Evolution-inspired engineering of nonribosomalpeptidesynthetases Non-ribosomal peptide synthetases (NRPSs) are colossal, modular enzymes that act as sophisticated molecular assembly lines, responsible for the biosynthesis of a vast array of complex peptides.Non-ribosomal peptide synthetases Unlike peptides synthesized by ribosomes, these non-ribosomal peptides (NRPs) are not dictated by mRNA templates. Instead, NRPSs directly assemble amino acids and other acyl substrates into structurally diverse and often biologically potent natural products作者：S Dincer·2022·被引用次数：6—NRPs, unlike other proteins,are synthesized on huge nonribosomal peptide synthetase (NRPS) enzyme complexes that are not dependent on ribosomal .... These enzymes are fundamental to the production of many secondary metabolites in microorganisms, contributing to a wide range of valuable compounds with applications in medicine and biotechnology.
At their core, NRPSs are multi-enzyme complexes, often referred to as "megasynthases" due to their immense size and intricate organization. Each NRPS is typically composed of multiple modules, and within each module are catalytic domains responsible for specific steps in the peptide assembly process. The modular nature of NRPSs allows for a combinatorial approach to peptide synthesis, where the arrangement and types of modules dictate the final peptide structure.Non-ribosomal peptides are synthesized by large enzyme complexes callednonribosomal peptide synthetases. These synthetases are independent of mRNA and each ... This inherent flexibility is key to generating the tremendous structural diversity observed in non-ribosomal peptides.作者：M Duban·2022·被引用次数：58—Nonribosomal peptides are microbial secondary metabolitesexhibiting a tremendous structural diversity and a broad range of biological activities.
Commonly, the catalytic domains within an NRPS module include:
* Adenylation (A) domain: Selects and activates the specific amino acid or carboxylic acid substrate.
* Thiolation (T) domain, also known as the peptidyl carrier protein (PCP): Covalently binds the activated substrate via a phosphopantetheine arm.
* Condensation (C) domain: Catalyzes the formation of the peptide bond between two activated substrates.
Additional domains, such as epimerization (E), methylation (MT), and oxidation (Ox) domains, can be present within modules to introduce further structural modifications, leading to complex cyclic or branched peptide structures, or incorporating non-proteinogenic amino acids.
The synthesis of a non-ribosomal peptide by an NRPS is a highly orchestrated process that begins with the recruitment of extender units. This process can be initiated by a starter unit, which can be a simple carboxylic acid or an amino acid, often modified.
1. Substrate Activation: The A domain of the first module recognizes and binds a specific amino acid or acyl substrate. ATP is then used to activate the carboxyl group of the substrate, forming an aminoacyl-adenylateNonribosomal Peptide Synthetases in Animals.
2. Substrate Loading: The activated substrate is transferred to the phosphopantetheine arm of the T domain within the same module, forming a thioester bond.
3作者：T Izoré·2021·被引用次数：85—Non-ribosomal peptide synthetases areimportant enzymes for the assembly of complex peptide natural products. Within these multi-modular .... Peptide Bond Formation: The C domain of the first module, or a subsequent module, catalyzes the formation of a peptide bond between the substrate on the first T domain and the growing peptide chain attached to the T domain of the preceding module.2022年12月14日—Nonribosomal peptide synthetase gene clusters arealmost exclusively restricted to prokaryotes(bacteria) and fungi, as single cell eukaryotes. This elongates the peptide chain.Structures and mechanism of condensation in non- ...
4. Translocation and Modification: The growing peptide chain is then translocated to the T domain of the next module2021年5月26日—Non-ribosomal peptide synthetases (NRPSs) aremultienzymes that produce complex natural metaboliteswith many applications in medicine and .... If present, additional modifying domains (e.g., E for epimerization, MT for methylation) can act on the peptide chain at various stages.
5Chapter 5: Peptide Natural Products II: Nonribosomal Peptides. Termination: The process continues sequentially through the modules until the final module, which often contains a thioesterase (TE) domain.De novo design and engineering of non-ribosomal peptide ... The TE domain typically releases the completed peptide from the NRPS complex, often by catalyzing cyclization or head-to-tail ligation, forming the final non-ribosomal peptide product作者：T Izoré·2021·被引用次数：85—Non-ribosomal peptide synthetases areimportant enzymes for the assembly of complex peptide natural products. Within these multi-modular ....
The ability of NRPSs to produce peptides with extensive structural diversity and unique modifications has led to the discovery of numerous bioactive compounds. Many clinically important drugs, including antibiotics (e.g., penicillin, vancomycin), antifungals, immunosuppressants (e.g.Nonribosomal Peptide Synthetases(NRPSs) are large, multimodular enzymes that are responsible for the construction of peptide-based natural products., cyclosporine), and anticancer agents, are derived from or inspired by non-ribosomal peptides.作者：C Shi·2020·被引用次数：21—Nonribosomal peptide synthetases (NRPSs) are remarkable modular enzymes thatsynthesize peptide natural products.
The study of NRPSs is crucial for several reasons:
* Drug Discovery: Understanding NRPS pathways can lead to the identification of novel antimicrobial agents or other therapeutic compounds, especially in the face of rising antibiotic resistance6LTA: Crystal Structure of Nonribosomal peptide ....
* Biotechnology and Engineering: NRPSs are attractive targets for bioengineeringThe inherent flexibility of type I non-ribosomal peptide .... By manipulating their modular structure and catalytic domains, scientists can design and synthesize novel peptides with tailored properties, expanding their potential applications in medicine, agriculture, and industry. This "evolution-inspired engineering" holds promise for creating new pharmaceuticals and biochemicals.
* Metabolic Engineering: Insights into NRPS biosynthesis enable metabolic engineering efforts in microorganisms to enhance the production of valuable natural products or to engineer strains for the production of novel compounds.
While NRPSs are predominantly found in prokaryotes (bacteria) and fungi, their complex structures and the diverse bioactivities of their products make them a subject of intense research in molecular biology, biochemistry, and synthetic biology. The ongoing exploration of NRPS structural biology and functional mechanisms continues to unveil new possibilities for harnessing these powerful enzymatic machines.
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