Genome sequence analyses of Streptomyces species have shown that
the number of biosynthetic gene clusters encoded on the chromosome
is much higher than the number of secondary metabolites isolated
from each species.12,13 The genome of S. reveromyceticus SN-593 was
sequenced in the course of the studies of the biosynthesis of
reveromycin A, which inhibits bone resorption and bone metastases
of tumor cells.14–16 Analysis of the draft genome data of
S. reveromyceticus revealed that a type III PKS named DpyA is
encoded on a linear plasmid derived from this bacterium. In this
study, we demonstrate that DpyA catalyzes the synthesis of the novel
dihydropyran compounds alkyldihydropyrone A–D (Figure 1) from
b-hydroxyl acid thioesters and methylmalonyl-CoA, both in vivo and
in vitro. DpyA preferentially uses the b-hydroxyl acid thioester rather
than the b-keto acid thioester as a starter substrate. A unique feature
of DpyA is an ability to catalyze lactonization of secondary alcohols
and thioesters. In addition, alkyldihydropyrones showed weak cytotoxicity
against the leukemia cell line HL-60.