A new pathway for polyketide synthesis in microorganisms

Chalcone synthases, which biosynthesize chalcones (the starting materials f or many flavonoids(1,2)), have been believed to be specific to plants. Howe ver, the rppA gene from the Gram-positive, soil-living filamentous bacteriu m Streptomyces griseus encodes a 372-amino-acid protein that shows signific ant similarity to chalcone synthases'. Several rppA-like genes are known, b ut their functions and catalytic properties have not been described. Here w e show that a homodimer of RppA catalyses polyketide synthesis: it selects malonyl-coenzyme-A as the starter, carries out four successive extensions a nd releases the resulting pentaketide to cyclize to 1,3,6,8-tetrahydroxynap hthalene (THN). Site-directed mutagenesis revealed that, as in other chalco ne synthases(4,5), a cysteine residue is essential for enzyme activity. Dis ruption of the chromosomal rppA gene in S. griseus abolished melanin produc tion in hyphae, resulting in 'albino' mycelium. THN was readily oxidized to form 2,5,7-trihydroxy-1,4-naphthoquinone(flaviolin), which then randomly p olymerized to form various coloured compounds. THN formed by RppA appears t o be an intermediate in the biosynthetic pathways for not only melanins but also various secondary metabolites containing a naphthoquinone ring. There fore, RppA is a chalcone-synthase-related synthase that synthesizes polyket ides and is found in the Streptomyces and other bacteria.