Insights into the complex biosynthesis of the leupyrrins in Sorangium cellulosum So ce690

Abstract

The anti-fungal leupyrrins are secondary metabolites produced by several strains of the myxobacterium Sorangium cellulosum. These intriguing compounds incorporate an atypically substituted γ-butyrolactone ring, as well as pyrrole and oxazolinone functionalities, which are located within an unusual asymmetrical macrodiolide. Previous feeding studies revealed that this novel structure arises from the homologation of four distinct structural units, nonribosomally-derived peptide, polyketide, isoprenoid and a dicarboxylic acid, coupled with modification of the various building blocks. Here we have attempted to reconcile the biosynthetic pathway proposed on the basis of the feeding studies with the underlying enzymatic machinery in the S. cellulosum strain So ce690. Gene products can be assigned to many of the suggested steps, but inspection of the gene set provokes the reconsideration of several key transformations. We support our analysis by the reconstitution in vitro of the biosynthesis of the pyrrole carboxylic starter unit along with gene inactivation. In addition, this study reveals that a significant proportion of the genes for leupyrrin biosynthesis are located outside the core cluster, a 'split' organization which is increasingly characteristic of the myxobacteria. Finally, we report the generation of four novel deshydroxy leupyrrin analogues by genetic engineering of the pathway.

Classification of the Adenylation and Acyl-Transferase Activity of NRPS and PKS Systems Using Ensembles of Substrate Specific Hidden Markov Models

“…In various cases other enzymes act on the created polypeptide and polyketide chains to tailor the final product (e.g. [21], [22]). These other enzymes are usually associated to the synth(et)ase complex and their genes are often organized in the same gene clusters [23].…”

Adaptation of an L-Proline Adenylation Domain to Use 4-Propyl-L-Proline in the Evolution of Lincosamide Biosynthesis

“…Several L-proline specific A-domains have been biochemically characterized [12-15], but no A-domain recognizing L-proline derivatives has so far been characterized in terms of kinetic parameters estimation. The objectives of the present work were to demonstrate that LmbC and CcbC function as amino acid activating subunits of the appropriate NDLS, a key enzyme of lincosamide biosynthesis, and, also to compare their substrate specificities and kinetic parameters to elucidate utilization of different amino acid precursors by NDLSs in lincomycin and celesticetin biosyntheses.…”

Current trends in myxobacteria research

“…Different strains of Sorangium produce several novel antimicrobial macrolides, the leupyrrins (Kopp et al 2011), the thuggacins (Irschik et al 2007;Buntin et al 2008), sorangicin (Irschik et al 2013), phoxalone (Guo et al 2008) and other components, like a new sesquiterpene, sorangiodenosine (Ahn et al 2008), a free radial scavenger, soraphinol C , as well as a novel class of antineoplastic agents, the epothilones and their analogs (Mulzer 2009). Epothilones and their analogues have demonstrated antitumor activity towards multidrug resistant tumor cells (Mulzer 2009;Gong et al 2014).…”