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Review
. 2004 Dec;14(6):748-56.
doi: 10.1016/j.sbi.2004.10.005.

Structural aspects of non-ribosomal peptide biosynthesis

Gregory L Challis  1 , James H Naismith
Affiliations
Review

Structural aspects of non-ribosomal peptide biosynthesis

Gregory L Challis et al. Curr Opin Struct Biol. 2004 Dec.

Abstract

Small peptides have powerful biological activities ranging from antibiotic to immune suppression. These peptides are synthesized by non-ribosomal peptide synthetases (NRPS). Structural understanding of NRPS took a huge leap forward in 2002; this information has led to several detailed biochemical studies and further structural studies. NRPS are complex molecular machines composed of multiple modules and each module contains several autonomously folded catalytic domains. Structural studies have largely focused on individual domains, isolated from the context of the multienzyme. Biochemical studies have looked at individual domains, isolated whole modules and intact NRPS, and the combined data begin to allow us to visualize the process of peptide assembly by NRPS.

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Figures

Figure 1
Figure 1
Structure of NRPS molecules
Figure 2
Figure 2
a The modules involved in NRPS biosynthesis b A schematic representation of the process
Figure 3
Figure 3
(a) The structure of the A domain DhbE [22]. A domains bind substrate in a common pocket which is located at the interface of protein domains. The product of this reaction AMP-2,3-dihydroxybenzoate is shown in space fill. (b) Close up of the active site highlighting the residues that contribute to the recognition of the 2,3-dihydroxybenzoate. Protein engineering will have to target these residues to alter specificity. Residue numbering is from the PDB file [22].
Figure 4
Figure 4
The structure of VibH, a condensation domain [26]. The residues identified by mutagenesis to be important for catalysis are shown. His 126 is not required for VibH catalysis although this may be a feature of its nucleophilic substrate, the residues is required in other C domains.
Figure 5
Figure 5
Thioesterase domain of surfactin synthetase [21]. The catalytic residues are shown. The helical structure provides recognition for residues adjacent to the cleavage site. The protein does not recognise residues far from the cleavage site. The coordinates for the co-complex are not yet available [19].
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