Abstract
Nonribosomal peptides are microbial secondary metabolites exhibiting a tremendous structural diversity and a broad range of biological activities useful in the medical and agro-ecological fields. They are built up by huge multimodular enzymes called nonribosomal peptide synthetases. These synthetases are organized in modules constituted of adenylation, thiolation, and condensation core domains. As such, each module governs, according to the collinearity rule, the incorporation of a monomer within the growing peptide. The release of the peptide from the assembly chain is finally performed by a terminal core thioesterase domain. Secondary domains with modifying catalytic activities such as epimerization or methylation are sometimes included in the assembly lines as supplementary domains. This assembly line structure is analyzed by bioinformatics tools to predict the sequence and structure of the final peptides according to the sequence of the corresponding synthetases. However, a constantly expanding literature unravels new examples of nonribosomal synthetases exhibiting very rare domains and noncanonical organizations of domains and modules, leading to several amazing strategies developed by microorganisms to synthesize nonribosomal peptides. In this review, through several examples, we aim at highlighting these noncanonical pathways in order for the readers to perceive their complexity.
Highlights
Thousands of microbial secondary metabolites display large structural biodiversity and, a broad range of activities that can be exploited in different areas such as plant, animal, and human health
If nonribosomal peptide synthetases (NRPSs) do catalyze the formation of peptidic bonds between amino acid monomers, their polyketide synthases (PKSs) counterparts form with a similar scheme of carbon-carbon linkages of aryl acid moieties, leading to the modular synthesis of polyketides (PKs) [4]
Microorganisms 2022, 10, 577 final peptide, as well as to the action of tailoring enzymes. The latter is usually encoded within the NRPS biosynthetic gene clusters (BGCs) and perform structural modifications such as hydroxylations, glycosylations, or formylation, for instance, on the neosynthesized peptides
Summary
Thousands of microbial secondary metabolites display large structural biodiversity and, a broad range of activities that can be exploited in different areas such as plant, animal, and human health. NRPs are built up by multifunctional mega-enzymatic complexes called nonribosomal peptide synthetases (NRPSs) that work in a thiotemplate-based sequential manner as assembly lines [1,2]. Due to their modular organization, the size of NRPSs is variable, but some of them can be exceptionally large (up to over a megadalton) and are encoded by giant genes or groups of genes that, together with the cell surface protein-encoding genes, are considered as among the biggest in the microbial world and more generally in nature [3]. Microorganisms 2022, 10, 577 final peptide, as well as to the action of tailoring enzymes The latter is usually encoded within the NRPS biosynthetic gene clusters (BGCs) and perform structural modifications such as hydroxylations, glycosylations, or formylation, for instance, on the neosynthesized peptides. This review is mostly limited to multimodular linear thiotemplate NRPSs, with a very few exceptions concerning some stand-alone module thiotemplate NRPSs [2,10]
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