Many
clinically useful pharmaceuticals are semi-synthesized from natural products
produced by microorganisms, which sometimes resulted in low yields and high
costs. Fusicoccin A (FC) is a diterpene glycoside produced by a fungus Phomopsis
amygdali, and semi-synthesized FC-derivatives without a hydroxyl group at
the 12-position are now examined for application to anti-cancer drugs. We
cloned FC biosynthetic
genes clusters, which were scattered at two different loci, one contained four
genes and another did nine genes, and characterized most of their products. Based
on the results, we assumed that a mutant, in which the gene responsible for the
12-hydroxylation is disrupted, accumulates FC H, an intermediate lacking the hydroxyl
group at the 12-position as a main metabolite, which can be efficiently
converted into the anti-cancer drugs. The disruptant was obtained by a
homologous recombination and produced FCH as a sole product as expected and its
productivity was the same as that of the sum of FC-related compound produced by
the parental strain. Moreover, the 19-hydroxylation gene disruptant also
produced FC J as the sole compound with high titer. Taken together, the
strategy, production of an intermediate compound by a gene-disruptant and its
use for semi-synthesis, would be applicable for development of some pharmaceuticals,
which are semi-synthesized from fungal metabolites.
(References: PNAS, 2007, 104, 3084; JACS, 2010, 133, 2548; Chembiochem, 2012, 13, 566).