Biosynthesis of swainsonine in Rhizoctonia leguminicola. Epimerization at the ring fusion

Identification of the Polyketide Biosynthetic Machinery for the Indolizidine Alkaloid Cyclizidine

“…2 Indolizidine alkaloids have been isolated from a myriad of sources, including ants, frogs, plants, and fungi. 3 Surprisingly, only cyclizidine (CLD) and two congeners, JBIR-102 and indolizomycin, are known to be of bacterial origin. 4 In particular, CLD was produced by Streptomyces NCIB 11649, and structural analysis revealed that the indolizidine core of CLD is substituted with two hydroxyl moieties (C9 and C10), a C12/C13 epoxide, and a monosubstituted cyclopropyl trans -dienic subunit at C8 (Figure 1).…”

“…5 The complexity in the molecular structure of CLD and the difficulty in its organic synthesis thus make the study of its biosynthetic pathway interesting. Although isotope-labeled precursor feeding studies have been performed to probe the possible biosynthetic origins of several indolizidines, 3c, 7 no dedicated genes or enzymes have yet been identified for this family of alkaloids. Here, we report the identification of the biosynthetic gene cluster for CLD from Streptomyces through genome scanning, targeted gene deletion, and enzymatic studies.…”

“…Similar chemical logic and enzymatic machinery are likely involved in JBIR-102 and indolizomycin biosynthesis, although indolizidine alkaloids lacking the extended olefinic appendage are probably generated differently. 3c, 7b Additional genetic and biochemical studies will provide more insight into the timing and mechanism of the biosynthetic enzymes in producing cyclizidine-type indolizidine alkaloids and promote the engineered biosynthesis of new indolizidine alkaloids for drug discovery.…”

The Indolizidine Alkaloids, Slaframine and Swainsonine: Contaminants in Animal Forages

“…Pipecolate and malonate (V) are thought to condense at the thiol ester level to form pipecolylacetate (VI, Figure 2) (9), which on reduction and cyclization would give the stable intermediate, l-ketooctahydroindolizine (VII, Figure 2) (25). The latter is then stereochemically reduced to the required isomeric form of l-hydroxyoctahydroindolizine (VIIIa, Figure 2) (25,47), which is then appropriately function ali zed to ultimately yield slaframine (23,25). This asymmetric synthesis of slaframine is compared below with swainso nine formation also arising from pipecolate metabolism in this fungus.…”

“…The latter is used in the fonnation of l-ketooctahydroindolizine (VII, Figure 2), which is then reduced from both the a and � faces to give the respective I-hydroxyoctahydroindolizines, VIlla and VIllb, leading ultimately to slaframine and swainsonine (47). Another interesting feature in the stereochemistry of slaframine and swainsonine is that the L-configuration of the a-carbon atom of pipecolate is retained with respect to the 8a H atom through out the entire sequence of transformations leading to slaframine, but it is epimerized at some stage in swainsonine biosynthesis (Figure 2) (47). It is now established (28) that 1,2-dihydroxyoctahydroindolizine (structure IX, Figure 2) is a swainsonine intermediate and that hydroxylation at C-8 and epimeriza tion at C-8a are the final steps in swainsonine biogenesis in R. leguminicola (28).…”