Setosphaeria khartoumensis

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. 

Zaragozic acids (squalestatins). Highly active, competitive inhibitors of squalene synthase (SQS) and thus of cholesterol biosynthesis. The different names are a result of the independent, simultaneous discovery of this class of natural products in various ascomycete strains (e. g., Phoma sp., Setosphaeria khartoumensis) by three research groups. All Z. possess a 4,6,7-tri-hydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarbox-ylic acid skeleton carrying acyl groups on the C-6 oxygen atom as lipophilic side chains and alkyl groups on the C-1 carbon atom. 

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