Aromatic polyketide biosynthesis

An important question for aromatic polyketide biosynthesis is the timing of the first ring cyclization, relative to ketoreduction. We found that the timing... 

Great advances have been made in the understanding of the role of multifunctional polyketide synthase enzymes (PKSs) in bacterial aromatic polyketide biosynthesis, and many such... 

The goal of this review is therefore to present our current knowledge of aromatic polyketide biosynthesis with emphasis on the most recent advances in the biochemistry and enzymology of PKSs. The so-called tailoring enzymes , which modify the initial products synthesized by PKSs to imbue them with... 

Hopwood has recently reviewed exhaustively the discovery, the cloning, and the architecture of genes encoding aromatic polyketide biosynthesis in bacteria, fungi, and plants [29]. Selected in this section are only a few examples, illustrating organizational variations and structural features of aromatic PKSs. 

ACP is a central component of type II PKS and is involved in possibly all reactions of bacterial aromatic polyketide biosynthesis. The starter unit (before its transfer to the KS subunit), the extender units, the growing poly-)5-ketone intermediates, as well as the full length linear poly-)8-ketone product, are covalently bound to ACP in a thioester linkage to the terminal sulfhydryl of the 4 -phos-phopantetheine prosthetic group (see Sect. 3.1.1). These ACP thioesters must have been recognized as substrates by type II PKSs and other associated enzymes such as KR, CYC, or ARC to build and process the poly- -ketone intermediates into aromatic polyketides. 

Reconstitution of the Act PKS [173,184] and Tcm PKS [183] in vitro from individually purified KSo, KS, holo-ACP, and MAT was one of the most exciting advances in the studies of aromatic polyketide biosynthesis, providing excellent model systems for mechanistic studies of bacterial aromatic type II PKS. The methods for Act PKS and Tcm PKS should be applicable to the purification and reconstitution of other aromatic type II PKSs. It will be extremely interesting to examine the effect on polyketide synthesis by swapping fimctional components of various PKSs in vitro. Siunmarized here are the highlights that bear fruit directly fi-om the in vitro systems, revealing mechanistic features otherwise inaccessible by in vivo studies. 

Fig. 11. Regiospecific cyclizations in engineered aromatic polyketide biosynthesis by (A) the minimal PKS, (B) co-action between the minimal PKS and CYC, and (C) co-action among the minimal PKS, KR, ARO, and CYC...

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