Polyketide inhibitors

Salomon AR, Vohringer DW, Herzenberg LA, Khosla C. Understanding and exploihng the mechanistic basis for selectivity of polyketide inhibitors of FOFl-ATPase. Proc. Nat. Acad. Sci. USA 2000 97(26) 14766-14771. 

A further natural product inhibitor is mithramydn A, a structurally complex anticancer antibiotic. Mithramycin A is a member of a group of aureolic add-type polyketides that are produced by the soil bacterium Streptomyces argillaceus [94]. 

The original DEBS 1-TE cell-free system allowed several other features of polyketide chain extension to be examined by using well-known inhibitors of specific enzyme activities. Incubation of DEBS 1 -TE with the serine protease inhibitor phenylmethylsulfonyl fluoride (PMSF) resulted in a significant decrease in biosynthetic activity. This result emphasized the mechanistic similarity between the targeted TE domain and the serine protease enzymes. Addition of the fatty acid inhibitor cerulenin [38] also reduced production of the lactone, consistent with the evolutionary kinship between these two classes of enzymes. Inhibition of DEBS 1+TE by cerulenin was also reported [33],... 

This precise sequence was discovered only through very careful double labelling experiments and after the discovery of specific inhibitors for the enzyme. Since polyketides can be made from the acyl polymalonate pathway with or without reduction and elimination at any step, the number of possible structures is vast. With more reduction, no aromatic ring can be formed macrolide antibiotics such as brefeldin A come from this route. 

Is a specific Inhibitor of type II fatty acid synthetase In higher plants and . coll 12401. The acetyl-CoA ACP S-acety1-transferase Is the apparent specific site of Inhibition 12411. Another antibiotic, cerulenin (structure not shown) Inhbits -ketococy1-ACP synthetase I In bacteria, fungi, and plants, but also Is Inhibitory to other sites such as polyketide and sterol biosynthesis 1242-2441. Cerulenin and thiolactomycin Inhibited CQ14W-acetate Incorporation Into fatty acids at 150 values of 50 and 4 uM, respectively 12451. Recently cydohexanedlone herbicides have been shown to Inhibit lipid biosynthesis by Inhibition of acetyl-CoA carboxylase 12461. 

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. 

While some success has been reported in analogous studies with polyketide assembly intermediates in Streptomyces metabolites, e.g. erythromycin [41] and tylosin [42], similar experiments on fungal polyketides have been more limited. The di- and tetraketide intermediates (44) and (45), variously doubly labelled with and as indicated in Scheme 14, have been incorporated into de-hydro curvular in (46) by cultures of Alternaria cineriae [43]. However, in contrast to the ease of incorporation of assembly intermediates into aspyrone by A. melleus, the experiments in A. cineriae required considerable experimentation to optimise the feeding conditions and the use of the jS-oxidation inhibitors. The initial experiments [43] depended on the use of UV mutants of A. cineriae which had lost the ability to utilise fatty acids and therefore to degrade the fatty... 

C. aphidicola. Other metabolites with a ten-membered lactone ring include the decarestrictins (4.76) from PenicUlium species such as P. simplicissimum and putaminoxin (4.77), which is a phytotoxic metabolite of Phoma putamimm. Recifeiolide (4.78) from C. recifei is a hexaketide with a 12-membered ring. Cladospolide A (4.79), also with a 12-membered ring, is a phytotoxic metabolite of Cladosporium fulvum. The decarestrictins affect cholesterol biosynthesis whilst the diplodialides were found to be steroid 11-hydroxylase inhibitors. Biosynthetic experiments with [ C]-labelled acetate established that the decarestrictins were polyketides. 

The combination of a lipophilic terpenoid fragment with a polar polyketide moiety has produced structures with significant biological activity. Thus the pyropenes A-R, e.g. 5.171, from a strain of Aspergillus fumigatus are powerful inhibitors of acyl CoA-cholesterol acyl transferase, an enzyme that contributes to the absorption of dietary cholesterol and the accumulation of cholesterol esters. These are problems that lead to atherosclerosis. 

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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