Mutasynthesis‐Derived Myxalamids and Origin of the Isobutyryl‐CoA Starter Unit of Myxalamid B

Abstract

Myxalamids are potent inhibitors of the eukaryotic electron transport chain produced by different myxobacteria. Here, we describe the identification of the myxalamid biosynthesis gene cluster from Myxococcus xanthus. Additionally, new myxalamids (5-13) have been obtained by mutasynthesis from bkd mutants of M. xanthus and Stigmatella aurantiaca. Moreover, as these bkd mutants are still able to produce myxalamid B (2), the origin of the isobutyryl-CoA (IB-CoA) starter unit required for its biosynthesis has been determined. In a M. xanthus bkd mutant, IB-CoA originates from valine, but in S. aurantiaca this starter unit is derived from alpha-oxidation of iso-odd fatty acids, thereby connecting primary and secondary metabolism.

IcmF Is a Fusion between the Radical B12 Enzyme Isobutyryl-CoA Mutase and Its G-protein Chaperone

“…These results were unexpected because the bkd mutants are unable to form isobutyryl-CoA starter units from valine. The authors suggested that fatty acid degradation by ␣-and ␤-oxidation of iso-odd fatty acid could be responsible for isobutyryl-CoA synthesis (37). We speculate that the ICM activity of IcmF found in both these bacteria might play a role in this process instead.…”

“…In studies on M. xanthus and S. aurantiaca mutants in which the branched-chain ketoacid dehydrogenase was disrupted (bkd mutants), it was shown that isobutyryl-CoA is incorporated into the final product (37). These results were unexpected because the bkd mutants are unable to form isobutyryl-CoA starter units from valine.…”

Die biosynthetische Grundlage der Polyketid‐Vielfalt

“…[137] Eines der wichtigsten Beispiele ist die manipulierte Biosynthese zum Avermectin-Derivat Doramectin, das klinische Anwendung als sehr wirksames Wurmmittel findet. [138] Weitere erfolgreiche Mutasynthesen lieferten neue biologisch aktive Analoga von Aureothin, [139] Rapamycin, [140,141] Borrelidin, [142] Myxalamid [143] und Ansamitocin.…”

Myxoprincomide: A Natural Product from Myxococcus xanthus Discovered by Comprehensive Analysis of the Secondary Metabolome

“…To date only five compound classes derived from NRPS and PKS biosynthetic machineries have been characterized and correlated to their gene clusters in DK1622 (see Figure 1 in the Supporting Information). [8][9][10][11][12][13] Intriguingly, evaluation at the transcriptomic and proteomic levels asserts that the remaining 13 unassigned pathways are active under standard conditions for the cultivation of DK1622. [14,15] We reasoned that the low abundance of the corresponding compounds may have previously prevented their detection, and thus set out to find these compounds by utilizing advanced analytical methods.…”