Biosynthesis of structurally unique fungal metabolite GKK1032A2:: Indication of novel carbocyclic formation mechanism in polyketide biosynthesis

The biosynthesis of the antitumor agent GKK1032A(2) (1) has been investigated by administration of isotopically labeled (C-13 and H-2) precursors to Penicillium sp. GKK1032. These studies showed that the backbone of 1 is constructed from h-tyrosine and a nonaketide chain flanked with five methyl groups probably by a polyketide synthase and a nonribosomal peptide synthetase hybrid. On the basis of the oxidation level of the starter unit and unusual 13-membered macroether formation between the tyrosine hydroxy group and the polyketide chain, novel cyclization mechanisms on the formation of a tricarbocyclic system and a macroether have been proposed. Involvement of a similar type of cyclization in the biosynthesis of structurally related metabolites is discussed.