FUNCTIONAL BIOSYNTHETIC ROLES OF POLYKETIDE SYNTHASES, CYCLASES & KETOREDUCTASES

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Iterative type II polyketide synthases (PKSs) have been determined to produce polyketide chains of variable but defined length from a specific starter unit and a certain number of extender units. They also specify the initial regiospecific folding and cyclization pattern of nascent polyketides either through the action of a cyclase (CYC) subunit or through the combined influence of site-specific ketoreductase (KR) and CYC subunits. Additional cyclases and other modifiactions may be necessary to yield the various known members of the class of linear aromatic compoinds, several of which have proven medical significance. However, it was not known whether angular aromatic polyketides would assemble using the same principles as described for PKSs that yield linear aromatic polyketides. Genes for angular polyketides including a cyclase gene thought to be responsible for folding of the polyketide chain to produce angular polyketide intermediates have been cloned and expressed in host strains S. lividans and S. glaucescens. We are now in the process of characterizing several polyketide intermediates produced in these host strains to further define the iterative functions of the PKSs, Cnd KRs in generating angular aromatic polyketide intermediates.