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

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 exptl.; however, the theor. anal. 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 no. of variables in the linear chain synthesis controlled by the PKS: the no., identity, stereochem. and sequence of the monomer units used in the elongation steps, and the degree of redn. that occurs after each of the condensation reactions. The theor. anal. 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 no. of possible structures led to the implementation of this system in BNICE, a computational framework that generates all possible biochem. pathways using a given set of enzyme reaction rules. This formulation allowed the anal. 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 exptl. approaches to engineer novel polyketides, a no. of which will likely have medicinal properties. [on SciFinder (R)]

Published in:
Journal of the American Chemical Society, 127, 27, 9930-9938
9-16 FIELD Section Title:Biochemical Methods
Department of Chemical and Biological Engineering,Northwestern University,Evanston,IL,USA. FIELD URL:
written in English.

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 Record created 2007-01-11, last modified 2018-03-17

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