Biosynthesis of Structurally Unique Fungal Metabolite GKK1032A₂:  Indication of Novel Carbocyclic Formation Mechanism in Polyketide Biosynthesis

The biosynthesis of the antitumor agent GKK1032A₂ (<b>1) </b>has been investigated by administration of isotopically labeled (¹³C and ²H) precursors to <i>Penicillium</i> sp. GKK1032. These studies showed that the backbone of <b>1</b> 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.