Molecule of the Month: Assembly Line Polyketide Synthases

Polyketide synthases (PKSs) are found in a variety of organisms, including bacteria, fungi, and plants, and are responsible for producing diverse bioactive natural compounds. Examples of medically important polyketides include antibiotics (erythromycin, tetracycline), immunosuppressants (rapamycin), cancer therapeutics (epothilone, doxorubicin), and antifungals (amphotericin B, avermectin).

Some PKSs are especially large complexes that are made up of several modules. Each module is built from a number of distinct enzymatic domains that each play a role in the synthesis of a specific polyketide. Domains that are typically found in PKSs include an acyl carrier protein (ACP), which is responsible for "carrying" the growing polyketide to and from different domains, an acyltransferase (AT) domain that loads the extender unit, an acyl-CoA molecule, onto the ACP, and a ketosynthase (KS) domain, which catalyzes the growth of the polyketide chain through a condensation reaction. Additional domains, such as a ketoreductase (KR) domain can further modify the growing polyketide. These different domains can be seen in the PKS module Lsd14, which is involved in the synthesis of the antibiotic lasalocid A by the bacterium Streptomyces lasalocidi (PDB 7S6B).

Lsd14 is a member of a class of polyketide synthases called assembly line PKSs. In these large complexes, the growing polyketide chain is acted upon exactly once by each enzymatic domain in each module in a sequential manner. The ACP domain, which holds one end of the polyketide and moves to different positions in order to deliver it to the next domain or module, plays a central role in this tight choreography.

Recent structures of different assembly line PKS modules, including Lsd14 and a module of 6-deoxyerythronolide synthase (DEBS M1), which is shown on the left, have described how domains within a module are arranged in space. These structures have revealed an unexpectedly asymmetric dimeric structure with two separate "reaction chambers." The asymmetry (seen in the DEBS M1 open state, PDB 7M7F, and in the Lsd14 structure above) suggests that only one side or reaction chamber of the PKS can be used at a time, which is thought to prevent a second round of polyketide growth by the same module. Conformational changes within the PKS module may also ensure that synthesis occurs in the correct order. In DEBS M1, a conformational switch in the AT domain, which is thought to be triggered by the condensation reaction in the KS domain, causes the module to enter a "closed" state (PDB 7M7J) that blocks the ACP from rebinding to KS. Similarly, in Lsd14, different conformational states have been found to block specific catalytic sites, and is also thought to prevent the ACP from binding enzymatic domains in the incorrect order.