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| Home > Publications database > Application of C3-methyltransferases for natural product synthesis |
| Book/Dissertation / PhD Thesis | FZJ-2025-04406 |
2025
Forschungszentrum Jülich GmbH Zentralbibliothek, Verlag
Jülich
ISBN: 978-3-95806-862-9
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Abstract: Natural products play a vital role in drug development, either directly as pharmaceuticals or as templates for designing target-specific therapeutics. The chemical synthesis of these compounds often presents significant challenges, requiring multiple reaction steps and hazardous reagents. One prominent structural motif found in numerous bioactive natural products is the hexahydropyrrolo[2,3- b]indole (HPI) framework. Its unique tricyclic structure and diverse biological activities have driven significant synthetic interest, yet traditional methods struggle to achieve stereoselectivity efficiently. This thesis aims to develop a biocatalytic route for synthesising the HPI motif using methyltransferases (MTases), which catalyses C3-methylation of tryptophan-based cyclic dipeptides (DKPs). The MTase StspM1 from Streptomyces sp. HPH0547 was selected as the starting point for these studies: Optimised reaction conditions, enzyme immobilisation, and S-adenosyl methionine (SAM) cofactor recycling were investigated to create a scalable, efficient method. To broaden the understanding of their catalytic functions, homologs of StspM1 were explored, focusing on their structure and mechanism. This investigation was supported by two crystal structures obtained during the study. Computational docking and mutagenesis confirmed key residues critical for activity. Among these homologs, SgMT from Streptomyces griseoviridis was successfully integrated into the total synthesis of the natural product lansai B, demonstrating its synthetic utility. The gene clusters linked to these C3-MTases involve additional enzymes contributing to the biosynthesis of lansai B, including a second MTase, a cyclodipeptide synthase (CDPS) and a prenyltransferase (PTase). The second MTase was confirmed to function as an N-MTase. The PTase was found to prenylate the C5-position, representing the final step in the biosynthesis of lansai B This work advances biocatalytic strategies for synthesising complex natural product frameworks, offering new methodologies for pharmaceutical development.
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