Polyketides Formed with Participation of Malonyl Co

Polyketides (acetogenins) show a regular pattern of oxygen-substituted and oxygen-free C-atoms at least in part of the molecule. Most are derivatives of (—CHg—CO—)n-polyketo acids. However, compounds are also formed from (—CHCHg—CO—)n-polyketo acids (D 4). With the exception of a few derivatives 

Polyketides are formed by multifunctional proteins (A 3.1), e.g., 6-methylsah-cylate synthase (D 3.3.1) and chalcone synthase (D 22.3.3), from a starter molecule, in most cases acetyl CoA, but also malonyl CoA, malonamido CoA, anthranilyl CoA, cinnamoyl/p-coumaroyl CoA or p-hydroxybenzoyl CoA. These starter molecules react with several molecules of malonyl CoA with the loss of one of the carboxy groups of the latter. According to the number of acid molecules involved in the formation of the individual polyketides di-, tri-, tetraketides, etc. may be distinguished (Table 33). 

The synthesis of polyketides resembles the formation of fatty acids by fatty acid synthase in terms of the precursors used and the mode of their alignment (D 3.2). In contrast to the formation of fatty acids, however, the biosynthesis of polyketides proceeds without obligate reduction of intermediates. Most probably polyketo acids are formed, which are unstable and have not yet been detected in the free state. They seem to be attached to the core unit of the enzyme complex, stabilized by hydrogen bonding or by chelation of its semieno-lates with metal ions held by the enzymes. 

Some of the bound keto groups may be reduced by pyridine nucleotide-dependent dehydrogenases (C 2.1, see the formation of 6-methylsalicylic acid, D 3.3.1), and some of the activated CHg-groups may be alkylated by S-adenosyl-L-meth-ionine (C 3.3, see the biosynthesis of tetracyclines, D 3.3.7), or may be substituted by dimethylaUyl pyrophosphate (D 6), see the formulas of lupulone and humulone, the bitter principles of hop cones used in brewing beer (F 1). 

The spatial arrangement of the polyketo acids leads to cyclization by aldol condensations, i.e., reaction of carbonyl groups with acidic CHg-groups, or by Claisen condensation, i.e., reaction of the ester group at the head of the molecule with one of the acidic CHg-groups. The actual type of condensation depends on the nature of the polyketide synthetase in question and the spatial arrangement of the polyketo acid directed by the enzyme. Thus several cyclic structures 

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