The ambruticins and jerangolids - chemistry, biology and chemoenzymatic synthesis of potent antifungal drug candidates.

Covering: 1977 to 2020The ambruticins and jerangolids are myxobacterial reduced polyketides, which are produced via highly unusual biosynthetic pathways containing a plethora of non-canonical enzymatic transformations. Since the discovery of the first congeners in the late 1970s, they have been in the focus of drug development due to their good antifungal activity and low toxicity in mammals, which result from interaction with an unusual innercellular target in fungi. Despite significant efforts, which have led to the development of various total syntheses, their structural complexity has yet avoided full exploitation of their pharmacological potential. This article summarises biological, total and semisynthetic as well as biosynthetic studies on both compounds. An outlook on the biosynthesis-based approaches to them and their derivatives is presented. Due to the structural and biosynthetic characteristics of the ambruticins and jerangolids, chemoenzymatic processes that make use of their biosynthetic pathway enzymes are particularly promising to gain efficient access to derivative libraries for structure activity relationship studies.

Rieske Oxygenase-Catalyzed Oxidative Late-Stage Functionalization during Complex Antifungal Polyketide Biosynthesis.

Rieske oxygenases (ROs) from natural product biosynthetic pathways are a poorly studied group of enzymes with significant potential as oxidative functionalization biocatalysts. A study on the ROs JerL, JerP, and AmbP from the biosynthetic pathways of jerangolid A and ambruticin VS-3 is described. Their activity was successfully reconstituted using whole-cell bioconversion systems coexpressing the ROs and their respective natural flavin-dependent reductase (FDR) partners. Feeding authentic biosynthetic intermediates and synthetic surrogates to these strains confirmed the involvement of the ROs in hydroxymethylpyrone and dihydropyran formation and revealed crucial information about the RO's substrate specificity. The pronounced dependence of JerL and JerP on the presence of a methylenolether allowed the precise temporal assignment of RO catalysis to the ultimate steps of jerangolid biosynthesis. JerP and AmbP stand out among the biosynthetic ROs studied so far for their ability to catalyze clean tetrahydropyran desaturation without further functionalizing the formed electron-rich double bonds. This work highlights the remarkable ability of ROs to highly selectively oxidize complex molecular scaffolds.