Biomedical Engineering Reference
In-Depth Information
14
PRECURSOR-DIRECTED
BIOSYNTHESIS OF POLYKETIDE
AND NONRIBOSOMAL PEPTIDE
NATURAL PRODUCTS
CHAPTER
COLIN J. B. HARVEY and CHAITAN KHOSLA
Department of Chemistry, Chemical Engineering, and Biochemistry, Stanford
University, Stanford, California, USA
14.1.
INTRODUCTION
All the natural products that have been discussed thus far and those that will be
mentioned in the subsequent chapters were isolated from organisms that have, over
millennia, evolved biosynthetic machinery that synthesize these complex molecules
with exquisite fidelity and efficiency.
Many efforts toward the synthesis of clinically relevant natural products and
their analogues attempt to mimic this machinery in an abiotic chemical environment.
This chapter concerns itself with an entirely different approach to the production
of natural product analogues—precursor-directed biosynthesis. Rather than attempting
to mimic the transformations effected by the biosynthetic machinery, this technique
uses the biosynthetic enzymes to catalyze these reactions on unnatural substrates.
Techniques such as those described here have been successfully used in the
production of analogues of a number of structurally diverse classes of natural
products. For the sake of simplicity, here we will limit ourselves to discussing their
application to the production of polyketides and nonribosomal peptides, two large
classes of natural products with extremely broad clinical relevance.
We will begin with a brief introduction into the biosynthesis of each of these
types of molecules, followed by an introduction to the approach itself. A discussion of
the various considerations that need to be taken into account when considering this
approach is then followed by examples of successful applications of precursor-
directed biosynthesis to prepare natural product analogues.
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