PGR and Other metabolic disease: Unexpectedly, no rate-limiting step was found and the FK506 production even decreased by substituting promoters of the core biosynthetic genes with the constructed promoter cassettes Pke or Pgr. This phenomenon might be explained by the fact that balanced metabolism between cell growth and product formation is critical and the insertion of strong constitutive promoters upstream of biosynthetic genes may cause metabolic disorders [44–46].