FEATURES

DESCRIPTION

Also known as MFL1_PHOSM, L1. Part of the gene cluster that mediates the biosynthesis of squalestatin S1 (SQS1, also known as zaragozic acid A), a lead compound for the treatment of hyper-cholesterolemia by targeting squalene synthase (SS) (PubMed:27056201). Both phenylalanine and benzoic acid are known precursors of SQS1 and so it is unsurprising that the cluster also contains genes potentially involved in benzoate production: phenyl-alanine ammonia lysase (PAL) M7, which catalyzes the first step in the degradation of phenylalanine, and the NADP-dependent dehydrogenase M3 (PubMed:27056201). The cluster contains two PKS encoding genes. The tetraketide synthase is responsible for the biosynthesis of the tetraketide sidechain of SQS1 (By similarity). The biosynthesis must involve 3 rounds of chain extension. After the first and second rounds methyl-transfer occurs, and in all rounds of extension the ketoreductase and dehydratase areactive. The enoyl reductase and C-MeT are not active in the final round of extension (By similarity). The other PKS is therefore likely to encode squalestatin hexaketide synthase (SQHKS) (PubMed:27056201). The hexaketide main chain is initiated by benzoate which is an unusual starter unit for a highly reducing polyketide synthase (PubMed:27056201). The cluster also contains a gene encoding a citrate synthase-like protein R3 presumably involved in linking the hexaketide to the oxaloacetate moiety (Probable). Formation of the tetraketide CoA may be catalyzed by the M9 CoA ligase, but the mechanism of release of the tetraketide and the hexaketide from their respective PKS remains unknown, although the cluster encodes a potential esterase (M8) and a possible hydrolase (M10) which could be involved in these processes (Probable). Two acyltransferases (AT), M4 and R4, are also encoded in the cluster. M4 is responsible for loading of the tetraketide sidechain from CoA onto the squalestatin core as the final step of biosynthesis (PubMed:27056201). M4 appears to have a broad substrate selectivity for its acyl CoA substrate, allowing the in vitro synthesis of novel squalestatins (PubMed:27056201). The biosynthesis of SQS1 requires several oxidative steps likely performed by oxidoreductases M1, R1 and R2 (Probable). Finally, in support of the identification of the cluster as being responsible for SQS1 production, the cluster contains a gene encoding a putative squalene synthase (SS) R6, suggesting a likely mechanism for self-resistance (PubMed:27056201). The function of protein L1 in the biosynthesis of squalestatin S1 has still to be determined (Probable).

EXTERNAL LINKS

L1

Squalestatin S1 biosynthesis cluster protein L1

L1

Molecular Synopsis