The cyclic depsipeptide FR900359 (FR, 1), a selective inhibitor of Gαq proteins (Ki= 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 Gαq 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:
[1] Schrage R, Schmitz AL, Gaffal E, Annala S, Kehraus S, Wenzel D, Büllesbach KM, Bald T, Inoue A, Shinjo Y, Galandrin S, Shridhar N, Hesse M, Grundmann M, Merten N, Charpentier TH, Martz M, Butcher AJ, Slodczyk T, Armando S, Effern M, Namkung Y, Jenkins L, Horn V, Stößel A, Dargatz H, Tietze D, Imhof D, Galés C, Drewke C, Müller CE, Hölzel M, Milligan G, Tobin AB, Gomeza J, Dohlman HG, Sondek J, Harden TK, Bouvier M, Laporte SA, Aoki J, Fleischmann BK, Mohr K, König GM, Tüting T, Kostenis E. The experimental power of FR900359 to study Gq-regulated biological processes. Nat Commun 2015; 6: 10156.
[2] Fujioka M, Koda S, Morimoto Y, Biemann K. Structure of FR900359, a cyclic depsipeptide from Ardisia crenata Sims. J Org Chem 1988; 53: 2820 – 2825.
[3] Ku C, Hu JM. Phylogenetic and cophylogenetic analyses of the leaf-nodule symbiosis in Ardisia subgenus Crispardisia (Myrsinaceae): Evidence from nuclear and chloroplast markers and bacterial rrn operons. Int J Plant Sci 2014; 175: 92 – 109.
[4] Miyamae A, Fujioka M, Koda S, Morimoto Y. Studies of FR900359, a novel cyclic depsipeptide from Ardisia crenata Sims 1989; 5: 873 – 878.
[5] Carlier A, Fehr L, Pinto-Carbó M, Schäberle T, Reher R, Dessein S, König GM, Eberl L. The genome analysis of Candidatus Burkholderia crenata reveals that secondary metabolism may be a key function of the Ardisia crenata leaf nodule symbiosis. Environ Microbiol 2015; doi: 10.1111/1462 – 2920.13184
