Nonribosomal Peptide Synthesis

5-Prime | Nonribosomal Peptide Synthesis What is it?

By | March 24, 2003

5-Prime | Nonribosomal Peptide Synthesis

What is it? As the name suggests, nonribosomal peptide synthesis (NRPS) generates polypeptides sans ribosome. The resultant peptides, generally short oligomers of two to perhaps 48 residues, are not genome-encoded.

Where ribosomal translation is limited to the standard complement of 20 L-amino acids, nonribosomal peptides may contain unusual building blocks, including D-amino acids, methylated variants of the standard amino acids, and nonproteinogenic, hydroxylated, and glycosylated residues; more than 300 precursors are currently known. Sometimes the peptide products are hetero-cyclized, and the peptide backbone may be branched.

How are the peptides made? Nonribosomal peptides are created on massive, assembly line-like synthetases. These enzymes are modular, comprising a series of functional units that can bind a naked amino acid, activate it as a thioester, and couple it to the growing peptide chain. In linear NRPSs, the sequence of modules acts as the template that defines the resulting peptide's sequence. But iterative and nonlinear NRPS configurations exist, too, which generate more complicated structures.

Many of the NRP's modifications are performed during synthesis, either by assembly line components or by external proteins. Other modifications are added postsynthetically. Some synthetases are multimeric complexes, while others are single, massive proteins. Each module is about 1,000-1,200 amino acids long, making the enzymes enormous: a single 15,281-residue (1.7 MDa) protein, for instance, synthesizes cyclosporin, an 11-residue long immunosuppressant.

Why is this important? NRPS produces several pharmacologically important compounds, including cyclosporin and the antibiotics penicillin and vancomycin. If researchers could learn peptide synthetase's "genetic code," they could manipulate it to produce novel compounds for drug development.

How do you know when it's NRPS that creates the protein? Ribosomal peptides can undergo extensive posttranslational modification, so the presence of unusual residues or structure is not enough to implicate NRPS in a molecule's genesis. Evidence against NRPS: a genomic sequence capable of producing the peptide's sequence. Evidence for: the presence of signature modular peptide synthetase gene segments.

I want to learn more. Where can I look? Chemical Reviews devoted an entire issue (vol. 97, no. 7, 1997) to NRPS and a related process, polyketide synthesis. (Polyketides are assembled from fatty acids and include the antibiotics rifamycin and erythromycin, and the immunosuppressant FK506.) See also H.D. Mootz et al., "Ways of assembling complex natural products on modular nonribosomal peptide synthetases," Chembiochem, 3:490-504, 2002.

--Jeffrey M. Perkel

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