This review covers peptide structures originating from the concerted action of enzyme systems without the direct participation of nucleic acids. Biosynthesis proceeds by formation of linear peptidyl intermediates which may be enzymatically modified as well as transformed into specific cyclic structures. The respective enzyme systems are constructed of biosynthetic modules integrated into multienzyme structures. Genetic and DNA-sequence analysis of biosynthetic gene clusters have revealed extensive similarities between prokaryotic and eukaryotic systems, conserved principles of organisation, and a unique mechanism of transport of intermediates during elongation and modification steps involving 4'-phosphopantetheine. These similarities permit the identification of peptide synthetases and related aminoacylligases and acyl-ligases from sequence data. Similarities to other biosynthetic systems involved in the assembly of polyketide metabolites are discussed.
Peptide antibiotics are known to contain non-protein amino acids, D-amino acids, hydroxy acids, and other unusual constituents. In addition they may be modified by N-methylation and cyclization reactions. Their biosynthetic origin has been connected in many cases to an enzymatic system referred to as the 'thiotemplate multienzymic mechanism'. This mechanism includes the activation of the constituent residues as adenylates on the enzymic template, the acylation of specific template thiol groups, epimerization or N-methylation at this thioester stage, and polymerization in the sequence directed by the multienzymic structure with the aid of 4 -phosphopantetheine as a cofactor, including possible cyclization or terminal modification reactions. The reaction sequences leading to gramicidin S, tyrocidine. cyclosporine, bacitracin, polymyxin, actinomycin, enniatin, beauvericin, &(L-a-aminoadipyl)-L-cysteinyl-D-vahne and linear gramicidin are discussed. The structures of the multienzymes,' their genetic organization, the biological functions of these peptides and results on related systems are discussed.Although the enzymatic formation of essential peptides such as glutathione and pantetheine was already known in the 'preribosomal era', the elucidation of the biosynthesis of more complex peptides followed the unravelling of the genetic code in the sixties [l -31. A prediction of a poly-or multienzymatic pathway to peptides had been presented by Fritz Lipmann as early as 1954 [4] and a similar biosynthetic scheme of multienzymes as templates for polypeptides has now been verified for various types of peptides. Some of these studies have been reviewed elsewhere [5 -121, but recent results have advanced the field considerably. We therefore attempt to present here a more general view of this biosynthetic mechanism, and discuss the current areas of research.
This review covers peptide structures originating from the concerted action of enzyme systems without the direct participation of nucleic acids. Biosynthesis proceeds by formation of linear peptidyl intermediates which may be enzymatically modified as well as transformed into specific cyclic structures. The respective enzyme systems are constructed of biosynthetic modules integrated into multienzyme structures. Genetic and DNA-sequence analysis of biosynthetic gene clusters have revealed extensive similarities between prokaryotic and eukaryotic systems, conserved principles of organisation, and a unique mechanism of transport of intermediates during elongation and modification steps involving 4'-phosphopantetheine. These similarities permit the identification of peptide synthetases and related aminoacylligases and acyl-ligases from sequence data. Similarities to other biosynthetic systems involved in the assembly of polyketide metabolites are discussed.
The biosynthesis of the peptide antibiotic gramicidin S involves successive peptidyl transfer reactions between intermediates bound in thioester linkages to two active enzyme fractions, I and II. Fraction II activates and recemizes phenylalanine, and then initiates peptidyl transfer by catalyzing a reaction between the carboxyl group of D-phenylalanine, bound to an enzymic sulfhydryl group, and the free imino group of L-proline, one of four L-amino acids all linked by their carboxyl functions to separate sulfhydryl groups on fraction I. Successive reactions of this type in the active centers of the multienzyme complex of fraction I lead to the formation of thioester-bonded nascent peptide chains and, ultimately, of the antibiotic product.
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