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A semipinacol rearrangement directed by an enzymatic system featuring dual-function FAD-dependent monooxygenase.

Nature has invented ingenious ways to biosynthesize biologically active small molecules that have been applied ever since to benefit human life in various ways. During the underlying biosynthetic processes, highly elaborate chemical reactions are often catalyzed by enzymatic systems, thereby enabling transformations under physiological conditions that would require harsh conditions or are hardly possible without enzymatic catalysis. Consequently, understanding novel biochemical transformations is of importance to eventually apply the knowledge gained to generate molecules of interest. Aurachins are quinoline alkaloids isolated from the myxobacterium Stigmatella aurantiaca Sg a15; they have various biological activities, including antibacterial, antifungal, antiplasmodial, and mitochondrial respiration inhibition properties. The biosynthesis of aurachin derivatives includes several interesting features in which the most intriguing reaction is the conversion of aurachin C (1) to B (2). This step involves the migration of the prenyl group from position C3 to C4, probably via a pinacol type rearrangement (Scheme 1). Pinacol rearrangements are proposed to occur during the biosyntheses of various secondary metabolites, including aflatoxin B1, (+)-liphagal, (+)-asteltoxin, brevianamides, paraherquamide B, verscicolamide B, and notoamides. However, no such biosynthetic hypotheses has been biochemically proven, although the proposed pathways in turn inspired biomimetic approaches for natural product synthesis. Therefore, an enzymatic system for pinacol-type rearrangement remained to be discovered in the biosynthesis of secondary metabolites. Even in primary metabolism there are only two reported examples in course of the biosynthesis of branched chain amino acids and 1-deoxy-d-xylulose-5phosphate. The biosynthetic conversion of aurachin C (1) to B (2) was initially studied by feeding experiments carried out by Hçfle and Kunze. Importantly, they reported that the hydroxy group of aurachin B (2) at C3 is derived from molecular oxygen. Recent work by Pistorius et al. discovered two gene loci containing aurachin biosynthetic genes in addition to the core biosynthetic gene cluster. The authors speculated that two enzymes encoded by auaG and auaH are responsible for the migration of the farnesyl group from C3 to C4. However, the detailed biosynthetic conversion still remains to be solved, mainly because of the lack of detection of putative intermediates in vivo in auaG and auaH mutants of S. aurantiaca Sg a15. To uncover the enzymatic chemistry behind this intriguing rearrangement reaction, we here describe in vitro experiments using recombinant AuaG and AuaH proteins. AuaG belongs to the family of flavin-dependent monooxygenases and appears to be relatively similar to PgaE involved in angucycline biosynthesis according to results from BLAST search and Phyre2 analysis, respectively. The Scheme 1. Biosynthetic pathway of aurachin B (2) from aurachin C (1).