Squalestatins polyketide synthase

Cox RJ, Glod F, Hurley D, Lazarus CM, Nicholson TP, Rudd BAM, Simpson TJ, Wilkinson B, Zhang Y. Rapid cloning and expression of a fungal polyketide synthase gene involved in squalestatin biosynthesis. Chem. Commun. 2004 2260-2261. 

Squalestatin SI 29 is a potent inhibitor of mammalian squalene synthase. It is produced by Phoma species, and like lovastatin, consists of two polyketide chains a main chain hexaketide and a sidechain tetraketide. Like lovastatin, both chains are methylated, but unusually for a fungal HR polyketide, the main chain is formed from a non-acetate starter unit— benzoate is incorporated at this position. 

The squalestatins, e.g. 6.28, also known as the zaragozic adds, have attracted considerable interest as inhibitors of squalene synthase and hence of cholesterol biosynthesis and lipid deposition in the circulatory system. They are also inhibitors of farnesyl protein transferase and thus they may have other potentially useful biological applications. They are formed by Phoma spedes and also by Setosphaeria khartoumensis. The squalestatins are characterized by a dioxabicyclo-octane core bearing three carboxyl groups and two polyketide chains, one of which is attached as an ester. The biosynthetic incorporation of succinic acid into part of the bicyclo-octane, together with its oxygenation pattern, indicate that it may be derived via oxaloacetic acid. Both the polyketide chains have several pendant methyl groups attached to them, which arise from methionine, whilst benzoic add ads as a starter unit for one of the chains. These complex structures are thus the summation of several biosynthetic pathways. 

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