Novel chemobiosynthetic approach for exclusive production of FK506

FK506, a widely used immunosuppressant, is produced by industrial fermentation processes using various Streptomyces species. Independently of the strain, structurally related compound FK520 is co-produced, resulting in complex and costly isolation procedures. In this paper, we report a chemobiosynthetic approach for exclusive biosynthesis of FK506. This approach is based on the Streptomyces tsukubaensis strain with inactivated allR gene, a homologue of crotonyl-CoA carboxylase/reductase, encoded in the FK506 biosynthetic cluster. This strain produces neither FK506 nor FK520; however, if allylmalonyl-S-N-acetylcysteamine precursor is added to cultivation broth, the production of FK506 is reestablished without FK506-related by-products. Using a combination of metabolic engineering and chemobiosynthetic approach, we achieved exclusive production of FK506, representing a significant step towards development of an advanced industrial bioprocess.

► Streptomyces tsukubaensis produces FK506 together with FK520 as a by-product.
► Inactivation of the allR gene abolishes biosynthesis of FK506 as well as FK520.
► allR encodes a broadly specific enoyl-CoA carboxylase/reductase.
► Feeding allylmalonyl-SNAC to ΔallR strain reestablishes biosynthesis of FK506.
► We describe a chemobiosynthetic procedure for exclusive production of FK506.