Polyketides formation

JEZ, J.M., FERRER, J.-L., BOWMAN, M.E., DIXON, R.A., NOEL, J.P., Dissection of malonyl-coenzyme A decarboxylation from polyketide formation in the reaction mechanism of a plant polyketide synthase, Biochemistry, 2000, 39, 890-902. 

Jez JM, Austin MB, Ferrer J, Bowman ME, Schroder J, Noel JP (2000) Structural control of polyketide formation in plant-specific polyketide synthases. Chem Biol 7 919-930... 

An additional problem is that polyketide formation requires acetyl-CoA, malonyl-CoA, and NADPH generated by primary metabolic pathways. These precursors and the cofactor are also used for fatty acid biosynthesis. An inverse relationship between the synthesis of fatty acids and polyketide compounds has been found in the mevinolin (lovastatin)-producing species ot Aspergillus (Dutton, 1988 Greenspan and Yudkovitz, 1985). Thus, any regulatory factor that substantially alters the rate or extent of formation of these precursors and cofactor may affect polyketide formation. 

Polyketide formation in AF biosynthesis utilizes a hexanoyl CoA starter unit that is synthesized by aid of two specialized FASs (39) (Figure 4A). The genes for these FASs are transcribed from a common promoter region (40). The alpha subunit FAS has separate ACP and PP domains as well as KS and KR domains while the beta subunit has KS, AT, ACP and thioesterase (TE) domains (41). 

Studies on nonribosomal peptide formation by multienzymes have demonstrated the modular organization of these systems. As in the case of polyketide formation, the linear arrangements of modules determine their sequential operation. Their various modes of integration, however, are still not understood. It is evident that substrate-activating sites introducing amino and imino acids as well as hydroxy acids have different specificities. Thus, variations in the structures of side chains are easily accomplished, and these exceed the variability of polyketide systems in this respect. Work is in progress to make use of such systems for structure-function studies in the analysis of natural products and in the biosynthesis of new products. Future efforts will be directed to linking system variations to various selection processes. 

Not only can different starter units, for example, propionyl CoA, and butryl CoA, be used in polyketide formation but different extenders (e.g., methylmalonyl CoA) are also found. A now classical example is the bacterial system Saccharopolyspora... 

Figure 11.15. Polyketide formation from malonyl addition (and decarboxylation) to a starter acetyl-CoA on a polyketide synthase. Two examples of thousands possible are shown. The heavy lines in each represent two carbons of an acetate unit, and in many cases, the patterns are confirmed by isotopic ( C) labeling experiments.

In examining the overall conversion of pyruvate into a fatty acid (Schemes 1.1 and 1.2) it is interesting to note the exploitation of particular chemical properties of sulphur (i), as an easily reduced disulphide (1.6) (ii), as an easily oxidized dithiol and (iii) in reactive thioesters which aid the Claisen-type condensation reactions. Also of crucial importance for the condensation is the use of a malonic acid derivative (1.14) as a source of a stable anion. (Further discussion of fatty acid biosynthesis in relation to polyketide formation is taken up in Chapter 3.)... 

Comparison of the illustrated pathway to 3.5) (Scheme 3.2 cf. Scheme 3.4) with that of fatty acid biosynthesis (Section 1.1.2 Scheme 1.2) indicates that a clear distinction between them is achieved by the absence of a reductase in polyketide formation, i.e. oxygen atoms of acetate are retained in polyketide metabolites. In the case of orsellinic acid 3.4), in particular, results of experiments with [ Ojacetate established this to be correct [10]. It should be noted, however, that universal retention of acetate oxygen through the poly-jS-keto-acyl-CoA to the final metabolite is not observed. One is missing, for example, in 6-methylsalicyclic acid 3.14) and several in curvularin 3.87). (See, especially. Section 3.9 for what appear to be polyketides formed with varying levels of oxidation and dehydration corresponding to the steps illustrated in Scheme 1.2, Section 1.1.2.)... 

The carbon skeleton of maltoryzine appears to be derived from poly-ketide 12. The oxygenation pattern in the phenol ring and side chain of this compound, however, differed from the general biogenetic principles of polyketide formation (Turner, 1971). No evidence to support the biosynthesis of maltoryzine has yet been obtained. 

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