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Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
In this subchapter a variety of enzyme inhibitors and (allosteric) activators—alone or in combination with other APIs—are discussed that entered the market in recent years or about which new findings were published. Inhibitors act either reversible or irreversible (Section 21.2.2). They are discovered by high-throughput screening of large libraries of compounds generated by combinatorial chemistry approaches against a target enzyme. Alternatively, rational design based on the knowledge of the enzyme’s structure is employed together with computational methods as, e.g., molecular docking, molecular mechanics, free energy calculation methods, etc. (e.g., De Vivo and Cavalli, 2017; Abel et al., 2017). Examples are treated in other volumes of this Series, too (e.g., Chapter 19 in Volume 4 of this Series).
Engineered enzymes and enzyme systems
Published in Ruben Michael Ceballos, Bioethanol and Natural Resources, 2017
With the development of polymerase chain reaction (PCR) for amplifying genomic DNA and with the development of methods in generating recombinant DNA, site-directed/specific mutagenesis became possible. Concurrently, methods in biomolecular imaging and modeling were rapidly under development. Using biochemical data, protein structures’ (e.g., from X-ray crystallography and protein NMR) biomolecular modeling, and molecular dynamics simulations, it became possible to make reasonable predictions about how changes in protein primary structure would result in changes in three-dimensional conformation (i.e., tertiary structure) and, ultimately, in function. Modifications to genes forcing substitutions, insertions, or deletions in the amino acid sequence at specific positions within protein primary structure ushered in the era of rational design. It is clear that success in rational design is dependent on reliable information about the enzyme structure, function, and mechanism of action. The process of rational design involves (1) choosing a suitable enzyme about which adequate information regarding structure, function, and mechanism is available; (2) identifying amino acid sites that when changed will likely result in structural alteration that produce the desired changes in function; and (3) characterizing the expressed mutants via purification, sequencing, and enzyme activity assays after each round of mutagenesis (Johnsson et al., 1993; Pleiss, 2012). With adequate information regarding structure, function, and mechanism about a target enzyme, rational design is probably the easiest and quickest approach to engineering enzymes. Computational modeling and in silico experiments are becoming more sophisticated each year making it even easier to make valid predictions on how function will change when an amino acid or group of amino acids is altered in the primary structure of the protein (Tiwari et al., 2012). Validated predictions are more probable when rational design of an enzyme is based on the knowledge of enzyme structure, function, and mechanism from several related species.
Advancements in Extremozymes and their Potential Applications in Biorefinery
Published in Pratibha Dheeran, Sachin Kumar, Extremophiles, 2022
Despite the potential advantages offered by extremozymes for application in biofuels, enzymes often require modification to achieve optimal activity in a particular process so as to improve process economics. Engineering of extremophilic enzymes is a routine approach taken by companies such as Novozymes and Verenium. The properties of individual enzyme components may be improved by rational design or directed evolution. Rational design relies on detailed knowledge of protein structure and structure–function relationships, ideally from high resolution crystallographic studies (Zhang and Fang 2006). Even with detailed knowledge of the enzyme structure, targets for rational design are difficult to predict. Directed evolution does not require detailed knowledge of enzyme structure or interactions between enzyme and substrate, but rather employs selective pressures, such as pH, thermostability and catalytic activity to ‘evolve’ enzymes according to desired characteristics. Directed evolution relies on the creation of large mutant libraries with DNA mutation techniques such as error-prone PCR (epPCR), DNA shuffling or staggered extension process (StEP) PCR (Zhao and Zha 2006). Rational and irrational designs have resulted in cellulases and hemicellulases with increased catalytic activity, enzyme stability, recombinant expression and tolerance to hydrolysis product inhibition (Maki et al. 2009). Specific modules targeted within enzymes include CBMs, catalytic sites, and surface structures. SCHEMA structure-guided recombination uses a modelling approach to generate novel enzymes by randomly shuffling “blocks” of amino acids between structurally closely related parent proteins. This approach was designed to reduce the number of inactive clones by limiting the extent of conformational disruption of the tertiary structure (Volkers et al. 2009). General trends and potential strategies for increasing internal stabilization have been reviewed and include the increase of ion-pair networks, disulphide- and salt-bridging, hydrogen bonding, hydrophobic and aromatic interactions and stabilization of surface exposed amino acids (Li et al. 2005).
A comprehensive review on enzymatic degradation of the organophosphate pesticide malathion in the environment
Published in Journal of Environmental Science and Health, Part C, 2019
Smita S. Kumar, Pooja Ghosh, Sandeep K. Malyan, Jyoti Sharma, Vivek Kumar
Protein engineering studies directed towards the understanding of similar structures and catalytic mechanisms across divergent organophosphate degradation enzymes can help in the development of better computational models and screening technologies. The most prevailing approaches available to us in the biotechnological advancement of human and environmental health is directed evolution. Though, with the integration of new technologies to research laboratories, techniques based on rational design approaches are expected to prevail in the near future. Researchers are taking advantage of the wealth of information about protein structure available nowadays. Moving forward, evolved variants of OPH, and opdA have been developed and are now ready to be tested. Phosphotriesterase activity has been observed to be an extremely uninhibited component of many different hydrolases including enzymes from extremophilic hosts. Enzymes purified from extremophiles possess better resilience to deviations in the external environment and are more amenable to genetic modifications, thus providing researchers with highly stable protein scaffolds for next-generation engineering technologies. A major drawback of most of the degradation studies is that they only rely on chemical analysis and study the presence/absence of malathion. However, sometimes degradation may lead to the formation of certain intermediary metabolites which may be more toxic than the parent compound such as malaoxon. So, it is important to ensure that the contaminated site is completely detoxified at the end of the treatment. This can be done efficiently by the use of mammalian cell line based in vitro bioassays which are rapid, simple, sensitive, as well as cost-effective. Thus, future studies should focus on the detoxification aspect along with degradation.
On the design of three-dimensional mechanical metamaterials using load flow visualization
Published in Mechanics Based Design of Structures and Machines, 2022
Sree Kalyan Patiballa, Girish Krishnan
Approaches for the design of mechanical metamaterials in literature can be broadly classified into insightful approaches and computational approaches. Insightful approaches use the rational intuition of the designer to design mechanical metamaterials. The realization of negative Poisson’s ratio by Lakes (1987) in foam structures fueled the field of mechanical metamaterials, specifically auxetic materials. A novel mechanism of missing ribs in foams leads to negative Poisson’s ratio according to Smith, Grima, and Evans (2000). Cherkaev (1995) proposed that the combination of isotropic compliant and rigid phases can lead to mechanical metamaterials. The rational design approaches, though intuitive, are difficult to generalize to any design problem. Computational approaches such as structural topology optimization, reconciled level sets, bi-directional evolutionary optimization (BESO) are used to design mechanical metamaterials. Taking inspiration from the seminal work by Sigmund (1994, 1995), many other researchers have published on the design of microstructures with extreme properties (Xia and Breitkopf 2015; Bendsøe and Kikuchi 1988; Theocaris and Stavroulakis 1998). While computational methods are mathematically robust, they are time-consuming, sensitive to the algorithm used and the obtained solutions may require extensive postprocessing to be practical. In some cases, the process may yield limited user insight. In this paper, we propose an alternative two-phase design methodology to tackle these challenges. In the first phase, we obtain conceptual designs that determine the topology of the unit cell microstructure using a kinetostatic building block-based design approach. In the second phase of design refinement, a shape/size optimization is performed on the conceptual topology to meet any given effective elastic properties and conform to manufacturing requirements. This process differs from SIMP-based structural topology optimization by offering the user control of the creative part of the design, while offsetting the more tedious phase to a computational shape-size refinement process. With the conceptual feasible topology determined in the first phase, the computational expensiveness for the second phase drastically reduces, leading to an overall robust framework. The two phase process is not entirely a new concept and has been featured in the design of compliant or deformable mechanisms by Joo, Kota, and Kikuchi (2000) and Joo and Kota (2004). The insightful phase for topology generation has been accomplished by instant center kinematics in planar space by Kim, Kota, and Mo-Moon (2006) to more recently a screw-theory based projective geometry scheme in three-dimensional (3D) domain by Hopkins and Culpepper (2010) and Su, Dorozhkin, and Vance (2009). Several refinement-based algorithms have been proposed to tune the base topology to match several secondary considerations such as stiffness, strength and manufacturability (Hetrick and Kota 1999; Saxena and Ananthasuresh 2001; Krishnan, Kim, and Kota 2013a; Patiballa and Krishnan 2017a). Since the functionality of both compliant mechanisms and mechanical metamaterials rely on the elastic deformation of its constituent members, we believe that a two-phase insightful approach and its benefits must translate to metamaterial design as well.