NDLI: Expanding the biosynthetic repertoire of plant type IIIpolyketide synthases by altering starter molecule specificity

Content Provider	PubMed Central
Author	Jez, Joseph M. Bowman, Marianne E. Noel, Joseph P.
Copyright Year	2002
Abstract	Type III polyketide synthases (PKS) generate an array ofnatural products by condensing multiple acetyl units derived frommalonyl-CoA to thioester-linked starter molecules covalently bound inthe PKS active site. One strategy adopted by Nature for increasing thefunctional diversity of these biosynthetic enzymes involves modifyingpolyketide assembly by altering the preference for starter molecules.Chalcone synthase (CHS) is a ubiquitous plant PKS and the first typeIII PKS described functionally and structurally. Guided by thethree-dimensional structure of CHS, Phe-215 and Phe-265, which aresituated at the active site entrance, were targeted for site-directedmutagenesis to diversify CHS activity. The resulting mutants werescreened against a panel of aliphatic and aromatic CoA-linked startermolecules to evaluate the degree of starter molecule specificity inCHS. Although wild-type CHS accepts a number of natural CoA thioesters,it does not use N-methylanthraniloyl-CoA as a substrate.Substitution of Phe-215 by serine yields a CHS mutant thatpreferentially accepts this CoA-thioester substrate to generate a novelalkaloid, namely N-methylanthraniloyltriacetic acidlactone. These results demonstrate that a point mutation in CHSdramatically shifts the molecular selectivity of this enzyme. Thisstructure-based approach to metabolic redesign represents an initialstep toward tailoring the biosynthetic activity of plant type III PKS.
Related Links	http://dx.doi.org/10.1073/pnas.082590499
Ending Page	5324
Page Count	6
Starting Page	5319
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	8
Volume Number	99
Language	English
Publisher	National Academy of Sciences
Publisher Date	2002-04-16
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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