TY - JOUR
T1 - Theoretical considerations and computational analysis of the complexity in polyketide synthesis pathways
AU - González-Lergier, Joanna
AU - Broadbelt, Linda J.
AU - Hatzimanikatis, Vassily
PY - 2005/7/13
Y1 - 2005/7/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=22144436255&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=22144436255&partnerID=8YFLogxK
U2 - 10.1021/ja051586y
DO - 10.1021/ja051586y
M3 - Article
C2 - 15998100
AN - SCOPUS:22144436255
SN - 0002-7863
VL - 127
SP - 9930
EP - 9938
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 27
ER -