Polyketides natural modularity

Menzella, H.G., Reid, R., Carney, J.R. et al. (2005) Combinatorial polyketide biosynthesis by de novo design and rearrangement of modular polyketide synthase genes. Nature Biotechnology, 23, 1171-1176. 

In this chapter, we will introduce an exciting class of natural product biosynthetic enzymes, the modular synthases, as well as their associated enzyme partners. We will discuss the use of metabolic engineering as a tool for small-molecule discovery and development, both through directed fermentation and combinatorial biosynthesis. In addition, we will review six classes of partner enzymes involved in the modification of polyketide (PK) and nonribosomal peptide (NRP) natural products. We believe that these enzymatic transformations hold great opportunities for synthetic chemists and will serve as the foundation for a new trend in both discovery and process chemistry. 

Until the biosynthesis of aromatic polyketides can be controlled as precisely as modular PKSs, the most likely utility for this class of PKS is in the generation of libraries to screen for new activities. Due to the highly reactive nature of the aromatic polyketide backbones, a variety of cyclization patterns have been created through combinatorial biosynthesis with aromatic PKS gene clusters... 

J Staunton, P Caffrey, JF Aparicio, GA Roberts, SS Bethell, PF Leadlay. Evidence for a double-helical structure for modular polyketide synthases. Nature Struct Biol 3 188-192, 1996. 

R Pieper, S Ebert-Khosla, DE Cane, C Khosla. Erythromycin biosynthesis kinetic studies on a fully active modular polyketide synthase using natural and unnatural substrates. Biochemistry 35 2054-2060, 1996. 

Experiments in vitro with modular PKSs are considerably more straightforward than those with aromatic synthases. Whereas synthesis of aromatic polyketides requires the expression and purification of at minimum three activities, and as many as seven, a single multienzyme from a modular PKS can be competent for synthesis. Additionally, the design rules for the modular PKSs are considerably simpler, as there is a direct correlation between the number and nature of activities present and the resulting structure of the polyketide product. 

C Bisang, PF Long, J Cortes, J Westcott, J Crosby, A-L Matharu, RJ Cox, TJ Simpson, J Staunton, PF Leadlay. A chain initiation factor common to both modular and aromatic polyketide synthases. Nature 401 502-505, 1999. 

The modular design of PKS and NRPS renders them convenient for protein engineering to generate hybrid enzymes that can synthesize a range of natural and unnatural metabolites. By independently manipulating what Cane et al. [143] call the four degrees of freedom in polyketide synthesis variation of chain length, choice of ACP... 

Many natural peptides are synthesized by a sequence of enzyme-controlled processes carried out by a multifunctional enzyme of modular arrangement, similar to some polyketide synthases. These nonribosomal peptide synthetases (NRPSs) typically consist of an adenylation domain, a peptidyl carrier protein domain, and a condensation or elongation domain in order to carry out amide bond formation and some derivations of amino acid residues. 

Xue, Y, and Sherman, D. (2000). Alternative modular polyketide synthase expression controls macrolactone structure. Nature 403, 571-575. 

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