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Author: Michael Burkart
Publisher: Springer Nature
ISBN: 1071632140
Category : Science
Languages : en
Pages : 324
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Book Description
This volume provides new technologies on NRPSs and related carrier protein dependent synthases, including polyketide synthases (PKS) and fatty acid synthases (FAS). Chapters detail enzymology, structural biology, proteopromics, chemical biology, natural product chemistry, and bioinformatics. Written in the format of the highly successful Methods in Molecular Biology series, each chapter includes an introduction to the topic, lists necessary materials and methods, includes tips on troubleshooting and known pitfalls, and step-by-step, readily reproducible protocols. Authoritative and cutting-edge, Non-Ribosomal Peptide Biosynthesis and Engineering: Methods and Protocols aims to feature methods that will be beneficial to new researchers, and those wanting to adopt new methodologies into their research.
Author: Michael Burkart
Publisher: Springer Nature
ISBN: 1071632140
Category : Science
Languages : en
Pages : 324
Get Book Here
Book Description
This volume provides new technologies on NRPSs and related carrier protein dependent synthases, including polyketide synthases (PKS) and fatty acid synthases (FAS). Chapters detail enzymology, structural biology, proteopromics, chemical biology, natural product chemistry, and bioinformatics. Written in the format of the highly successful Methods in Molecular Biology series, each chapter includes an introduction to the topic, lists necessary materials and methods, includes tips on troubleshooting and known pitfalls, and step-by-step, readily reproducible protocols. Authoritative and cutting-edge, Non-Ribosomal Peptide Biosynthesis and Engineering: Methods and Protocols aims to feature methods that will be beneficial to new researchers, and those wanting to adopt new methodologies into their research.
Author: Philipp Stephan
Publisher:
ISBN:
Category :
Languages : de
Pages : 0
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Book Description
Over the last decades, discovery rates of new antibiotics have declined while the occurrence of multi-resistant pathogens has increased, leading towards a post-antibiotic era. Many current antibiotics are natural products or derivatives, known for their excellent bioactivities but complex structures that complicate synthetic production. Many antibiotics, like penicillin and vancomycin, are peptides produced by nonribosomal peptide synthetases (NRPS). These multi-modular enzyme complexes function like assembly lines, with each module adding a specific amino acid to the peptide through the biocatalytic activities of distinct domains. Targeted NRPS engineering to alter structures of the produced peptides has faced challenges, but directed evolution of NRPS domains seems to offer a promising solution. This thesis presents a straightforward method for the directed evolution of adenylation (A) domains using LC-MS/MS detection of dipeptides in cell lysates, demonstrating its power by engineering the GrsB1 A domain from gramicidin S biosynthesis to select for L-piperazic acid (Piz) instead of its native substrate L-Pro without reducing enzyme activity. The modified antibiotic, Piz-gramicidin S, showed improved bioactivity. Despite compatibility issues between NRPS domains, kinetic analyses revealed that A domain substrate preferences ultimately determine final product ratios. Additionally, the thesis proposes a novel DNA-based approach for NRPS engineering, using zinc finger domains that bind specific DNA sequences to simplify module rearrangement by making NRPSs DNA-templated. This method offers a more efficient alternative to traditional cloning techniques by replacing the handling of large NRPS genes with much shorter sequences of the zinc finger domains. Overall, this research advances the engineering of NRPSs for developing new antibiotics with better efficacy against resistant pathogens and highlights the usefulness of directed evolution in this context.
Author: Farzaneh Pourmasoumi
Publisher:
ISBN:
Category :
Languages : de
Pages : 0
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Book Description
Nonribosomal peptide synthetases (NRPSs) are an important source of pharmaceutically valuable natural products, including antibiotics. In depth understanding of enzymatic interactions responsible for the biosynthesis of these compounds by NRPSs is essential for re-engineering of these proteins to create structural diversity. In this work, we establish tools that expand the understanding and engineering of nonribosomal peptide synthetases.
Author: Jennifer Fick Brannock
Publisher:
ISBN:
Category :
Languages : en
Pages : 184
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Book Description
Author: Reto Daniel Zwahlen
Publisher:
ISBN: 9789403406732
Category :
Languages : en
Pages :
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Author: Andreas Tietze
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Book Description
Author: Yanyan Li
Publisher: Springer
ISBN: 1493910108
Category : Medical
Languages : en
Pages : 113
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Book Description
Lasso peptides form a growing family of fascinating ribosomally-synthesized and post-translationally modified peptides produced by bacteria. They contain 15 to 24 residues and share a unique interlocked topology that involves an N-terminal 7 to 9-residue macrolactam ring where the C-terminal tail is threaded and irreversibly trapped. The ring results from the condensation of the N-terminal amino group with a side-chain carboxylate of a glutamate at position 8 or 9, or an aspartate at position 7, 8 or 9. The trapping of the tail involves bulky amino acids located in the tail below and above the ring and/or disulfide bridges connecting the ring and the tail. Lasso peptides are subdivided into three subtypes depending on the absence (class II) or presence of one (class III) or two (class I) disulfide bridges. The lasso topology results in highly compact structures that give to lasso peptides an extraordinary stability towards both protease degradation and denaturing conditions. Lasso peptides are generally receptor antagonists, enzyme inhibitors and/or antibacterial or antiviral (anti-HIV) agents. The lasso scaffold and the associated biological activities shown by lasso peptides on different key targets make them promising molecules with high therapeutic potential. Their application in drug design has been exemplified by the development of an integrin antagonist based on a lasso peptide scaffold. The biosynthesis machinery of lasso peptides is therefore of high biotechnological interest, especially since such highly compact and stable structures have to date revealed inaccessible by peptide synthesis. Lasso peptides are produced from a linear precursor LasA, which undergoes a maturation process involving several steps, in particular cleavage of the leader peptide and cyclization. The post-translational modifications are ensured by a dedicated enzymatic machinery, which is composed of an ATP-dependent cysteine protease (LasB) and a lactam synthetase (LasC) that form an enzymatic complex called lasso synthetase. Microcin J25, produced by Escherichia coli AY25, is the archetype of lasso peptides and the most extensively studied. To date only around forty lasso peptides have been isolated, but genome mining approaches have revealed that they are widely distributed among Proteobacteria and Actinobacteria, particularly in Streptomyces, making available a rich resource of novel lasso peptides and enzyme machineries towards lasso topologies.
Author: Janik Kranz
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Author: Rebecca Schomer
Publisher:
ISBN:
Category :
Languages : en
Pages : 140
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Book Description
Natural products (NPs) are an important source for antibacterial, antifungal and anticancer drugs. One medically relevant class of NP, nonribosomal peptides (NRPs), are constructed by a conserved enzymology called nonribosomal peptide synthetases (NRPSs). Efforts to metabolically engineer next generation antibacterial NRPs has been slow due to an incomplete understanding of NRPS enzymology. The recent discovery that MbtH-like proteins (MLPs), a superfamily of short polypeptides with chaperone-like properties, are required for the solubility and activity of many NRPSs was a significant breakthrough in our ability to characterize NRPSs in vitro. While MLP-encoding genes are usually found within the NRPS-encoding gene cluster they influence, cross pathway MLP/NRPS interactions occur when more than one MLP is encoded in a genome. These interactions are complex and have been shown to be variable between both noncognate and cognate MLP/NRPS partners. Prior to this thesis, we did not have a detailed understanding of which aspects of the MLP are required for functional interaction with an NRPS. Using Enterobactin (ENT) biosynthesis from Escherichia coli as a model system, this thesis makes progress characterizing the role of the MbtH-like protein (MLP) in NRPS enzymology by dissecting MLP/NRPS interactions by two approaches. First, I probe the ability of noncognate MLPs to interact in vivo and in vitro with the MLP-dependent NRPS, EntF. Second, I target the cognate MLP, YbdZ, and perform a complete survey of the MLP residues involved in functional interactions with EntF. These analyses of this model MLP/NRPS pair is the most detailed to date and offers valuable insight into future directed evolution studies of MLPs and MLP-dependent NRPSs. Significantly, this work demonstrates the complexities of MLP/NRPS interactions and highlights challenges that must be addressed when engineering MLP-dependent NRPS.
Author: Christoph Wittmann
Publisher: Springer Science & Business Media
ISBN: 9400745346
Category : Medical
Languages : en
Pages : 391
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Book Description
Systems Metabolic Engineering is changing the way microbial cell factories are designed and optimized for industrial production. Integrating systems biology and biotechnology with new concepts from synthetic biology enables the global analysis and engineering of microorganisms and bioprocesses at super efficiency and versatility otherwise not accessible. Without doubt, systems metabolic engineering is a major driver towards bio-based production of chemicals, materials and fuels from renewables and thus one of the core technologies of global green growth. In this book, Christoph Wittmann and Sang-Yup Lee have assembled the world leaders on systems metabolic engineering and cover the full story – from genomes and networks via discovery and design to industrial implementation practises. This book is a comprehensive resource for students and researchers from academia and industry interested in systems metabolic engineering. It provides us with the fundaments to targeted engineering of microbial cells for sustainable bio-production and stimulates those who are interested to enter this exiting research field.
