Polyketide synthases catalyze the assembly of complex natural products from
simple precursors such as propionyl-CoA and methylmalonyl-CoA in a biosynt
hetic process that closely parallels fatty acid biosynthesis. Like fatty ac
ids, polyketides are assembled by successive decarboxylative condensations
of simple precursors, But whereas the intermediates in fatty acid biosynthe
sis are fully reduced to generate unfunctionalized alkyl chains, the interm
ediates in polyketide biosynthesis may be only partially processed, giving
rise to complex patterns of functional groups. Additional complexity arises
from the use of different starter and chain extension substrates, the gene
ration of chiral centers, and further functional group modifications, such
as cyclizations. The structural and functional modularity of these multienz
yme systems has raised the possibility that polyketide biosynthetic pathway
s might be rationally reprogrammed by combinatorial manipulation. An essent
ial prerequisite for harnessing this biosynthetic potential is a better und
erstanding of the molecular recognition features of polyketide synthases. W
ithin this decade, a variety of genetic, biochemical, and chemical investig
ations have yielded insights into the tolerance and specificity of several
architecturally different polyketide synthases. The results of these studie
s, together with their implications for biosynthetic engineering, are summa
rized in this review.