Polyketide Synthase Modules Redefined

Abstract

Modular redefinition: A long-standing paradigm in modular polyketide synthase enzymology, namely the definition of a module, has been challenged by Abe and co-workers in their recent study. With this new understanding has emerged renewed hope for engineering these assembly lines to produce new materials and medicines.

Keywords: assembly lines; enzymology; evolution-guided engineering; modules; polyketides.

Figure 1.

Evolutionary comigration of PKS domains. Analysis of four related polyketide assembly lines of 25–30 modules revealed the enzymatic domains that move together during the evolution of the assembly lines (colored equivalently in this hypothetical synthase). The definition of a module needs to be revised such that processing enzymes, such as the ketoreductase (KR), dehydratase (DH), and enoylreductase (ER), are grouped with the ketosynthase (KS) that is downstream, not upstream, of them. The analysis also shows that acyltransferase (AT) domains, which select the carbon monomers, move independently between different types of modules during assembly line evolution. Polyketide intermediates are shown bound to KSs instead of the acyl carrier protein (ACP) domains (black circles) as this study and other investigations have indicated that KSs select between intermediates presented to them. Abe and co-workers described recombination hotspots upstream and downstream of the AT domain that may be utilized in evolution-guided engineering to produce new polyketides. The symbol for a twofold axis indicates that only half of the homodimeric assembly line is shown. A- and B-type KRs produce l- and d-oriented hydroxy groups, respectively.

Figure 2.

The pikromycin synthase, color-coded with the traditional and updated module boundaries. The numbering of KS domains is not altered but the numbering of all other domains is increased by one. Employing the updated module boundaries, an ACP visits its own AT to acquire an extender unit, the KS of the previous module to collect the growing acyl chain through carbon–carbon bond formation, and its own processing enzymes before delivering the properly processed intermediate to its own KS. KS^Q generates the priming propionyl group for the first KS through the decarboxylation of a methylmalonyl group, and belongs to the first module. The KS from module 4 selects between two intermediates interconverted by the epimerase KR⁰.