A chain initiation factor common to both modular and aromatic polyketide synthases

Antibiotic-producing polyketide synthases (PKSs) are enzymes responsible fo r the biosynthesis in Streptomyces and related filamentous bacteria of a re markably broad range of bioactive metabolites, including antitumour aromati c compounds such as mithramycin(1) and macrolide antibiotics such as erythr omycin(2). The molecular basis for the selection of the starter unit on aro matic PKSs is unknown(3). Here we show that a component of aromatic PKS, pr eviously named 'chain-length factor'(4), is a factor required for polyketid e chain initiation and that this factor has decarboxylase activity towards malonyl-ACP (acyl carrier protein). We have re-examined the mechanism of in itiation on modular PKSs and have identified as a specific initiation facto r a domain of previously unknown function named KSQ, which operates like ch ain-length factor. Both KSQ and chain-length factor are similar to the keto synthase domains that catalyse polyketide chain extension in modular multif unctional PKSs and in aromatic PKSs, respectively, except that the ketosynt hase domain active-site cysteine residue is replaced by a highly conserved glutamine in KSQ and in chain-length factor. The glutamine residue is impor tant both for decarboxylase activity and for polyketide synthesis.