Theoretical Considerations and Computational Analysis of the Complexity in Polyketide Synthesis Pathways

Abstract

The emergence of antimicrobial resistance has led to an increase in research directed toward the engineering of novel polyketides. To date, less than 10 000 polyketide structures have been discovered experimentally; however, the theoretical analysis of polyketide biosynthesis performed suggests that over a billion possible structures can be synthesized. Polyketide synthesis, which involves the formation of a linear chain and its subsequent cyclization, is catalyzed by an enzyme complex called polyketide synthase (PKS). There are a number of variables in the linear chain synthesis controlled by the PKS: the number, identity, stereochemistry and sequence of the monomer units used in the elongation steps, and the degree of reduction that occurs after each of the condensation reactions. The theoretical analysis performed demonstrates that changes in these variables lead to the formation of different polyketide linear chains and, consequently, a high diversity of polyketide structures. The complexity in the number of possible structures led to the implementation of this system in BNICE, a computational framework that generates all possible biochemical pathways using a given set of enzyme reaction rules. This formulation allowed the analysis of the evolution of diversity in the synthesis mechanism and the construction of the pathway architecture of polyketide biosynthesis. It is expected that, after future implementation of the cyclization reactions, this framework can be used to identify all possible polyketides and their corresponding synthesis pathways. Consequently, this formulation would prove useful in guiding experimental approaches to engineer novel polyketides, a number of which will likely have medicinal properties.

Emergent gene order in a model of modular polyketide synthases

“…This modularity allows, in principle, the synthesis of at least 4 L different polyketides by rearrangement of the four flavors of catalytic modules (L being the length of the polyketide). Additional levels of complexity, such as chirality and alternative acylthioester monomers, further increases this combinatorial potential (11). Realization of this diversity depends crucially on the observed substrate tolerance of catalytic modules (5).…”

Propionate Analogues of Zearalenone Bind to Hsp90

“…The combined organic layers were dried over MgSO 4 , filtered, and concentrated under reduced pressure to give the pure phthalide 14 (862 mg, 78 %) as a slightly brown solid; R f = 0. 17 (20 mL) at 0 8C and the mixture was stirred for 0.5 h at the same temperature. Then phthalide 14 (100 mg, 0.475 mmol) was added to this solution and the mixture was stirred for 1.5 h at room temperature.…”

“…In recognizing that benzolactones like zearalenone (10) or curvularin (11) are only made from acetate building blocks [15,16] we planned to use these naked lactones as scaffolds and to decorate them with typical substituents found in polyketides, like methyl or hydroxyl functions (Scheme 3). [17] For example, we conceived the concept of propionate scanning, [18] which refers to the systematic replacement of an acetate building block by propionate through organic synthesis. An additional methyl group might be able to take advantage of hydrophobic pockets or restrict the conformation of the macrocyclic ring in a positive way.…”

Modular Polyketide Synthases

“…Taking a theoretic view of polyketide diversity, González-Lergier et al (41) have suggested that even if the starter and extender units are fixed, over 100,000 linear heptaketide structures are possible using only the 5 common reductive outcomes at the β-carbon position (ketone, (R-or S -) alcohol, trans-double bond, or alkane). Recently, it has become apparent that even this does not represent the upper limit for polyketide diversification.…”