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With the discovery of penicillin as an efficient antibacterial agent isolated from the fungus Penicillium notatum, microor- ganisms attracted considerable attention as a new source for pharmaceutical agents. Screening of microbial extracts re- vealed the large structural diversity of natural compounds with broad biological activities, such as antimicrobial, antiviral, im- munosuppressive, and antitumor activities. Like penicillin, many of these products are small peptide molecules consisting of 3 to 22 residues with often unusual structural elements. These include heterocyclic elements, D-amino acids, and gly- cosylated and N-methylated residues, suggesting a nonriboso- mal origin of biosynthesis. Due to the potent pharmacological activities of these compounds, there was an overwhelming in- terest in exploring their mechanism of synthesis. Lipmann et al. reported as early as the 1970s that the cyclic peptides grami- cidin S and tyrocidine from Bacillus spp. were produced in a nucleic acid-independent way through the use of large enzyme complexes similar to fatty acid synthases (17). Subsequently, other peptidic natural products were shown to be assembled by large enzymes, referred to as nonribosomal peptide syntheta- ses (NRPS), which utilize the multiple-carrier thiotemplate mechanism (34). A common feature of many nonribosomally produced peptides is their constrained structure, which ensures a precise functionality important for a proper interaction with the dedicated molecular target in the cell. Nature achieves this rigidity in molecular structure through several strategies: the molecule can be oxidatively cross-linked, as in vancomycin, heterocyclized, as in penicillin or, more commonly, cyclized, as in fengycin (Fig. 1). Cyclization seems to be the predominant way of constraining nonribosomally synthesized peptides. Be- cause peptide cyclization from the point of view of chemical synthesis is difficult to achieve without protection of all of the side chains, there has been rapidly growing interest in explo- ration of the enzymatic cyclization mechanism for the devel- opment of new synthesis routes.

Learning from Nature's Drug Factories: Nonribosomal Synthesisof MacrocyclicPeptides