In Vitro to In Vivo Extrapolation of Metabolic Rate Constants for Physiologically Based Pharmacokinetic Models
John C. Lipscomb, Edward V. Ohanian in Toxicokinetics and Risk Assessment, 2016
Some enzymes are membrane bound to cellular organelles, such as the endoplasmic reticulum or mitochondria, while others are present in the soluble portion of the cell known as the cytoplasm. However, the aqueous cytoplasm of the cell is highly organized via a group of polymeric proteins called the cytomatrix, and soluble enzymes appear to be associated with this dynamic network (3–5). This intracellular organization can influence the efficiency of enzyme catalysis and promote the coupling of metabolic processes. For example, a chemical that is hydroxylated by endoplasmic reticulum-bound cytochrome P450 (CYP) can be so efficiently conjugated with glucuronic acid by neighboring membrane-bound glucuronosyl transferase that the free alcohol product cannot be detected in the cell. The coupling of metabolic processes can lead to very efficient detoxication of toxicants, but it can also promote toxication processes that can ultimately lead to cellular damage and death.
Hydrolytic Enzymes for the Synthesis of Pharmaceuticals
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
Biocatalysis has acquired maturity in the twenty-first century since enzyme catalysis preserves the 12 principles of green chemistry (Anastas et al., 1994), allowing the efficient production of agrochemicals, functionalised material, pharmaceuticals and high-added value products. Both the academic and the industrial sector have implemented this technology for practical purposes, which nowadays can be considered as an additional tool for most of the organic chemists (Patel, 2007; Hudlicky and Reed, 2009; Clouthier and Pelletier, 2012; Solano et al., 2012; Bezborodov and Zagustina, 2016; Patel, 2016; Alcántara and Alcántara, 2018). In addition, the advances in enzyme immobilisation techniques (García-Galan et al., 2011; Barbosa et al., 2015), possibility to create evolved enzymes by modification of their amino acid sequence (Porter et al., 2016; Wang et al., 2017), design of novel enzyme through chemical modifications (Filice and Palomo, 2015), and rationalisation of the experimental results by means of computational calculations (Romero-Rivera et al., 2017) made biotransformations adequate solutions for challenging synthetic targets.
Sponge Enzyme's Role in Biomineralization and Human Applications
Se-Kwon Kim in Marine Biochemistry, 2023
There are two possible mechanisms for enzyme catalysis: (1) to stabilize one molecule of deprotonated silicic acid (the nucleophile) at the active site, which will then react with another molecule of silicic acid, or (2) stabilize a protonated silicic acid (the electrophile) at the active site, which will then react with another molecule of silicic acid (Fairhead et al., 2008). Sclerocytes release axial filaments that are primarily made up of silicateins but also include other organic compounds. The highly structured mesoporous axial filament is formed using silicatein as a structural template. Silicate is utilized or actively taken up into the sclerocyte and complexed with certain proteins to generate an organic-silica substrate that has yet to be characterized. The organo-silica compound is delivered to the “silica deposition space” by silica lemma. The complexing protein is released and may be recycled to the sclerocyte cytoplasm after silica from the organo-silica substrate polymerizes as nanospheres on the outer surface of the mesoporous axial filaments, possibly at serine and histidine catalytic center sites. The axial filament continues to grow at spicule tips, giving primarily a spicule pattern, while silica transport and deposition proceed on lateral spicule surfaces between the tips. The axial filament’s silicateins can no longer exhibit enzymatic activity once the first few layers of silica nanospheres have encased it. Silicatein at active areas on the silica lemma facilitates and controls the continued deposition of silica on the outer surface of spicules, resulting in the creation of distinct patterned morphologies of spicules. Several aspects of this approach are still unproven. The roles of minor non-silicatein organic compounds incorporated in axial filaments, whether silicateins associated with the silica lemma are the same forms as those in the axial filaments, and how the final high-fidelity submicroscopic external patterning on spicule surfaces is genetically controlled are some of the other unknown factors. However, in the nonspicule-forming marine sponge Acanthodendrilla spp. silicatein genes were discovered (AcSilA and AcSilB; Veremeichik et al., 2011).
Recent advances in the development of polyethylenimine-based gene vectors for safe and efficient gene delivery
Published in Expert Opinion on Drug Delivery, 2019
Cuiping Jiang, Jiatong Chen, Zhuoting Li, Zitong Wang, Wenli Zhang, Jianping Liu
As the substances that are inherently present in the human body, biological molecules draw growing interests as promising triggering motifs in the design of smart PEI-based gene vectors. Among different classes of biological components, ATP, enzyme, glucose, and antigen are the most attractive endogenous stimuli that enable biomolecule-responsive release. As we all know, enzymes are potent catalysts during almost all biological processes, and enzyme catalysis is highly selective towards specific substrates under mild conditions. Using tumor as an example again, several enzymes (i.e. proteases, lipase, hyaluronidase (HAase), etc.) have great potential to be specific stimuli in a controlled gene delivery system [117]. For instance, Yin et al. [118] reported an HA-conjugated PEI polymer for the active tumor targeting via interaction of HA with CD44 receptor. Once the nanocarrier reached the tumor extracellular matrix, the surface layer of HA would be deshielded under the catalysis of HAase, leading to the enhanced cellular uptake owing to the exposure of positive charges.
Production, purification and biochemical characterisation of a novel lipase from a newly identified lipolytic bacterium Staphylococcus caprae NCU S6
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Junxin Zhao, Maomao Ma, Zheling Zeng, Ping Yu, Deming Gong, Shuguang Deng
Temperature is one of the most important factors affecting the reaction rate of enzyme catalysis. As shown in Figure 5(A), the lipase was active in the wide range of temperatures from 10 to 60 °C. The maximum hydrolytic activity was found at 40 °C, with the relative activity and specific activity of 100% and 503 U/mg respectively. The optimal reaction temperature was lower than the lipase from Aureobasidium pullulans (55 °C)18. Activity analyses of the lipase at temperatures from 10 to 60 °C for 240 min showed that the remaining activity at 40 °C was at the highest level (Figure 5(B)). Only the extremely high temperatures, such as 50 or 60 °C, significantly inhibited the lipase activity, and prolonged incubation may rapidly inactivate the lipase. The highest remaining activity was at 40 °C for 80 min, and the lipase activity decreased with an increase of culture period. The decrease may be because the molecular structure of the enzyme was irreversibly changed, which may have altered the configuration of the active site, thereby decreasing interaction of the lipase with substrates19.
The prodrug approach in the era of drug design
Published in Expert Opinion on Drug Delivery, 2019
While current trends point toward an age of biological treatments such as antibodies, prodrugs still prove viable products. I believe that the prodrug approach has a strong potential to grow rapidly in such a way that it will provide more than 25% of the marketed therapeutics during the coming decade if the researchers in the field utilize the computational methods used in the drug design and discovery. Computational methods based on quantum mechanics and MM could be used for the design of prodrugs. Prodrugs targeting transporters could be designed with the assistance of computational methods such as docking and etc. In a similar way, prodrugs targeting esterases, amidases and, etc., can be more effective if their design is relied on DFT and ab-inito methods that they have a great ability to predict kinetics of chemical systems. In our group we have used DFT methods for unraveling mechanisms of intramolecular processes that were previously studied in the labs of others to comprehend enzyme catalysis. Our goal was to establish a correlation between experimental and calculated kinetic values and to use the resulting correlation’s equation for the design of a number of novel prodrugs [17].
Related Knowledge Centers
- Active Site
- Biochemistry
- Biomolecule
- Catalysis
- Cofactor
- Enzyme
- Reaction Rate
- Process
- Protein Complex
- Adenosine Triphosphate