Where chemistry meets biology: the chemoenzymatic synthesis of nonribosomal peptides and polyketides

摘要

Many drugs isolated from microorganisms have sophisticated molecular architectures built on conformationally constrained macrocyclic peptide or polyketide scaffolds, which are often further decorated by the attachment of sugar molecules. In light of this, natural product biosyn-thetic enzymes are of great interest for synthetic purposes, since chemoenzymatic approaches can provide rapid access to structurally complex compounds that are often extremely difficult to synthesize by classical chemical means. For example macrocyclic type B strep-togramin antibiotics including variants and related structures to the parental compounds could be prepared by the use of recombinant TE domains. In addition to this, stereospecific enzymatic epoxidation is an attractive alternative to traditional chemical methodology and enabled the synthesis of cryptophycin type compounds. A large number of novel glycopeptides, as illustrated for vancomycin and calicheamycin are accessible by the use of biosynthetic enzymes, which facilitate the production of variants of these scaffolds in the search for improved drugs. The rapid identification of new pharmacophores, in turn opens the door for in vivo genetic engineering, which can be used as a platform for the high-yield