Chemistry Reference
In-Depth Information
NONRIBOSOMAL PEPTIDES
GEORG SCHOENAFINGER AND MOHAMED A. MARAHIEL
Philipps-University of Marburg, FB Chemie/Biochemie, Marburg, Germany
Many microorganisms have evolved an unusual way of producing secondary peptide
metabolites. Large multidomain enzymatic machineries, the so-called nonribosomal
peptide synthetases (NRPSs), are responsible for the production of this structurally
diverse class of peptides with various functions, such as cytostatic, immunosuppres-
sive, antibacterial, or antitumor properties. These secondary metabolites differ from
peptides of ribosomal origin in several ways. Their length is limited to a mere 20 build-
ing blocks, roughly, and mostly a circular or branched cyclic connectivity is found.
Furthermore, aside from the proteinogenic amino acids, a larger variety of chemical
groups is found in these bioactive compounds: D-configurated amino acids, fatty acids,
methylated, oxidized, halogenated, and glycosylated building blocks. These functional
and structural features are known to be important for bioactivity, and often natural
defense mechanisms are thus evaded. In this chapter, we describe the enzymatic
machineries of NRPSs, the chemical reactions catalyzed by their subunits, and the
potential of redesigning or using these machineries to give rise to new nonribosomal
peptide antibiotics.
Nonribosomal peptide synthetases (NRPSs) compose a unique class of multido-
main enzymes capable of producing peptides (1-4). In contrast to the ribosomal
machinery where the mRNA template is translated, the order of catalytically
active entities within these synthetases intrinsically determines the sequence of
building blocks in the peptide product (Fig. 4.1). As a consequence, generally
speaking, each NRPS can only produce one defined peptide product. This is
chemically implemented by the fact that all substrates and reaction intermediates
are spatially fixed to the synthetase by covalent linkage—thereby eliminating
