Biosynthesis of Structurally Unique Fungal Metabolite GKK1032A(2): 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 ((13)C and (2)H) precursors to Penicillium sp. GKK1032. These studies showed that the backbone of 1 is constructed from l-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.