title: Novel chemobiosynthetic approach for exclusive production of FK506.
abstract: 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.
authors.affiliation: Acies Bio d.o.o., Tehnološki Park 21, SI-1000 Ljubljana, Slovenia.
authors.forename: Gregor
authors.initials: G
authors.lastname: Kosec
authors.forename: Dušan
authors.initials: D
authors.lastname: Goranovič
authors.forename: Peter
authors.initials: P
authors.lastname: Mrak
authors.forename: Stefan
authors.initials: S
authors.lastname: Fujs
authors.forename: Enej
authors.initials: E
authors.lastname: Kuščer
authors.forename: Jaka
authors.initials: J
authors.lastname: Horvat
authors.forename: Gregor
authors.initials: G
authors.lastname: Kopitar
authors.forename: Hrvoje
authors.initials: H
authors.lastname: Petković
mesh_terms: D044944:Acyl-CoA Dehydrogenases / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D005798:Genes, Bacterial / Q000235:genetics; D013302:Streptomyces / Q000235:genetics / Q000378:metabolism*; D016559:Tacrolimus / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D044944:Acyl-CoA Dehydrogenases; C100154:acyl-CoA dehydrogenase (NADP+); D016559:Tacrolimus