Analysis of the Valgamicin Biosynthetic Pathway Reveals a General Mechanism for Cyclopropanol Formation across Diverse Natural Product Scaffolds

Abstract

Cyclopropanol rings are highly reactive and may function as molecular "warheads" that affect natural product bioactivity. Yet, knowledge on their biosynthesis is limited. Using gene cluster analyses, isotope labeling, and in vitro enzyme assays, we shed first light on the biosynthesis of the cyclopropanolsubstituted amino acid cleonine, a residue in the antimicrobial depsipeptide valgamicin C and the cytotoxic glycopeptide cleomycin A2. We decipher the biosynthetic origin of valgamicin C and show that the cleonine cyclopropanol ring is derived from dimethylsulfoniopropionate (DMSP). Furthermore, we demonstrate that part of the biosynthesis is analogous to the formation of malleicyprol polyketides in pathogenic bacteria. By genome mining and metabolic profiling, we identify the potential to produce cyclopropanol rings in other bacterial species. Our results reveal a general mechanism for cyclopropyl alcohol biosynthesis across diverse natural products that may be harnessed for bioengineering and drug discovery.

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“…Gene cluster analyses, labelling experiments and in vitro enzyme assays have been used to investigate cyclopropanol formation in the amino acid, cleonine, a component of the antimicrobial depsipeptide valgamicin C 28 from Amycolatopsis species ML1-hF4. 25 These studies showed that cleonine is biosynthesised from methionine via dimethylsulfoniopropionate, using ValA, a bimodular polyketide synthase–nonribosomal peptide synthetase hybrid. Heterologous expression of the biosynthetic gene cluster of the sterol O -acyltransferase inhibitor helvamide 29 in Aspergillus nidulans has revealed a novel analogue helvamide B 30 .…”

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“…Furthermore, these changes are not related to the cyclo-propanol backbone of 5, as shown by the comparison between BurJ and the enzyme ValAI that activates Scleonine, the analogous amino acid compared to 5. [28] Only a few biosynthetic pathways are known that use adenylation enzymes in trans, and these pathways require specialized enzymes for building block transfer. Examples include refined thioesterases [29] and α/β hydrolases [30] that act as aminoacyl transferases.…”