully reconstituted the activities of the minimal bimodular non-ribosomal peptide synthetase (NRPS) AacA and the methyltransferase AacB both in vivo and in vitro. Our findings demonstrate that AacA catalyzes the condensation and cyclization of two non-proteinogenic amino acids, <span style="font-variant: small-caps;">l</span>-Kyn and <i>N</i>-methyl-<span style="font-variant: small-caps;">l</span>-alanine, to produce aspkyncin without the involvement of any release domain. Notably, the <i>N</i>-methyl-<span style="font-variant: small-caps;">l</span>-alanine is generated by a specialized <span style="font-variant: small-caps;">l</span>-alanine <i>N</i>-methyltransferase AacB prior to NRP assembly. This study reveals an unconventional pathway for the biosynthesis of fungal DKPs. |
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| ISSN: | 2309-608X |