Polyketides and nonribosomal peptides constitute a large and diverse set of natural products with biological activity in microbial survival and pathogenesis, as well as broad pharmacological utility as antineoplastics, antibiotics or immunosupressants. These molecules are biosynthesized by the ordered condensation of monomer building blocks, acyl-CoAs or amino acids, leading to construction of linear acyl chains. Many of these natural products are constrained to their bioactive conformations by macrocyclization whereby, in one of the terminal steps of biosynthesis, parts of the molecule distant in the constructed linear acyl chain are covalently linked to one another. Typically, macrocyclization is catalyzed by a thioesterase domain at the C-terminal end of the biosynthetic assembly line, although alternative strategies are known. The enzymology of these macrocyclization catalysts, their structure, mechanism, and catalytic versatility, is the subject of this review. The diversity of macrocyclic structures accessed by enzyme catalyzed cyclization of linear acyl chains as well as their inherent substrate tolerance suggests their potential utility in reprogramming natural product biosynthesis pathways or accessing novel macrocyclic structures.
"The termini of polypeptide chains, however, represents target points for the attack of proteolytic enzymes affecting the stability of the molecule thereby affecting functionality. The non ribosomally synthesized proteins such as toxins, antibiotics, pigments, siderophores etc. that are synthesized by condensation of monomer building blocks by an enzyme-driven process to produce a linear acyl chain (Kohli and Walsh 2003); avoid this problem with some post-translational modifications such as acetylations, hydroxylations and/or glycosylations. Such modifications may give the producing organism an advantage, as the modified molecules are less susceptible to the normal proteolytic cleavage reactions of proteins (Sanchez-Hidalgo et al. 2007). "
[Show abstract][Hide abstract] ABSTRACT: During the recent years extensive efforts have been made to find out bacteriocins from lactic acid bacteria (LAB) active against various food spoilage and pathogenic bacteria, and superior stabilities against heat treatments and pH variations. Bacteriocins isolated from LAB have been grouped into four classes. Circular bacteriocins which were earlier grouped among the four groups of bacteriocins, have recently been proposed to be classified into a different class, making it class V bacteriocins. Circular bacteriocins are special molecules, whose precursors must be post translationally modified to join the N to C termini with a head-to-tail peptide bond. Cyclization appears to make them less susceptible to proteolytic cleavage, high temperature and pH, and, therefore, provides enhanced stability as compared to linear bacteriocins. The advantages of circularization are also reflected by the fact that a significant number of macrocyclic natural products have found pharmaceutical applications. Circular bacteriocins were unknown two decades ago, and even to date, only a few circular bacteriocins from a diverse group of Gram positive organisms have been reported. The first example of a circular bacteriocin was enterocin AS-48, produced by Enterococcus faecalis AS-48. Gassereccin A, produced by Lactobacillus gasseri LA39, Reutericin 6 produced by Lactobacillus reuteri LA6 and Circularin A, produced by Clostridium beijerinickii ATCC 25,752, are further examples of this group of antimicrobial peptides. In the present scenario, Gassericin A can be an important tool in the food preservation owing to its properties of high pH and temperature tolerance and the fact that it is produced by LAB L. gasseri, whose many strains are proven probiotic.
World Journal of Microbiology and Biotechnology (Formerly MIRCEN Journal of Applied Microbiology and Biotechnology) 05/2013; 29(11). DOI:10.1007/s11274-013-1368-3 · 1.78 Impact Factor
"In addition to domain ACP3, domain KS5 also interacts with domain ACP4 simultaneously (Figure S4C). The bioconstruction of symmetric molecules by oligomerization of the basic units through an ester or amide bond is usually mediated by the thioesterase domain, which catalyzes the cycloologomerization process (Kohli and Walsh, 2003; Watanabe et al., 2006; Cheng, 2006). QMNs bear a 32-member carbocyclic architecture consisting of four spirotetronic acid units connected by enone linkers in a head-to-tail fashion, so the carbon frameworks are composed of only C-C linkages. "
[Show abstract][Hide abstract] ABSTRACT: The antiviral compounds quartromicins represent unique members of a family of spirotetronate natural products. In this study, a biosynthetic gene cluster of quartromicins was identified by degenerate primer PCR amplification of specific genes involved in the biosynthesis of the tetronate moiety. The biochemical results confirmed that 1,3-bisphosphoglycerate was incorporated into the tetronate ring, and the intermediates of this ring were also reconstructed in vitro. The data also suggested a module skipping strategy for the production of two alternative polyketide chains by the same polyketide synthase assembly line. These findings set the stage for further investigations of the stereodivergent intermolecular cyclization mechanism, and highlight how nature has constructed this type of C2 symmetric molecule through intermolecular dimerization.
"Another possibility is that the donor is an acyl-ACP, which must be encoded, together with the putative thioesterase, elsewhere on the chromosome . At the C terminus of ErcD, instead of a conventional thioesterase (TE) domain (Kohli and Walsh, 2003), a C domain is present which we propose catalyzes the cyclization of the tetrapeptide to form the 2,5-diketopiperazine. The fungal NRPS that governs the biosynthesis of the diketopiperazine (DKP) core of gliotoxin has been characterized and it also lacks a C-terminal TE. "
[Show abstract][Hide abstract] ABSTRACT: The genome of the erythromycin-producing bacterium Saccharopolyspora erythraea contains many orphan secondary metabolite gene clusters including two (nrps3 and nrps5) predicted to govern biosynthesis of nonribosomal peptide-based siderophores. We report here the production by S. erythraea, even under iron-sufficient conditions, of a 2,5-diketopiperazine siderophore candidate we have named erythrochelin. Deletion of the nonribosomal peptide synthetase (NRPS) gene ercD within the nrps5 cluster abolished erythrochelin production. The tetrapeptide backbone of erythrochelin (alpha-N-acetyl-delta-N-acetyl-delta-N-hydroxyornithine-serine-delta-N-hydroxyornithine-delta-N-acetyl-delta-N-hydroxyornithine) suggests an orthodox colinear model for erythrochelin assembly. Curiously, the delta-N-acetyltransferase required for erythrochelin biosynthesis is encoded within a remote NRPS-cluster (nrps1) whose own NRPS contains an inactivating mutation. Disruption of the nrps1 gene mcd abolished erythrochelin biosynthesis, which could then be restored by addition of synthetic L-delta-N-acetyl-delta-N-hydroxyornithine, confirming an unprecedented example of functional crosstalk between nrps clusters.
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