The endophyte Candidatus Burkholderia crenata of the TCM plant Ardisia crenata produces the selective Gq-inhibitor FR900359

The cyclic depsipeptide FR900359 (FR, 1), a selective inhibitor of Gα_q proteins (K_i= 6.90 ± 1.30nM), is applied as an extremely useful pharmacological tool. Additionally, this highly active molecule is evaluated for the treatment of pulmonary diseases and melanoma [1].

FR is present in the higher plant Ardisia crenata [2], which is known to harbor symbiotic bacteria of the genus Burkholderia [3,5]. In the current study, the novel, closely related cyclic depsipeptide AC-1 (2) was isolated as a minor metabolite from A. crenata. Structure elucidation was performed by extensive 2D-NMR and MS² analysis. Despite only little structural differences in AC-1 as compared to FR (see figure below), its bioactivity towards Gα_q proteins is altered. These findings together with results from the semi-synthetically derived FR-Hexanoate (3) allowed us to deduce first structure-activity-relationships.

These cyclic depsipeptides show several structural peculiarities, (i) rare, non-proteinogenic amino acids with manifold N- and O-methylations, (ii) multiple ester bonds, and (iii) cis-configurated amide bonds [4], which makes their non-ribosomal and bacterial origin likely. Indeed, sequencing the genome of Candidatus Burkholderia crenata, the leaf nodule symbiont of A. crenata, revealed a non-ribosomal peptide synthetase (NRPS) gene cluster, putatively encoding FR biosynthesis.⁵ First results verified the deduced biosynthetic hypothesis and serve as basis for further genetic and biochemical studies.

Acknowledgements: We thank Dr. Marc Sylvester for measuring Tandem-MS data and Nina Heycke for technical assistance. DFG is acknowledged for funding research unit FOR 2372.

Keywords: Endophyte, Gq-Inhibitor, FR900359, cyclic Depsipeptide, NRPS, SAR.

References:

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