Understanding and Improving Designed Enzymes by Computer Simulations

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ISBN 13 :
Total Pages : 110 pages
Book Rating : 4.:/5 (994 download)

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Book Synopsis Understanding and Improving Designed Enzymes by Computer Simulations by : Asmit Bhowmick

Download or read book Understanding and Improving Designed Enzymes by Computer Simulations written by Asmit Bhowmick and published by . This book was released on 2016 with total page 110 pages. Available in PDF, EPUB and Kindle. Book excerpt: Abstract Understanding and Improving Designed Enzymes by Computer Simulations By Asmit Bhowmick Doctor of Philosophy in Chemical Engineering University of California, Berkeley Professor Teresa Head-Gordon, Chair The ability to control for protein structure, electrostatics and dynamical motions is a fundamental problem that limits our ability to rationally design catalysts for new chemical reactions not known to have a natural biocatalyst. Current computational approaches for de novo enzyme design seek to engineer a small catalytic construct into an accommodating protein scaffold as exemplified by the Rosetta strategy. Here we consider 3 designed enzymes for the Kemp elimination reaction (KE07, KE70 and KE15) that showed minimal catalytic activity. KE07 and KE70 were subsequently improved by 2 orders of magnitude in catalytic efficiency by directed evolution and highlighted the shortcomings of the design process. This work studies two keys issues plaguing the designs - side chain conformational variability and electrostatics. For the first part, a new Monte Carlo sampling method was developed that uses a physical forcefield and coupled with backbone variability and a backbone dependent rotamer library. Using transition state theory with energies/entropies calculated from Monte Carlo simulations, it is shown that in both KE07 and KE70, the initial design was over-optimized to stabilize the enzyme-substrate complex. Mutations introduced by directed evolutions led to destabilization of the enzyme-substrate complex and stabilization of the transition state. Furthermore, analysis of residue correlations via mutual information yielded hotspots, several of which were mutations during directed evolution. Laboratory mutations of these hotspots in the best variant of KE07 led to a drop in catalytic performance, demonstrating their importance. The metrics identified in KE07/KE70 studies were used to predict mutations to improve enzyme KE15 that had not been improved prior to this study. Several mutants, all predicted through computer simulations have now yielded better catalytic activity in the laboratory with the best one 10-fold better than the starting enzyme. In order to quantify the role of electrostatics, a new method was developed using the AMOEBA polarizable forcefield that allowed splitting the contribution of electric field at the substrate by residues and solvent. The improvement in KE07 series could be tracked directly through changes in electric field at the substrate. In comparison, KE70 did not show a significant shift in electrostatic field, suggesting other factors like substrate binding may have been the reason for enhancement of activity. However, the common theme in both enzymes was the lack of participation (and in fact detrimental role) of the scaffold in the reaction. Future design efforts would benefit from an expanded theozyme and careful selection of scaffold based on electrostatic properties. Generating efficient biocatalysts without using laboratory directed evolution would be an inflection point in the field of enzyme design. This work is a step in that direction.

Understanding Enzymes

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Publisher : CRC Press
ISBN 13 : 9814669334
Total Pages : 884 pages
Book Rating : 4.8/5 (146 download)

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Book Synopsis Understanding Enzymes by : Allan Svendsen

Download or read book Understanding Enzymes written by Allan Svendsen and published by CRC Press. This book was released on 2016-04-27 with total page 884 pages. Available in PDF, EPUB and Kindle. Book excerpt: Understanding Enzymes: Function, Design, Engineering, and Analysis focuses on the understanding of enzyme function and optimization gained in the past decade, past enzyme function analysis, enzyme engineering, and growing insights from the simulation work and nanotechnology measurement of enzymes in action in vitro or in silico. The book also prese

Computer Simulations of Enzymes

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ISBN 13 :
Total Pages : 244 pages
Book Rating : 4.:/5 (126 download)

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Book Synopsis Computer Simulations of Enzymes by : Jianzhuang Yao

Download or read book Computer Simulations of Enzymes written by Jianzhuang Yao and published by . This book was released on 2014 with total page 244 pages. Available in PDF, EPUB and Kindle. Book excerpt: Enzymes are important catalysts in living systems, and understanding catalytic mechanisms of enzymes is an important task for modern biophysics and biochemistry. Computer simulations have emerged as very useful tools for understanding how enzymes work. In this dissertation, QM/MM MD simulations were applied to study the catalytic mechanisms of several enzymes, including sedolisin, S-adenosyl-L-methionine (AdoMet)-dependent methyltransferases, and salicylic acid binding protein 2. For sedolisin, we focus on the acylation and deacylation reactions catalyzed by the enzymes. We proposed a general acid/base mechanism involving the Glu/Asp residues at the active site. MD and QM/MM free energy simulations on pro-kumamolisin show that the protonation of Asp164 would be able to trigger conformational changes and generate the functional active site for autocatalysis. The free energy simulations reported for SAMT, an AdoMet-dependent methyltransferase, showed that while the structure of the reactant complex containing salicylate, its natural substrate, is rather close to the corresponding TS structure, this is not the case for 4-hydroxybenzoate. The simulations demonstrated that additional energy is required to generate the TS-like structure for 4-hydroxybenzoate, consistent with the low activity of the enzyme toward this substrate. For protein lysine methyltransferase SET7/9, we showed that while the wild type SET7/9 may act like a mono-methylase, the Y245→A mutation could increase the ability of SET7/9 to add two more methyl groups on the target lysine. The substrate specificity of salicylic acid binding protein 2 (SABP2) has also been studied during my graduate study. This enzyme has promiscuous esterase activity toward a series of substrates, but shows high activity toward its natural substrate methyl salicylate (MeSA). We demonstrated that SABP2 seems to represent a case in which the enzyme itself might have not been perfectly evolved and that substrate-assisted catalysis (SAC) involving its natural substrate may be used to enhance the activity and achieve substrate discrimination. In addition to enzymes, the prediction of protein-protein interactions (PPI) is also included in my dissertation. We established a robust pipeline for PPI prediction by integrating multiple classifiers using random forests algorithm. This pipeline could be very useful for predicting PPI.

Simulating Enzyme Reactivity

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Publisher : Royal Society of Chemistry
ISBN 13 : 1782626832
Total Pages : 558 pages
Book Rating : 4.7/5 (826 download)

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Book Synopsis Simulating Enzyme Reactivity by : Inaki Tunon

Download or read book Simulating Enzyme Reactivity written by Inaki Tunon and published by Royal Society of Chemistry. This book was released on 2016-11-16 with total page 558 pages. Available in PDF, EPUB and Kindle. Book excerpt: The simulation of enzymatic processes is a well-established field within computational chemistry, as demonstrated by the 2013 Nobel Prize in Chemistry. It has been attracting increasing attention in recent years due to the potential applications in the development of new drugs or new environmental-friendly catalysts. Featuring contributions from renowned authors, including Nobel Laureate Arieh Warshel, this book explores the theories, methodologies and applications in simulations of enzyme reactions. It is the first book offering a comprehensive perspective of the field by examining several different methodological approaches and discussing their applicability and limitations. The book provides the basic knowledge for postgraduate students and researchers in chemistry, biochemistry and biophysics, who want a deeper understanding of complex biological process at the molecular level.

Frontiers

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Publisher :
ISBN 13 :
Total Pages : 60 pages
Book Rating : 4.M/5 ( download)

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Book Synopsis Frontiers by :

Download or read book Frontiers written by and published by . This book was released on with total page 60 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Catalysis in Chemistry and Enzymology

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Publisher : Courier Corporation
ISBN 13 : 9780486654607
Total Pages : 866 pages
Book Rating : 4.6/5 (546 download)

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Book Synopsis Catalysis in Chemistry and Enzymology by : William P. Jencks

Download or read book Catalysis in Chemistry and Enzymology written by William P. Jencks and published by Courier Corporation. This book was released on 1987-01-01 with total page 866 pages. Available in PDF, EPUB and Kindle. Book excerpt: Exceptionally clear coverage of mechanisms for catalysis, forces in aqueous solution, carbonyl- and acyl-group reactions, practical kinetics, more.

Computer Simulations Of Enzymes

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ISBN 13 :
Total Pages : pages
Book Rating : 4.:/5 (894 download)

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Book Synopsis Computer Simulations Of Enzymes by : Philip Hanoian

Download or read book Computer Simulations Of Enzymes written by Philip Hanoian and published by . This book was released on 2014 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Enzymes are proteins that perform the essential function of facilitating chemical reactions within living organisms, and the rate enhancements provided by enzymes are so significant that they remain a marvel for chemists today. The study of enzymes is thus pervaded by attempts to understand the precise mechanisms by which enzymes achieve these rate enhancements, with additional focus on the impressive level of specificity and selectivity these protein catalysts display as well. In this thesis, four studies on enzymatic systems are presented with the goal of further elucidating the mechanisms by which enzymes confer enormous rate enhancements to chemical reactions. In the first study, mixed quantum mechanical/molecular mechanical calculations are applied to study a series of phenolate inhibitors of increasing pKa bound to ketosteroid isomerase to explore the catalytically relevant hydrogen bonds in the enzyme active site. The second study uses molecular dynamics simulations to explore the use of water in the active site in lieu of the native enzymatic hydrogen bonds. The third study focuses on the positioning of the catalytic base in ketosteroid isomerase using molecular dynamics simulations, and this positioning is suggested to arise from non-local contributions involving nearby hydrophobic residues and an active site loop. In the final study, an additional enzyme, dihydrofolate reductase is examined, and empirical valence bond molecular dynamics simulations are applied to evaluate the free energy barriers of the wild-type enzyme and several evolutionarily motivated mutants. Overall, these studies help to further our understanding of enzymes and the roles of individual factors in enzyme catalysis.

Simulating Enzyme Reactivity Computational Methods in Enzyme Catalysis

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Publisher : Createspace Independent Publishing Platform
ISBN 13 : 9781548041595
Total Pages : 446 pages
Book Rating : 4.0/5 (415 download)

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Book Synopsis Simulating Enzyme Reactivity Computational Methods in Enzyme Catalysis by : John Maclane

Download or read book Simulating Enzyme Reactivity Computational Methods in Enzyme Catalysis written by John Maclane and published by Createspace Independent Publishing Platform. This book was released on 2017-06-07 with total page 446 pages. Available in PDF, EPUB and Kindle. Book excerpt: The simulation of enzymatic processes is a well-established field within computational chemistry, as demonstrated by the 2013 Nobel Prize in Chemistry. It has been attracting increasing attention in recent years due to the potential applications in the development of new drugs or new environmental-friendly catalysts. Featuring contributions from renowned authors, including Nobel Laureate Arieh Warshel, this book explores the theories, methodologies and applications in simulations of enzyme reactions. It is the first book offering a comprehensive perspective of the field by examining several different methodological approaches and discussing their applicability and limitations. The book provides the basic knowledge for postgraduate students and researchers in chemistry, biochemistry and biophysics, who want a deeper understanding of complex biological process at the molecular level.

Novel Applications and Methods for the Computer-aided Understanding and Design of Enzyme Activity

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ISBN 13 :
Total Pages : 160 pages
Book Rating : 4.:/5 (13 download)

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Book Synopsis Novel Applications and Methods for the Computer-aided Understanding and Design of Enzyme Activity by : Brian M. Bonk

Download or read book Novel Applications and Methods for the Computer-aided Understanding and Design of Enzyme Activity written by Brian M. Bonk and published by . This book was released on 2018 with total page 160 pages. Available in PDF, EPUB and Kindle. Book excerpt: Despite great progress over the past several decades in the development and application of computer-aided tools for engineering enzymes for a vast array of industrial applications. rational enzyme design remains an ongoing challenge in biotechnology. This thesis presents a set of novel applications and methods for the computer-aided understanding and design of enzyme activity. In the first part. we apply biophysical modeling approaches in order to design non-native substrate specificity in a key enzymatic step (the thiolase-catalyzed condensation of two acyl-CoA substrates) of an industrially useful de novo metabolic pathway. We present a model-guided. rational design study of ordered substrate binding applied to two biosynthetic thiolases. with the goal of increasing the ratio of C6/C4 products formed by the 31HIA pathway, 3-hydroxyhexanoic acid and 3-hydroxybutyric acid. We identify thiolase mutants that result in nearly ten-fold increases in C6/C4 selectivity. Our findings can extend to other pathways that employ the thiolase for chain elonglation, as well as expand our knowledge of sequence-structure-function relationship for this important class of enzymes. In the second part, we apply methods from machine learning to an ensemble of reactive and non-reactive, but "almost reactive" molecular dynamics trajectories in order to elucidate catalytic drivers in another industrially important model enzyme system, ketol-acid reductoisomerase. Using a small number of molecular features, we show that we can identify conformational states that are highly predictive of reactivity at specific time points relative to the progress of the prospective catalytic event and also that provide mechanistic insight into the reaction catalyzed by this enzyme. We then present a novel theoretical framework for evaluating the contribution to the overall catalytic rate of the conformational states found in the previous part to be predictive of reactivity. Leveraging a computational enhanced sampling technique called transition interface sampling, we show that trajectories sampled in such a manner as to selectively visit the conformations predicted to be characteristic of reactivity exhibit rate constants many orders of magnitude greater than trajectories not required to visit these reactive conformations. The results of this analysis illustrate the importance of incorporating dynamical information into existing frameworks for biocatalyst design.

Enzyme Catalysis in Organic Synthesis, 3 Volume Set

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Publisher : John Wiley & Sons
ISBN 13 : 3527325476
Total Pages : 2143 pages
Book Rating : 4.5/5 (273 download)

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Book Synopsis Enzyme Catalysis in Organic Synthesis, 3 Volume Set by : Karlheinz Drauz

Download or read book Enzyme Catalysis in Organic Synthesis, 3 Volume Set written by Karlheinz Drauz and published by John Wiley & Sons. This book was released on 2012-03-26 with total page 2143 pages. Available in PDF, EPUB and Kindle. Book excerpt: This comprehensive three-volume set is the standard reference in the field of organic synthesis, catalysis and biocatalysis. Edited by a highly experienced and highly knowledgeable team with a tremendous amount of experience in this field and its applications, this edition retains the successful concept of past editions, while the contents are very much focused on new developments in the field. All the techniques described are directly transferable from the lab to the industrial scale, making for a very application-oriented approach. A must for all chemists and biotechnologists.

Enzyme-Based Organic Synthesis

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Publisher : John Wiley & Sons
ISBN 13 : 1118995155
Total Pages : 719 pages
Book Rating : 4.1/5 (189 download)

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Book Synopsis Enzyme-Based Organic Synthesis by : Cheanyeh Cheng

Download or read book Enzyme-Based Organic Synthesis written by Cheanyeh Cheng and published by John Wiley & Sons. This book was released on 2022-02-03 with total page 719 pages. Available in PDF, EPUB and Kindle. Book excerpt: Enzyme-Based Organic Synthesis An insightful exploration of an increasingly popular technique in organic chemistry In Enzyme-Based Organic Synthesis, expert chemist Dr. Cheanyeh Cheng delivers a comprehensive discussion of the principles, methods, and applications of enzymatic and microbial processes for organic synthesis. The book thoroughly explores this growing area of green synthetic organic chemistry, both in the context of academic research and industrial practice. The distinguished author provides a single point of access for enzymatic methods applicable to organic synthesis and focuses on enzyme catalyzed organic synthesis with six different classes of enzyme. This book serves as a link between enzymology and biocatalysis and serves as an invaluable reference for the growing number of organic chemists using biocatalysis. Enzyme-Based Organic Synthesis provides readers with multiple examples of practical applications of the main enzyme classes relevant to the pharmaceutical, medical, food, cosmetics, fragrance, and health care industries. Readers will also find: A thorough introduction to foundational topics, including the discovery and nature of enzymes, enzyme structure, catalytic function, molecular recognition, enzyme specificity, and enzyme classes Practical discussions of organic synthesis with oxidoreductases, including oxidation reactions and reduction reactions Comprehensive explorations of organic synthesis with transferases, including transamination with aminotransferases and phosphorylation with kinases In-depth examinations of organic synthesis with hydrolases, including the hydrolysis of the ester bond Perfect for organic synthetic chemists, chemical and biochemical engineers, biotechnologists, process chemists, and enzymologists, Enzyme-Based Organic Synthesis is also an indispensable resource for practitioners in the pharmaceutical, food, cosmetics, and fragrance industries that regularly apply this type of synthesis.

Computer-aided Rational Enzyme Design for Industrial and Technological Applications

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ISBN 13 :
Total Pages : 229 pages
Book Rating : 4.:/5 (113 download)

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Book Synopsis Computer-aided Rational Enzyme Design for Industrial and Technological Applications by : Gerard Santiago Morcillo

Download or read book Computer-aided Rational Enzyme Design for Industrial and Technological Applications written by Gerard Santiago Morcillo and published by . This book was released on 2019 with total page 229 pages. Available in PDF, EPUB and Kindle. Book excerpt: "The massive industrial production exploited by our society since the XIX century has growth at expenses of the planet. Environmental damages are already visible, and they urge us to find new and sustainable production ways. Among all contributors, this thesis is focused on enzymes and its potential application in industry. Enzymes are biomolecules capable of performing and speeding up chemical reactions. Their versatility makes them a perfect choice for green chemistry proposals, allowing the substitution of damaging process involving hard chemical compounds or heavy energy usage. The work done focus on the better understanding of enzymatic properties and behavior to improve them for industrial application, by applying state-of-the-art modeling techniques. This knowledge has allowed the development of a new classification method for substrate promiscuity, the Effective Volume, and the design of enhanced enzyme variants. In the enzyme engineering line, this thesis presents a mutant laccase obtained through computer-aided rational design, with an improved activity over arylamines, tailored explicitly for polyaniline production. Moreover, we introduce, for the first time in our knowledge, the concept of PluriZymes, an enzyme with two fully functional active sites: an original one and a "de novo" artificially added one." -- TDX.

Research and Highlights

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Publisher :
ISBN 13 :
Total Pages : 60 pages
Book Rating : 4.:/5 (3 download)

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Book Synopsis Research and Highlights by : Argonne National Laboratory

Download or read book Research and Highlights written by Argonne National Laboratory and published by . This book was released on 1994 with total page 60 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Industrial Biotransformations

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Publisher : John Wiley & Sons
ISBN 13 : 3527607900
Total Pages : 570 pages
Book Rating : 4.5/5 (276 download)

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Book Synopsis Industrial Biotransformations by : Andreas Liese

Download or read book Industrial Biotransformations written by Andreas Liese and published by John Wiley & Sons. This book was released on 2006-08-21 with total page 570 pages. Available in PDF, EPUB and Kindle. Book excerpt: The completely revised second edition of this user-friendly and application-oriented overview of one-step biotransformations of industrial importance. Based on extensive literature and patent research, this book is unique in arranging each process in a systematic way to allow for easy comparison. All the chapters have been rewritten, with all the processes updated and more than 30 new processes added. Each set of data is accompanied by key literature citations, supported by flow sheets where available, reduced to their significant elements. In addition, an extensive index classified by substrates, products, enzymes, and companies provides direct access to each process, organized according to enzyme class. Biotechnologists, biochemists, microbiologists, process engineers and those working in the chemical and biotechnological industries will find here all the significant parameters characterizing both the biotransformation and the process.

Opportunities in the Nutrition and Food Sciences

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Publisher : National Academies Press
ISBN 13 : 0309048842
Total Pages : 329 pages
Book Rating : 4.3/5 (9 download)

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Book Synopsis Opportunities in the Nutrition and Food Sciences by : Institute of Medicine

Download or read book Opportunities in the Nutrition and Food Sciences written by Institute of Medicine and published by National Academies Press. This book was released on 1994-02-01 with total page 329 pages. Available in PDF, EPUB and Kindle. Book excerpt: Thanks to increased knowledge about nutrition, many threats to human health have been curbed. But there is much more to be learned. This new volume identifies the most promising opportunities for further progress in basic and clinical research in the biological sciences, food science and technology, and public health. The committee identifies cross-cutting themes as frameworks for investigation and offers a history of nutrition and food science research with nine case studies of accomplishments. The core of the volume identifies research opportunities in areas likely to provide the biggest payoffs in enhancing individual and public health. The volume highlights the importance of technology and instrumentation and covers the spectrum from the effects of neurotransmitters on food selection to the impact of federal food programs on public health. The book also explores the training of nutrition and food scientists. This comprehensive resource will be indispensable to investigators, administrators, and funding decisionmakers in government and industry as well as faculty, students, and interested individuals.

Modern Biocatalysis

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Publisher : Royal Society of Chemistry
ISBN 13 : 1788014537
Total Pages : 594 pages
Book Rating : 4.7/5 (88 download)

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Book Synopsis Modern Biocatalysis by : Gavin Williams

Download or read book Modern Biocatalysis written by Gavin Williams and published by Royal Society of Chemistry. This book was released on 2018-05-31 with total page 594 pages. Available in PDF, EPUB and Kindle. Book excerpt: The synergy between synthetic biology and biocatalysis is emerging as an important trend for future sustainable processes. This book reviews all modern and novel techniques successfully implemented in biocatalysis, in an effort to provide better performing enzymatic systems and novel biosynthetic routes to (non-)natural products. This includes the use of molecular techniques in protein design and engineering, construction of artificial metabolic pathways, and application of computational methods for enzyme discovery and design. Stress is placed on current ‘hot’ topics in biocatalysis, where recent advances in research are defining new grounds in enzyme-catalyzed processes. With contributions from leading academics around the world, this book makes a ground-breaking contribution to this progressive field and is essential reading for graduates and researchers investigating (bio)catalysis, enzyme engineering, chemical biology, and synthetic biology.

Enzyme Cascade Design and Modelling

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Publisher : Springer Nature
ISBN 13 : 3030657183
Total Pages : 181 pages
Book Rating : 4.0/5 (36 download)

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Book Synopsis Enzyme Cascade Design and Modelling by : Selin Kara

Download or read book Enzyme Cascade Design and Modelling written by Selin Kara and published by Springer Nature. This book was released on 2021-02-24 with total page 181 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book provides a comprehensive overview of the recent developments achieved in the field of chemo/enzymatic cascades with topics spanning from design (in vitro and in vivo) to kinetic- and process modelling as well as process control. Opportunities and challenges of building multi-step chemo/enzymatic reactions are discussed, whereby the latter are critically assessed in each chapter and methods to ease the implementation are explored. Both, multi-enzymatic cascades and chemo-enzymatic cascades are presented with the motivation of combining the strengths of these two worlds (e.g. selectivity, activity and robustness) not neglecting the obstacles and challenges of such endeavour. Furthermore, the use of non-conventional media for catalytic cascade reactions, recent achievements and potential for future developments in a technical environment are addressed.